Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:45])[CH2:31][C@@H:32]([C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)[C:33]1[CH:37]=[CH:36][O:35][N:34]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:45])[CH2:31][C@@H:32]([C:38]1[CH:39]=[CH:40][C:41]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)=[CH:42][CH:43]=1)[C:33]1[CH:37]=[CH:36][O:35][N:34]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Reaction time: 16 h
Yield: 96.2 %

Procedure:
To a solution of alcohol 27.1 (179 mg, 0.765 mmol) in THF (7 mL), was added phenol 7.5 (300 mg, 0.765 mmol), DIAD (0.155 mL, 0.803 mmol), and triphenylphosphine (211 mg, 0.803 mmol). The solution was stirred for 16 hours and then concentrated to a reduced volume. The residue was purified by medium pressure chromatography (silica gel, 0 to 50% EtOAc:hexanes) to give 27.2 (440 mg). MS ESI (pos.) m/e 598.2 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (1H, d, J=1.6 Hz), 7.38 (1H, s), 7.08-7.29 (8H, m), 7.00 (1H, d), 6.82 (2H, d, J=8.6 Hz), 6.54 (1H, s), 6.33 (1H, br. s.), 6.05 (1H, d, J=1.6 Hz), 4.92 (2H, s), 4.85-4.90 (1H, m), 4.66 (1H, dd, J=1.6 Hz), 4.49-4.58 (1H, m), 4.01-4.04 (1H, m), 3.93 (1H, dd, J=17.6, 8.2 Hz), 3.45 (1H, dd, J=17.6, 6.7 Hz), 3.11 (1H, dd, J=13.5, 3.3 Hz), 2.68 (1H, dd, J=13.3, 9.4 Hz), 1.43 (9H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:12]3[C:21]([C:24]#N)=[CH:22][N:23]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1)=[O:2].C[Zn]Cl>>[CH3:24][C:21]1[N:12]2[CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[N:10][C:11]2=[N:23][CH:22]=1
Reactant: N#Cc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Agent: C[Zn]Cl
Product: Cc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12

Procedure:
The compound was synthesized in a manner according to 7-(4-formylphenyl)-6-phenylimidazo[1,2-a]pyrimidine-3-carbonitrile by using MeZnCl instead of Zn and ZnCN2.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([CH3:14])([CH3:13])[O:11][B:10]([OH:15])[C:9]=2[CH:16]=1)([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:50][C:51]1[CH:52]=[C:53]([C:59]2([C:76]([F:79])([F:78])[F:77])[O:63][N:62]=[C:61]([C:64]3[N:65]4[C:69]([C:70]([C:73](O)=[O:74])=[CH:71][CH:72]=3)=[CH:68][CH:67]=[CH:66]4)[CH2:60]2)[CH:54]=[C:55]([Cl:58])[C:56]=1[Cl:57]>C1COCC1.CC(=O)OCC>[OH:15][B:10]1[C:9]2[CH:16]=[C:5]([C:2]([NH:1][C:73]([C:70]3[C:69]4[N:65]([CH:66]=[CH:67][CH:68]=4)[C:64]([C:61]4[CH2:60][C:59]([C:53]5[CH:54]=[C:55]([Cl:58])[C:56]([Cl:57])=[C:51]([Cl:50])[CH:52]=5)([C:76]([F:79])([F:77])[F:78])[O:63][N:62]=4)=[CH:72][CH:71]=3)=[O:74])([CH3:4])[CH3:3])[CH:6]=[CH:7][C:8]=2[C:12]([CH3:14])([CH3:13])[O:11]1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reactant: CC(C)(N)c1ccc2c(c1)B(O)OC2(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(NC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(2-aminopropan-2-yl)-3,3-dimethylbenzo[c][1,2]-oxaborol-1(3H)-ol (100 mg), HATU (277 mg, 0.73 mmol) and DIPEA (0.2 mL, 1.1 mmol) in THF (5 mL) can be added 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.37 mmol). The reaction mixture can be stirred at rt overnight. EA can be added and the mixture can be washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue can be purified by prep-HPLC to give the final title compound.
Reaction SMILES: C([Li])CCC.CCCCCC.CN(CCN(C)C)C.[CH2:20]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=O)[CH2:26][CH2:25]2)[CH3:21].[CH2:32]([N:34]1[C:43]2[C:38](=[CH:39][C:40]([CH:44]([CH3:46])[CH3:45])=[CH:41][CH:42]=2)[C:37](=[O:47])C=C1C1OC=CC=1)[CH3:33]>C1COCC1.[Cl-].[NH4+]>[CH2:20]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27]1[N:34]([CH2:32][CH3:33])[C:43]3[CH:42]=[CH:41][C:40]([CH:44]([CH3:45])[CH3:46])=[CH:39][C:38]=3[C:37](=[O:47])[C:26]=1[CH2:25]2)[CH3:21]
Reactant: CCn1c(-c2ccco2)cc(=O)c2cc(C(C)C)ccc21
Reactant: CCc1ccc2c(c1)CCC2=O
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc2c(c1)Cc1c-2n(CC)c2ccc(C(C)C)cc2c1=O

Procedure:
To a 1.53M solution of n-butyl lithium in hexane (13.2 mL, 20.2 mmol) was added TMEDA (3.1 mL, 20.2 mmol) under argon atmosphere at room temperature with stirring. To this was added with ice cooling a solution of 5-ethyl-1-indanone(3.24 g, 20.2 mmol) in anhydrous THF followed by stirring at room temperature for 1 hour. After ice cooling the mixture, a solution of 1-ethyl-6-isopropylisatoic anhydride (Example 6, step 1) (2.35 g, 10.1 mmol) in anhydrous THF was added dropwise thereto. The mixture was stirred at room temperature overnight and diluted with saturated aqueous solution of ammonium chloride. The orgaic layer was separated and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution and dried with sodium sulfate. After removing the solvent, the residue was purified by silica gel-chromatography (chloroform:acetone=20:1) and crystallization from diethyl ether to give the desired compound. 1H-NMR(CDCl3) δ 1.32(3H,t,CH2CH3), 1.34(6H,d,CH(CH3)2), 1.70(3H,t,NCH2CH3), 2.78(2H,q,CH2CH3), 3.10(1H,septet,CH), 3.91(2H,s,H-11), 4.72(2H,q,NCH2), 7.30-7.85(5H,m,Ar-H), 8.45(1H,s,H-9)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>ClCCl>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Solvent: ClCCl
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 39.2 %

Procedure:
A solution of 0.050 g (0.20 mmol) of (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) in 1 ml of dichloromethane was treated with 0.030 g (0.20 mmol) of 3,4-dichlorophenyl isocyanate. After 1 h the reaction was evaporated and purified by flash silica gel column (dichloromethane/methanol 98/2 to 9:1) to yield 0.039 g (48%) of the titled compound as white foam. MS: 495.2 (M−H−, 2Cl).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:15])[CH3:14])=[CH:9][CH:8]=1)[CH3:5])[CH3:2].[C:16](OCC(Cl)(Cl)Cl)(=[O:20])[CH2:17][CH2:18][CH3:19]>C(OCC)C>[CH2:1]([O:3][CH:4]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][CH:12]=1)[CH3:5])[CH3:2].[C:16]([O:15][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])=[CH:12][CH:11]=1)[CH3:14])(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)OCC(Cl)(Cl)Cl
Agent: CCOC(C)Oc1ccc(C(C)O)cc1
Solvent: CCOCC
Product: CCCC(=O)OC(C)c1ccc(OC(C)OCC)cc1
Temperature: 25 °C
Reaction time: 90 h
Yield: 93 %

Procedure:
To 120 ml of anhydrous diethyl ether was added 21 g (0.1 mole) of 1-(4-(1-ethoxyethoxy)phenyl)ethanol, 22.4 g (0.1 mole) of 2,2,2-trichloroethyl butyrate and 25.2 g of Lipase P (commercially available from Amano Seiyaku Kabushiki Kaisha) and the mixture was reacted with stirring at 25° C. for 90 hours. The reaction mixture was filtered by suction to remove Lipase P, the filtrate was concentrated and the concentrate was then purified by silica gel chromatography [ethyl acetate/n-hexane=1/4 by volume (hereinafter the same)] to give 9.6 g of S-form of 1-(4-(1-ethoxyethoxy)phenyl)ethanol (yield: 91%) and 13.0 g of R-form of 1-(4-(1-ethoxyethoxy)phenyl)ethyl butyrate (yield: 93%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:34])(=[O:33])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29][C:30](=[O:32])[CH3:31])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:35])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH:36](=O)[C:37]1[O:41][CH:40]=[CH:39][CH:38]=1>C(OCCOCCOCC)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:33])(=[O:34])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29][C:30](=[O:32])[CH3:31])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:35][CH2:36][C:37]2[O:41][CH:40]=[CH:39][CH:38]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccco1
Reactant: CC(=O)Nc1ccc(Nc2c(N)cc(C(=O)O)cc2S(=O)(=O)Nc2ccccc2NC(C)=O)cc1
Solvent: CCOCCOCCOCC
Product: CC(=O)Nc1ccc(Nc2c(NCc3ccco3)cc(C(=O)O)cc2S(=O)(=O)Nc2ccccc2NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The mixture of 4-(4-acetamidophenylamino)-3-amino-5-(2-acetamidophenylsulfamoyl)-benzoic acid, 60 ml of diethyleneglycol diethyl ether and 30 ml of furfural is heated to 110° for 4 hours and evaporated under reduced pressure. The residue is taken up in 100 ml of anhydrous ethanol, the solution cooled with an ice bath and 4.5 g of sodium borohydride are added portionwise while stiring. After one hour the ice bath is removed and the mixture stirred overnight at room temperature. Thereupon 2.25 g of sodium borohydride are added, the mixture stirred for 90 minutes and diluted with 150 ml of water. It is filtered, the filtrate concentrated and the concentrate strongly acidified with hydrochloric acid. The precipitate formed is collected and recrystallized twice from 50% aqueous ethanol, to yield the 4-(4-acetamidophenylamino)-3-furfurylamino-5-(2-acetamidophenylsulfamoyl)-benzoic acid melting at 258° with decomposition. [Analogously the 5-(4-acetamidophenylsulfamoyl)-isomer is prepared m.p. 266° (dec.)].
Reaction SMILES: [Al](Cl)(CC)CC.[C:7](Cl)(=[O:9])[CH3:8].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH:21][C:22]([C:24]2[S:25][CH:26]=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=2)=[O:23])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1>C(Cl)Cl>[C:7]([C:14]1[C:13]([O:12][CH3:11])=[CH:18][C:17]([O:19][CH3:20])=[CH:16][C:15]=1[NH:21][C:22]([C:24]1[S:25][CH:26]=[C:27]([CH:29]([CH3:31])[CH3:30])[N:28]=1)=[O:23])(=[O:9])[CH3:8]
Reactant: CC(=O)Cl
Reactant: COc1cc(NC(=O)c2nc(C(C)C)cs2)cc(OC)c1
Agent: CC[Al](Cl)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2nc(C(C)C)cs2)c(C(C)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a suspension of Et2AlCl (1.61 g, 12.04 mmol) in DCM at 0° C. was added acetyl chloride (630 mg, 8.02 mmol). The mixture was stirred at 0° C. for 30 min. Compound 216e (1.23 g, 4.01 mmol) was then added and the reaction mixture was stirred at 80° C. for 90 min. The reaction was poured in ice and DCM was added. The organic layers were separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (EtOAc/DCM) to yield compound 217e as a white solid in 82% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.41 (s, 3H), 1.43 (s, 3H), 2.63 (s, 3H), 3.20-3.27 (m, 1H), 3.89 (s, 3H), 3.90 (s, 3H), 6.27 (d, J=2.30, 1H), 7.19 (s, 1H), 8.12 (d, J=2.30 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH3:13][NH:14][C:15]([NH:17][CH2:18][C:19]#[CH:20])=[O:16].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[NH2:12][C:3]1[C:4]2[O:8][CH2:7][O:6][C:5]=2[C:9]([C:20]#[C:19][CH2:18][NH:17][C:15]([NH:14][CH3:13])=[O:16])=[CH:10][C:2]=1[Cl:1]
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#CCNC(=O)NC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CNC(=O)NCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.4 %

Procedure:
5-Chloro-7-iodo-1,3-benzodioxol-4-amine (500 mg, 1.68 mmol) and N-methyl-N′-prop-2-yn-1-ylurea (226 mg, 2.02 mmol) in ethyl acetate (10 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (118 mg, 10 mol %) followed by copper(I) iodide (32 mg, 10 mol %) and diisopropylamine (339 mg, 4.03 mmol). The reaction was allowed to warm to room temperature and stirred 3 hr. then filtered through Celite. The filtrate was purified by column chromatography on silica using ethyl acetate as eluent to give N-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]-N′-methylurea (177 mg, 37%) as an colourless solid; NMR Spectrum:(DMSOd6) 2.55 (d, 3), 4.00 (d, 2H), 5.52 (s, 2H), 5.84 (q, 1H), 6.05 (s, 2H), 6.27 (t, 1H), 6.78 (s, 1H).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([C:8]1[CH:23]=[C:22]2[C:11]([CH2:12][C:13]3[CH:17]=[CH:16][N:15]([CH2:18][C@H:19](O)[CH3:20])[C:14]=32)=[CH:10][CH:9]=1)[CH3:7].C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+]>ClCCl.CN(C)C=O.O>[N:31]([C@@H:19]([CH3:20])[CH2:18][N:15]1[CH:16]=[CH:17][C:13]2[CH2:12][C:11]3[C:22]([C:14]1=2)=[CH:23][C:8]([CH2:6][CH3:7])=[CH:9][CH:10]=3)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc2c(c1)-c1c(ccn1C[C@H](C)N=[N+]=[N-])C2
Yield: 39.4 %

Procedure:
1.1 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.7 g of (R)-1-(7-ethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 3.9 ml of triethylamine in 55 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 50 ml of anhydrous dimethylformamide, treated with 0.84 g of sodium azide and the reaction mixture was heated to 60° for 16 hours while stirring. After cooling, the solution was poured into 120 ml of water and extracted twice with 120 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). 0.74 g (40%) of (S)-1-(2-azido-propyl)-7-ethyl-1,4-dihydro-indeno[1,2-b]pyrrole was obtained as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3].[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:6]4[CH:7]=[C:8]([C:11]([F:13])([F:12])[F:14])[CH:9]=[CH:10][C:5]=4[O:4][CH2:2][CH3:3])[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Agent: Cl
Product: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCN(C(C)=O)CC3)c(C)[nH]c12

Procedure:
Starting from 4-[2-ethoxy-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f34) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([N:8]([C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[NH:9]C(OCC1C=CC=CC=1)=O)([CH3:7])[CH3:6])[CH3:2].CCN(CC)CC.[SiH](CC)(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[C:5]([N:8]([C:20](=[O:29])[C:21]1[CH:22]=[C:23]([CH3:28])[CH:24]=[C:25]([CH3:27])[CH:26]=1)[NH2:9])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)N(N)C(=O)c1cc(C)cc(C)c1
Yield: 160.7 %

Procedure:
Into a flask containing 1.5 g (0.0036 mol, 80% pure) of 2-[N′-benzyloxycarbonyl-N-(3,5-dimethyl-benzoyl)-hydrazino]-2-methyl-propionic acid ethyl ester, was added 20 mL of dry CH2Cl2, 1.5 mL of Et3N, and 1.27 g (0.010 mol) of Et3SiH. While stirring, small portions of a total of 0.010 g of Pd(OAc)2 was added and the reaction was stirred for 2 hours at room temperature. To the reaction mixture was added 100 mL of CH2Cl2 and some MgSO4 to aid in the filtration/removal of the Pd product. The CH2Cl2 solution was shaken with saturated NH4Cl, CH2Cl2 dried, and evaporated to yield 1.61 g of 2-[N-(3,5-dimethyl-benzoyl)-hydrazino]-2-methyl-propionic acid ethyl ester. The product was purified by chromatography, elution with 21-24% ethyl acetate in hexane. 1H NMR (CDCl3, 300 MHz) δ (ppm): 7.045 (s 2H), 7.0 (s 1H), 4.4 (s, 2H), 2.324 (s 6H), 2.236 (s 31-1), 1.487 (s, 6H).
Reaction SMILES: [C:1]([N:9]1[CH:14]=[CH:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CN(C)C(=O)C>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1C=CC(c2c[nH]c3cc(F)ccc23)C=C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Temperature: 80 °C

Procedure:
A mixture of 95 parts of 1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-1,4-dihydropyridine and 540 parts of N,N-dimethylacetamide is hydrogenated in the Parr-apparatus with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over Hyflo and the filtrate is poured onto water while stirring: an oil is precipitated. The supernatant aqueous phase is decanted and the residual oil is washed with water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is washed successively with a mixture of petroleumether and 2,2'-oxybispropane, with a hydrochloric acid solution 2 N and with water, and dissolved in trichloromethane. The latter is washed with a sodium hydroxide solution 1 N and with water, dried, filtered and evaporated. The residue is heated in a small amount of N,N-dimethylacetamide at 80° C. and the mixture is allowed to stand over week-end. The solid product is filtered off, washed with a mixture of water and ethanol, and dried in vacuo at 80° C., yielding 25 parts of 1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-piperidine; mp. 220° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(C)=O>[CH2:30]([N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CN(Cc2ccccc2)C(=O)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.6 %

Procedure:
A mixture of 9.6 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 8.3 g of potassium carbonate, 20 g of benzyl bromide and 200 ml of acetone is stirred at room temperature for 3 days. Then, the reaction mixture is treated in the same manner as described in Preparation 1-(2). 9.3 g of tert.-butyl (4S)-1-benzyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless viscous oil. Yield: 75.6%
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[N+]=[N-])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)C(=[N+]=[N-])c1ccccc1
Solvent: ClCCCl
Product: CCOC(=O)C(OC1CCN(C(=O)OC(C)(C)C)CC1)c1ccccc1

Procedure:
To a solution of diazophenylacetic acid ethyl ester (2.55 g) in 1,2-dichloroethane is added 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (5.4 g). The flask is evacuated and filled with argon. Rhodium(II) acetate-dimer (60 mg) is added to the reaction mixture. Evolution of nitrogen occurs until the end of the reaction (about 1 hour). The solvent is removed under reduced pressure. The residue is purified by chromatography (gradient heptane/ethyl acetate from 95/5 to 80/20) to give 4-(ethoxy-carbonylphenylmethoxy)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:6]=2[N:20]=1.I[CH3:22].[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:6]=2[N:20]=1
Reactant: CI
Reactant: CC1CN(C2CCOCC2)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(C2CCOCC2)c2nc(Cl)ncc2N(C)C1=O
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a cooled mixture of 1.57 g (0.00529 mole) of (rac)-2-chloro-7-methyl-9-(tetrahydro-pyran-4-yl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-45), 0.49 mL (0.00794 mole) of iodomethane and 15 mL of N,N-dimethyl-formamide at 0 degrees was added 0.32 g (0.00794 mole) of 60% oil dispersion of sodium hydride. The mixture was stirred at 0 degrees for 2 hours and then partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed successively with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-60:40) to give 1.64 g of (rac)-2-chloro-5,7-dimethyl-9-(tetrahydro-pyran-4-yl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-45) as white powder. HRMS (ES+) m/z Calcd for C14H19CIN4O2+H [(M+H)+]: 311.1270. Found: 311.1269.