Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[F:10][C@H:11]1[CH2:15][N:14]([CH3:16])[C@H:13]([C:17](O)=[O:18])[CH2:12]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:17]([C@@H:13]2[CH2:12][C@@H:11]([F:10])[CH2:15][N:14]2[CH3:16])=[O:18])=[N:6][CH:7]=1
Reactant: CN1C[C@H](F)C[C@H]1C(=O)O
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1C[C@H](F)C[C@H]1C(=O)NNc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.9 %

Procedure:
A solution of (5-fluoro-pyridin-2-yl)-hydrazine (378 mg, 2.98 mmol), Intermediate 91a (600 mg, 4.08 mmol) and HOBt.H2O (44 mg, 0.12 mmol) in DCM (10 mL) and DMF (3 mL) was added EDC (628 mg, 3.28 mmol) portionwise at RT and the mixture stirred at RT for 17 h. The solution was diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-7.5% [2M NH3 in MeOH] in DCM, to give the title compound as light orange powder (366 mg, 35%). LCMS (Method 3): Rt 0.56 min, m/z 257 [MH+].
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:7][C:8]([CH2:11][NH2:12])=[CH:9][CH:10]=1)=[NH:4].I[CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].C(OC(=O)C)C.CCCCCC>CN(C)C=O.C(OC(=O)C)C>[CH:21]([O:1][NH:2][C:3]([C:5]1[C:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:7][C:8]([CH2:11][NH2:12])=[CH:9][CH:10]=1)=[NH:4])([CH3:23])[CH3:22]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)c1nc(CN)ccc1C(=N)NO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)ONC(=N)c1ccc(CN)nc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of the product of Example 54 (11-6) (0.43 g, 1.39 mmol) in dimethylformamide (5 ml) was added 2-iodopropane (210 μl, 2.1 mmol), followed by cesium carbonate (0.68 g, 2.1 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethylacetate and washed with sodium bicarbonate (saturated). The organic layer was dried over sodium sulfate, filtered and concentrated to give an orangish oil. Flash column chromatography performed in 1/1 ethylacetate/hexane followed by ethylacetate yielded 229 mg (53%) product as a crystalline solid. NMR δ (ppm) CDCl3: 8.8 (d, 1H), 7.9 (dd, 1H), 7.3 (d, 1H), 5.5 (bs, 1H), 4.7 (bs, 2H), 4.4 (d, 1H), 1.4 (s, 9H), 1.3 (d, 6H).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([NH2:7])=[O:6])[CH2:3][OH:4].[CH3:8][CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][CH3:14].Cl.CO.C([BH3-])#N.[Na+].[P:23](=[O:27])([OH:26])([OH:25])[OH:24]>CO>[P:23]([OH:27])([OH:26])([OH:25])=[O:24].[CH3:8][CH2:9][CH2:10][CH:11]([NH:1][C@H:2]([CH2:3][OH:4])[C:5]([NH2:7])=[O:6])[CH2:12][CH2:13][CH3:14]
Reactant: NC(=O)[C@H](N)CO
Reactant: CCCC(=O)CCC
Agent: Cl
Agent: O=P(O)(O)O
Agent: [BH3-]C#N
Solvent: CO
Product: CCCC(CCC)N[C@H](CO)C(N)=O

Procedure:
A solution of D-serinamide (0.01 moles, 1 g) and 4-heptanone (0.01 moles, 1.1 g) in methanol (50 ml) is added with 4M methanol HCl (0.0033 moles, 0.85 ml) and sodium cyanoborohydride (0.005 moles, 0.33 g). The mixture is reacted at r.t. for 10 days, acidified with methanol HCl to pH=2, and evaporated to dryness under vacuum. The residue is taken up with water (100 ml), washed with ethyl ether (100 ml), alkalinized with sodium carbonate and extracted with chloroform (3×100 ml). The resulting oil (1.3 g) is dissolved in methanol (50 ml) and treated with 85% phosphoric acid (0.0065 moles, 0.75 g), then evaporated to dryness under vacuum to obtain the product as a very light solid foam. Yield: 2 g (77%)--m.p.=150-156° C. ]589 (c=1, water)=+1.9
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].Cl[C:10]([O:12][CH3:13])=[O:11].P(=O)(O)(O)O>>[CH3:13][O:12][C:10]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:11]
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N[C@@H](C)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a stirred solution of L-alanine (300 g, 3.37 mol sodium hydroxide (1N, 1800 cm3) at 0° C. in an ice bath was added dropwise, over 2 hours, methyl chloroformate (274 cm3, 3.54 mol). The pH of the solution was maintained at 9 by the addition of sodium hydroxide (5N). The reaction mixture was stirred at 0° C. for 3 hours whereupon it was acidified to pH 1 by the addition of phosphoric acid solution (15%) and extracted with diethyl ether (5×1000 cm3). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to yield the product as a viscous green oil (386 g, 78%). 1H NMR (250 MHz; C2HCl3) 1.48 (3H, d, J7.25, CH3), 3.72 (3H, s, COCH3), 4.40 (1H, quintet, J7.25, CH), 5.31 (1H, bs, NH).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH2:16]([C:19]([CH3:26])([NH2:25])[C:20]#[C:21][C:22]([OH:24])=O)[CH:17]=[CH2:18].[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH2:45])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1>O1CCCC1.N1C=CC=CC=1>[Br:27][C:28]1[CH:29]=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([NH:45][C:22](=[O:24])[C:21]#[C:20][C:19]([CH2:16][CH:17]=[CH2:18])([CH3:26])[NH2:25])[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: C=CCC(C)(N)C#CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=CCC(C)(N)C#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Isobutyl chloroformate (0.845 g, 6.2 mmol) and N-methylmorpholine (1.0 g, 9.9 mmol) were added to an ice cold solution of 1.53 g (10.0 mmol) of allyl-methyl-amino-but-2-ynoic acid in 100 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 1.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, then it was poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (5:95), gave 0.750 g of allyl-methyl-amino-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 450.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=NO)=[C:24]([Cl:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH3-]C#N.[Na+].C([O-])(=[O:40])C.[NH4+].N>CO.[Cl-].[Ti+3].[Cl-].[Cl-]>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:40])=[C:24]([Cl:29])[N:23]=[C:22]3[O:30][CH2:31][CH3:32])=[C:16]([F:33])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(Cl)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: CC(=O)[O-]
Agent: [Ti+3]
Agent: N
Agent: [BH3-]C#N
Solvent: CO
Product: CCOc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
Titanium(III) chloride (448 mg, 2.90 mmol) was added to a solution of intermediate (27b) (459.0 mg, 1.0 mmol), NaBH3CN (274 mg, 4.4 mmol) and ammonium acetate (164 mg, 2.1 mmol) in MeOH (8 mL) at 0° C. The mixture was stirred at room temperature for 3 hours. The mixture was added to a solution of sat. aq. ammonia (15 mL) and MeOH (15 mL). The solution was filtered, and concentrated in vacuo. The concentrate was extracted with DCM (2×80 mL) and sat. aq. NaHCO3 (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography [DCM:MeOH (5% triethylamine)] afforded the title compound (85 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](OB(O)O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:12][C:13]1[N:14]=[N:15][C:16]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:17][CH:18]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccc(Cl)nn2)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere a solution of 11.3 g (70.5 mmol) 4-chlorophenylboric acid in 50 mL 1,4-dioxane is added to a solution of 10.8 g (70.5 mmol) 3,6-dichloropyridazine, 10 mL (20 mmol) of a 2 M Na2CO3 solution and 600 mg (0.73 mmol) Pd(dppf)Cl2 in 150 mL 1,4-dioxane at 110° C. over 2 h. The reaction mixture is stirred for 1 h at 110° C. 100 mL water are added and the aqueous phase is extracted with 100 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Purification is carried out by column chromatography on silica gel (cyc/EtOAc 4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10](O)=[O:11])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([NH2:33])=[O:32])[CH2:26]1.[Cl-].C(N=C=NCCC[NH+](C)C)C.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>CN(C=O)C.CO>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH2:9][C:10]([N:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([NH2:33])=[O:32])[CH2:26]3)=[O:11])[N:7]=[N:8][C:4]=2[C:3]=1[O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([Cl:24])[CH:17]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)O)c1
Reactant: NC(=O)C1CCCNC1
Agent: CCN=C=NCCC[NH+](C)C
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3CC(=O)N2CCCC(C(N)=O)C2)c1
Reaction time: 1 h

Procedure:
[5-chloro-4-(3-chloro-5-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]acetic acid (13 mg, 0.036 mmol) (see step 2 in Example 16), piperidine-3-carboxamide (4.6 mg, 0.036 mmol), 3-{[(ethylimino)methylene]amino}-N,N-dimethylpropan-1-aminium chloride (6.9 mg, 0.036 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (4.9 mg, 0.036 mmol), and triethylamine (0.005 mL, 0.036 mmol) were dissolved in DMF (0.5 mL). After 1 hour, the reaction mixture was diluted with aqueous MeOH (1 mL) and purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. Product fractions were lyophilized to yield the title product. 1H NMR (DMSO-d6) δ 7.84 (m, 1H), 7.77 (d, J=4.4 Hz, 1H), 7.76 (s, 2H), 7.58 (m, 1H), 7.51 (m, 1H), 7.44 (m, 1H), 7.36 (m, 1H), 7.02 (m, 1H), 6.84 (m, 1H), 5.97 (m, 2H), 5.93 (m, 1H), 5.87 (m, 0.5H), 5.83 (m, 0.25H), 4.29 (m, 2H), 3.80 (m, 4H), 3.40 (m, 1H), 3.10 (m, 1H), 2.95 (m, 1H), 2.65 (m, 1H), 2.20 (m, 1H), 1.90 (m, 2H), 1.70 (m, 4H), 1.40 (m, 1H). HRMS (M+1)=473.0867.
Reaction SMILES: [C:1]1([CH:7]([NH2:22])[CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH3:21])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1>[CH2:34]([O:33][C:31]([NH:22][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[CH:13][CH:12]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(OCCC(N)c2ccccc2)c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC(CCOc1ccc(C)c2ccccc12)c1ccccc1
Temperature: 25 °C
Yield: 103.3 %

Procedure:
A solution of 2.12 g (7.3 mmol) of 1-phenyl-3-(4-methyl-1-naphthalenyloxy)propanamine, 1.12 ml (8.0 mmol) of triethylamine and 100 ml of THF was cooled to approximately 0° C. under a nitrogen atmosphere. To the mixture was added 0.766 ml (8.0 mmol) of ethyl chloroformate dropwise. The resulting mixture was stirred at room temperature for approximately five and one-half hours and concentrated under vacuum. The residue was dissolved in diethyl ether, toluene and water. The mixture was extracted with diethyl ether. The organic extracts were combined, washed with water, 2N hydrochloric acid, water, 1N sodium hydroxide water, and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum to provide 2.74 g of the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:4]=1[C:5]([CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6].Cl[CH2:19][CH2:20][C:21]1[C:26](=[O:27])[N:25]2[CH2:28][CH2:29][CH2:30][CH2:31][C:24]2=[N:23][C:22]=1[CH3:32].C(=O)([O-])O.[Na+].[I-].[K+]>O.C(#N)C>[F:2][C:3]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:4]=1[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH2:19][CH2:20][C:21]2[C:26](=[O:27])[N:25]3[CH2:28][CH2:29][CH2:30][CH2:31][C:24]3=[N:23][C:22]=2[CH3:32])[CH2:11][CH2:12]1)=[O:6]
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2
Reactant: O=C(c1ccc(F)cc1F)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: Cc1nc2n(c(=O)c1CCN1CCC(C(=O)c3ccc(F)cc3F)CC1)CCCC2
Reaction time: 10 h

Procedure:
A suspension of 29.2 g (0.1116 mole) of 4-(2,4-difluoro-benzoyl)-piperidine-hydrochloride, 25.3 g (0.1117 mole) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 500 ml of acetonitrile, 19.6 g (0.2333 mole) of sodium hydrogencarbonate and 0.25 g (0.0015 mole) of potassium iodide is heated to boiling for 10 hours with stirring. The reaction mixture is cooled to room temperature, to the residue 200 ml of water are added. The mixture is stirred for 30 minutes and extracted with 200 ml of dichloromethane. The organic phase is separated, dried over magnesium sulfate, filtered and the filtrate is evaporated. The oily residue thus obtained is purified as follows:
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][C@@H:7]([C:11]([OH:13])=[O:12])[C@H:8]([CH3:10])[OH:9].Cl[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16]>C1COCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:9][C@@H:8]([CH3:10])[C@@H:7]([NH:6][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[C:11]([OH:13])=[O:12]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: CCCCCCCCOC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Yield: 26.6 %

Procedure:
In a round bottom flask, NaHCO3 (9.74 g, 116 mmol) was suspended in THF (25 mL) and water (50 mL), then D-threonine (5.47 g, 46.0 mmol) and tetrabutylamonium bromide (0.547 g) were added. n-Octyl chloroformate (10 mL, 51.1 mmol) was added dropwise and the reaction vigorously stirred 18 h at rt. The mixture was then diluted with water, washed twice with Et2O and pH adjusted to 2 with 2M HCl solution. The aqueous phase was extracted with AcOEt, the collected organic phases were dried over Na2SO4, filtered and the solvent removed under vacuum to give the title compound (3.37 g, 27%) as pale yellow oil, which was used in the next step without further purification. Rf=0.26 (Cy/EtOAc 2:8+1% CH3COOH; detection: ninhydrin, bromocresol green). FTIR (cm−1): 3340 (br), 2928, 2856, 1724 (br), 1526, 1261, 1074.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].O>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:11]1[C:12]2[C:13]3[C:3](=[CH:2][CH:16]=[CH:15][CH:14]=3)[C:4](=[O:5])[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Nc1ccccc1)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c2ccccc2c2ccccc12
Temperature: 160 °C
Yield: 52 %

Procedure:
Then, in a nitrogen atmosphere, 2-bromo-N-phenylbenzamide (17.3 g, 62.7 mmol), palladium acetate (0.70 g, 3.1 mmol), and sodium carbonate (13.3 g, 125 mmol) were dissolved in dimethylacetamide (300 mL), followed by stirring and heating at 160° C. for 6 hours to cause reaction. The reaction solution was cooled to room temperature and then poured into cooled water, followed by extraction with ethyl acetate. The organic layer was dried with sodium sulfate, followed by filtration. The filtrate was concentrated using a rotary evaporator. The residue was collected by filtration and then successively washed with hexane and water. Thus, 6-phenanthridinone (6.36 g, 32.6 mmol) was obtained in a yield of 52%.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[C:21]1[CH:22]=[C:23]2[CH:29]=[CH:28][NH:27][C:24]2=[CH:25][N:26]=1.[Na+].[Cl-]>C(Cl)Cl>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[C:21]1[CH:22]=[C:23]2[C:29]([C:4](=[O:5])[CH:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[CH:28][NH:27][C:24]2=[CH:25][N:26]=1
Reactant: Cc1cccc(C)c1-c1cc2cc[nH]c2cn1
Reactant: CCC(CC)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(CC)C(=O)c1c[nH]c2cnc(-c3c(C)cccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Ethyl-butyryl chloride (0.799 mL, 5.8 mmol) is added to a suspension of AlCl3 (770 mg, 5.8 mmol) in DCM (20 mL) at −10° C. The resultant solution is stirred for 15 min at the same temperature, and 5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (0.5 g, 2.2 mmol) is added as a solution in DCM (3 mL). The mixture is stirred for 18 h at room temperature. A saturated aqueous NaCl solution (30 mL) is carefully added to the mixture, and stirring is continued for 2 h. Organic layer is separated, and the aqueous solution is extracted with DCM. The combined organic solutions are washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Chromatography of the residue on silica gel 10% MeOH-DCM affords 1-[5-(2,6-dimethyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-2-ethyl-butan-1-one as colorless oil.
Reaction SMILES: N1CCCCC1.C(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([CH2:18][C:19]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])=[O:20])(O)=O.Cl>C1(C)C=CC=CC=1>[O:20]=[C:19]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])/[CH:18]=[CH:15]/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C(/C=C/c1ccccc1)Nc1ccccc1C(=O)O
Yield: 96.1 %

Procedure:
Piperidine (0.42 mL, 4.2 mmol) was added to a suspension of benzaldehyde (0.43 mL, 4.2 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.83 g, 3.7 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[(1-oxo-3-phenyl-2-propenyl)amino]benzoic acid (0.95 g, 96%) was obtained as a pale yellow crystalline solid; mp 188-189° C., lit. [23] 196-197° C.; δH (500 MHz, DMSO-d6) 6.88 (d, J=16.0 Hz, 1H, CH═CHCO), 7.18 (t, J3,4=J4,5=8.0, 1H, H4), 7.41-7.45 (m, 3H, H3′, H4′, H5′), 7.62 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 7.62 (d, J=16.0 Hz, 1H, CH═CHCO), 7.72-7.74 (m, 2H, H2′, H6′), 8.00 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.59 (d, J5,6=8.0 Hz, 1H, H6), 11.32 (s, 1H, NH).
Reaction SMILES: CN(C)C=O.[F:6][C:7](=[CH2:11])[C:8]([O-:10])=[O:9].[NH4+].S(Cl)(Cl)=O.C(N(CC)CC)C.[F:24][C:25]([F:33])([F:32])[CH:26](O)[C:27]([F:30])([F:29])[F:28]>CC1C=CC=CC=1C>[F:6][C:7](=[CH2:11])[C:8]([O:10][CH:26]([C:27]([F:30])([F:29])[F:28])[C:25]([F:33])([F:32])[F:24])=[O:9]
Reactant: C=C(F)C(=O)[O-]
Reactant: OC(C(F)(F)F)C(F)(F)F
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Solvent: O=S(Cl)Cl
Product: C=C(F)C(=O)OC(C(F)(F)F)C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
A 2-Liter glass flask which had been equipped with a thermometer, a stirrer, a reflux condenser and a dropping funnel was charged with 1.2 l of o-xylene, 29 g (0.4 mol) of dimethylformamide and 200 g (1.87 mol) of ammonium α-fluoroacrylate. To this initial charge were then added dropwise in the course of 1 hour 238 g (2.0 mol) of thionyl chloride. The reaction mixture was then maintained at a temperature of 80° C. for 2 hours. After subsequently cooling down to a temperature of 0° C., the mixture had added to it a mixture of 202 g (2 mol) of triethylamine and 336 g (2 mol) of hexafluoroisopropanol in the course of 30 minutes. The resulting mixture was stirred for a further 30 minutes, and the resulting precipitate was filtered off. The filtrate was treated with 1 g of hydroquinone monomethyl ether and rapidly distilled under a pressure of 266 mbar. The fraction obtained within the temperature range from 45° to 85° C. was washed with hydrochloric acid (2.4 molar) and with water, was dried and was distilled again, giving 232 g (52 percent of theory) of pure hexafluoroisopropyl α-fluoroacrylate. This ester was a colorless liquid with a refractive index nD23 =1.3145, a boiling point of 46.8° C. (at 213 mbar) and a density of 1.453 g/cm3 (at 25° C.). In the wavelength range from 380 to 680 nm this ester had an average transmission of more than 99 percent.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:22]=[C:21]2[C:10]([CH2:11][C:12]3[CH:16]=[CH:15][N:14]([CH2:17][C@H:18](O)[CH3:19])[C:13]=32)=[CH:9][CH:8]=1.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.CN(C)C=O.O>[N:30]([C@@H:18]([CH3:19])[CH2:17][N:14]1[CH:15]=[CH:16][C:12]2[CH2:11][C:10]3[C:21]([C:13]1=2)=[CH:22][C:7]([Br:6])=[CH:8][CH:9]=3)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](O)Cn1ccc2c1-c1cc(Br)ccc1C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc2c1-c1cc(Br)ccc1C2)N=[N+]=[N-]
Yield: 73.5 %

Procedure:
0.63 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.19 g of (R)-1-(7-bromo-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 2.27 ml of triethylamine in 40 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The green oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.53 g of sodium azide and the reaction mixture was heated to 60° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of water and extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 0.95 g (74%) of (S)-1-(2-azido-propyl)-7-bromo-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a colorless oil.