Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15](=[O:26])[N:16]([CH3:25])[C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([N:16]([CH3:25])[C@@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[O:26])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)N(C)[C@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)N(C)[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 3-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-1-methyl-1-((R)-1-phenyl-ethyl)-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]#[N:34])=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:22][CH:23]=1)#[N:34]
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4ccccc4C#N)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4′-bromomethyl-2-cyanobiphenyl in N,N-dimethylformamide. Trituration with diethyl ether provided an off-white solid. 1H NMR: δ 7.93 (dd, J=7.0, 2.0 Hz, 2H), 7.75 (dd, J=7.7, 1.0 Hz, 1H), 7.64 (dt, J=1.3, 7.7 Hz, 1H), 7.42-7.50 (m, 4H), 7.31 (d, J=8.3 Hz, 2H), 7.07 (dd, J=7.1, 1.9 Hz, 2H), 4.00 (A of AB, J=13.7 Hz, 1H), 3.93 (s, 3H), 3.42 (B of AB, J=13.7 Hz, 1H) MS (m/e): 477.3 (M−H)+. Anal: Calc for C24H18N2O5S2.0.167 C3H9NO: 59.92% C, 4.00% H, 6.18% N; Found: 59.60% C, 4.04% H, 5.99% N.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]([NH:36][CH2:37][CH2:38][NH:39][CH3:40])=O)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]>P(Cl)(Cl)(Cl)=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:39]([CH3:40])[CH2:38][CH2:37][N:36]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(C(=O)NCCNC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc2c(C)cc(C3=NCCN3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared by heating of tert.butyl 4'-[[2-n-propyl-4-methyl-6-[2-(N-methylamino)-ethylaminocarbonyl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate in phosphorus oxychloride and isolating analogously to Example 151.
Reaction SMILES: [C:1]([CH:3]([C:14]#[N:15])[C:4]1[N:9]([CH3:10])[C:8](=[O:11])[N:7]([CH3:12])[C:6](=O)[CH:5]=1)#[N:2].P(Cl)(Cl)([Cl:18])=O>O>[Cl:18][C:6]1[N:7]([CH3:12])[C:8](=[O:11])[N:9]([CH3:10])[C:4](=[C:3]([C:14]#[N:15])[C:1]#[N:2])[CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(C(C#N)C#N)cc(=O)n(C)c1=O
Solvent: O
Product: CN1C(=O)N(C)C(=C(C#N)C#N)C=C1Cl

Procedure:
To 6.1 g (0.03 mol) of the resulting 6-dicyanomethyl-1,3-dimethyluracil was added 1.5 ml of water, and 40 ml of phosphorus oxychloride was added dropwise thereto. After heating the mixture at reflux for 1.5 hours, the phosphorus oxychloride was removed by distillation under normal pressure, and the residue was poured onto ice. The precipitated crystals were collected by filtration. The filtrate was extracted three times with chloroform and dried over anhydrous sodium sulfate. The chloroform was distilled away and the resulting residue was combined with the above obtained crystals. Recrystallization from water-methanol yielded 6.15 g of 6-chloro-1,3-dimethyl-2-oxo-4-dicyanomethylenepyrimidine.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH2:31]([O:33][C:34]([C:36]1([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([N:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)=[O:61])[CH2:44][C:43]2[C:38](=[C:39]([O:51]C)[C:40]([O:49][CH3:50])=[C:41]([O:47][CH3:48])[C:42]=2[O:45]C)[CH2:37]1)=[O:35])[CH3:32]>O>[CH2:31]([O:33][C:34]([C:36]1([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([N:62]2[CH2:63][CH2:64][O:65][CH2:66][CH2:67]2)=[O:61])[CH2:37][C:38]2[C:39](=[O:51])[C:40]([O:49][CH3:50])=[C:41]([O:47][CH3:48])[C:42](=[O:45])[C:43]=2[CH2:44]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)C1(CCCCCCCC(=O)N2CCOCC2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(CCCCCCCC(=O)N2CCOCC2)CC2=C(C1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
A water (1.2 ml) solution of CAN (323 mg, 0.590 mmols) was dropwise added to an acetonitrile (2.5 ml) solution of N-[8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoyl]morpholine (123 mg, 0.236 mmols) with cooling with ice and stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried. The solvent was evaporated out in vacuo and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to obtain the entitled compound (66.6 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=S)[NH:10][NH2:11].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[NH:11][N:10]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(=S)Nc1ccccc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccccc2Cl)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A solution of 10.05 g (0.05 mole) of 4-(2-chlorophenyl)-3-thiosemicarbazide in 75 mL of absolute ethanol was treated with 8.48 g (0.05 mole) of ethyl 2-choroacetoacetate and stirred under nitrogen atmosphere at room temperature for 1 hr. The reaction mixture was treated with 40 mL of 2N ethanolic hydrogen chloride and heated at reflux for 1 hr, during which time the yellow slurry became a clear, deep orange solution. The characteristic insoluble amorphous sulfur was removed by filtration. The filtrate began to solidify. It was allowed to cool for approximately 16 hr to yield 10.1 g of yellow crystalline product. The filtrate was concentrated in vacuo to yield an additional 3 g of yellow product. The 2 solids were combined and recrystallized from benzene to give 10.4 g of white crystalline product, mp 188°-189° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@:13]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[OH:14])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC#N>[Cl:21][C:17]1[CH:16]=[C:15]([C@:13]([C@@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]2)([OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCCO[Si](C)(C)C(C)(C)C)c2cccc(Cl)c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCCO)c2cccc(Cl)c2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of (R)-tert-butyl 3-((S)-5-(tert-butyldimethylsilyloxy)-1-(3-chlorophenyl)-1-hydroxypentyl)piperidine-1-carboxylate (511 mg, 1 mmol) in CH3CN (10 mL) was added tetrabutylammonium fluoride (550 mg, 2 mmol) in one portion. The reaction mixture was stirred at 60° C. for 2 h. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with EtOAc/hexane to give (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)piperidine-1-carboxylate (350 mg, 80%). 1H NMR (400 MHz, CDCl3): 1.05-1.42 (m, 6H), 1.46 (s, 9H), 1.52-1.79 (m, 4H), 1.94-2.03 (m, 2H), 2.55 (m, 2H), 3.56 (m, 2H), 3.97 (m, 1H), 4.36 (m, 1H), 7.20-7.25 (m, 3H), 7.37 (s, 1H). MS (E/Z): 398 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21].[NH2:23][CH:24]([CH2:28][CH3:29])[CH:25]([OH:27])[CH3:26]>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH:23][CH:24]([CH2:28][CH3:29])[CH:25]([OH:27])[CH3:26])=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=1[CH3:21]
Reactant: CCC(N)C(C)O
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(Cl)cc1C
Solvent: CN1CCCC1=O
Product: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)O
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acid methyl ester (500 mg, 1.47 mmol) and 3-amino-pentan-2-ol (758 mg, 7.35 mmol) in 1-methyl-2-pyrrolidinone was heated in 130° C. oil bath for 24 hr. The mixture cooled to rt and quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give an oil. The oil was purified through silica gel column chromatography using 20% ethyl acetate in hexane as eluent to give the title compound as a white crystal, mp 133–135° C.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[NH2:11][C:12]1[N:17]=[C:16]([CH2:18]Cl)[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1>CO.O>[NH2:11][C:12]1[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([CH2:18][S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=2)[N:17]=1
Reactant: COc1cc(CCl)nc(N)n1
Reactant: Sc1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(CSc2ccccn2)nc(N)n1

Procedure:
18 g of 30% methanolic sodium methylate solution are added to a solution of 11.1 g of 2-mercaptopyridine in 100 ml of methanol, and stirring is then maintained at 20°-25° C. for 1 hour. To this solution are added portionwise 17.4 g of 2-amino-4-chloromethyl-6-methoxy-pyrimidine, and the mixture is stirred at 20°-25° C. for a further 2 hours. In further processing, the mixture is diluted with 1 liter of water, and the precipitating crystalline product is separated and dried. The yield is 22.5 g (91% of theory) of 2-amino-4-methoxy-6-(pyridin-2-yl-thiomethyl)-pyrimidine, m.p. 115°-116° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C[Si](C)(C)[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]>C1(C)C=CC=CC=1>[O:4]([C:2]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: O=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CCCN1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a solution of phenyl chloroformate (3.13 g, 20.0 mmol) in anhydrous toluene (10 ml) was added a solution of 1-trimethylsilyl-2-pyrrolidinone (3.46 g, 22.0 mmol) in anhydrous toluene (10 ml). The mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated under reduced pressure to dryness to give a solid material. Recrystallization from ethanol afforded 2.37 g of colorless prisms. Yield 57.7%.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:5]([C:15]([F:18])([F:17])[F:16])[CH:4]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:9]1([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][C:5]=2[C:15]([F:16])([F:17])[F:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COc1ccc(N2CCCCC2)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(N2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of crude 1-(4-Methoxy-2-trifluoromethyl-phenyl)-piperidine in dry DCM (3 mL) cooled to −78° C. is added BBr3 (1M in DCM, 3 eq., 1.2 mL). Following this addition, the cooling bath is removed and the reaction is stirred at 25° C. for 12 hours. Upon completion, the reaction is cooled in an ice bath, and water is added dropwise. The quenched reaction is basified to pH=8 by the slow addition of 10% NaHCO3 (aq). The reaction mixture is diluted with DCM and washed with H2O followed by saturated aqueous NaCl. The organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (3:1 hexanes/EtOAc) to give 4-Piperidin-1-yl-3-trifluoromethyl-phenol. [MS: (ES+) 246.1 (M+1)+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH:22]1([CH2:30]O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:30][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: OCC1CCCCCCC1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC2CCCCCCC2)c1

Procedure:
Mitsunobu reaction of phenol 58 with cyclooctane methanol gave 2-(3-(3-(cyclooctylmethoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.920 g, 65%): 1H NMR (400 MHz, CDCl3) δ 7.80-7.86 (m, 2H), 7.68-7.73 (m, 2H), 7.10-7.13 (m, 1H), 6.72-6.79 (m, 2H), 6.64-6.68 (m, 1H), 3.65 (d, J=6.4 Hz, 2H), 2.64 (t, J=7.6 Hz, 2H), 1.98-2.06 (m, 4H), 1.65-1.78 (m, 7H), 1.56-1.64 (m, 5H), 1.30-1.40 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=2[N:17]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:14])[CH2:13][CH2:12][N:11]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2cccc(Cl)c2)CCNCC1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Product: OC1(c2cccc(Cl)c2)CCN(c2nc3ccc(C(F)(F)F)cc3[nH]2)CC1

Procedure:
4-(3-Chloro-phenyl)-piperidin-4-ol (0.25 g, 1.18 mmol, Aldrich) reacted with 2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.26 g, 1.18 mmol, Example 1c) under the conditions of Example 94d to give the title compound as a white solid. M.p. 246.7-247.4° C. MS (ESI, pos. ion) m/z: 424 (M+1).
Reaction SMILES: C([NH:4][C:5]1([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=O)C.[ClH:31]>>[ClH:31].[NH2:4][C:5]1([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: CC(=O)NC1(CCCc2ccccc2)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Product: NC1(CCCc2ccccc2)c2ccccc2-c2[nH]c(=O)c3nccn3c21

Procedure:
A suspension of 550 mg of (10 RS)-10-acetamido-10-(3-phenylpropyl)-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one in 30 ml of 4N hydrochloric acid is refluxed for 2 hours. The reaction medium is cooled and filtered on a sinter funnel. The solid obtained is recrystallized from 40 ml of ethanol. 130 mg of (10 RS)-10-amino-10-(3-phenylpropyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride are obtained in the form of a grey solid melting above 260° C. (Analysis, % calculated C: 67.3, H: 5.4, Cl: 9.0, N: 14.3, O: 4.1; % found C: 67.1, H: 5.3, Cl: 9.0, N: 14.1, O: 4.1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH:26]([CH3:30])[CH2:27][O:28][CH3:29])[CH2:21][CH2:20]3)=[C:15]([O:31][CH3:32])[CH:14]=1)[CH2:6][CH2:5]2.CS([CH2:37][C@H:38]1[CH2:42][CH2:41][CH2:40][O:39]1)(=O)=O>>[CH3:32][O:31][C:15]1[CH:14]=[C:13]([N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:37][C@H:38]4[CH2:42][CH2:41][CH2:40][O:39]4)[CH:3]=3)[C:8]2=[O:12])[CH:18]=[CH:17][C:16]=1[N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH:26]([CH3:30])[CH2:27][O:28][CH3:29])[CH2:21][CH2:20]1
Reactant: COCC(C)N1CCCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2OC)CC1
Reactant: CS(=O)(=O)C[C@H]1CCCO1
Product: COCC(C)N1CCCN(c2ccc(N3CCc4cc(OC[C@H]5CCCO5)ccc4C3=O)cc2OC)CC1

Procedure:
6-Hydroxy-2-{3-methoxy-4-[4-(2-methoxy-1-methyl-ethyl)-[1,4]diazepan-1-yl]-phenyl}-3,4-dihydro-2H-isoquinolin-1-one and (R)-2-methanesulfonylmethyl-tetrahydrofuran were reacted according to Method K1. In this way the product was obtained with molecular weight 523.68 (C30H41N3O5); MS (ESI): 524 (M+H+).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH3:15].[C:16](Cl)(=[O:18])[CH3:17].[Al+3].[Cl-].[Cl-].[Cl-]>>[CH3:15][O:14][C:2]1[CH:1]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:16](=[O:18])[CH3:17])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)Cc1ccccc1-2
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2

Procedure:
1-(7-Methoxy-fluoren-2-yl)-ethanone is prepared by the acylation of fluoren-2-yl-methyl ether with acetyl chloride/AlCl3 according to Kajigaeshi, et al., Bull. Chem. Soc. Jpn., 52, 3569-3572 (1979) or Gray et al, J. Chem Soc., 1955; 2686-2688, both of which are incorporated herein by reference.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([O:11][CH3:12])(OC)OC.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])C[CH2:17]2.CC1C=CC(S(OI(O)C2C=CC=CC=2)(=O)=O)=CC=1>CO>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[CH:6]([O:11][CH3:12])[CH2:17]2
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC1Cc2cc(Cl)ccc2C1=O
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
A 22 L multi-neck reactor equipped with a temperature probe, a nitrogen inlet, a cooling bath and an overhead mechanical stirrer was charged with methanol (2400 mL) and cooled to −20° C. Sulfuric acid (384 mL, 7.22 mol) was charged via an addition funnel over 1 hour. The temperature was maintained at about −25° C. and peaked at −18° C. for ˜5 minutes. Trimethyl orthoformate (906 mL, 8.3 mol) was added over 10 minutes followed by 5-chloro-2,3-dihydro-1H-inden-1-one (17) (600.00 g, 3.61 mol) as a solid. The internal temperature slightly increased by 2° C. Koser's reagent (1553 g, 3.97 mol) was dissolved in methanol (2400 mL) over 20 minutes which was added to the reaction vessel over 1 hour and 15 minutes. The addition was exothermic and the internal temperature was maintained at about −20° C. Upon completion of addition, the dark red solution was stirred at −20° C. for 1 hour, at which point HPLC analysis indicated complete conversion to the desired product. Water (7200 mL) was added in small portions. After the addition of a small amount of water (˜50 mL), the product suddenly precipitated. The agitation became slow and difficult. The mixture was stirred at 0˜10° C. for 1 hour and was filtered through a 3000 mL coarse fritted funnel. The filtration was complete in 2 hours and the cake was rinsed with water (7200 mL) until the pH of the filtrate reached about 5. The wet cake was added back to the reactor and heptane (3000 mL) was added. The mixture was stirred at −20° C. for 1 h and filtered. The cake was rinsed with heptanes (1200 mL) and conditioned for 30 minutes. The wet cake was dried under high vacuum for 3 days to completely remove heptane and reduce the water content to <2%. The material had purities of 99% (AUC by HPLC) and 93 wt % by wt % assay (622.88 g, 88%). 1H NMR (300 MHz, CDCl3, δ): 7.69 (m, 1H), 7.43 (s, 1H), 7.38 (m, 1H), 4.18 (m, 1H), 3.63 (s, 3H), 3.47 (m, 1H) and 2.99 (m, 1H).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[F:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[F:14])[NH2:10].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.Cl>CC(O)CC.C1COCC1>[F:14][C:13]1[CH:12]=[C:11]2[C:9](=[CH:8][C:7]=1[F:6])[N:10]=[C:3]([CH3:4])[CH:2]=[CH:1]2
Reactant: Nc1ccc(F)c(F)c1
Reactant: C/C=C/C=O
Agent: Cl
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: C1CCOC1
Solvent: CCC(C)O
Product: Cc1ccc2cc(F)c(F)cc2n1
Temperature: 0 °C
Yield: 56.7 %

Procedure:
Crotonaldehyde (226.34 g, 3.23 mol) in 100 mL of 2-butanol was added dropwise to a refluxing solution of 3,4-difluoroaniline (417.27 g, 3.23 mol), p-chloranil (794.65 g, 3.23 mol) and HCl conc. (808 mL) in 5.4 L of 2-butanol. After 2 hours of heating 2.7 L of solvent was removed under vacuum at ca. 60° C. Then 2 L of toluene was added to the reaction mixture followed by removal of 2.5-3 L of solvent until a very pasty solid formed. THF (2 L) was added and the mixture heated 30 min. after which it was cooled to 0° C. The solid was collected and washed with THF until pure by tlc. The solid was then dissolved in aq. K2CO3 /EtOAc and the organic phase separated. The aqueous phase was extracted with EtOAc (2×) and the organic phases combined, dried over MgSO4 and the solvent removed. The product was crystallized in the minimum amount of EtOAc to give 328.08 g (57%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]#[CH:19])=[CH:11][C:10]=1[CH3:20])([CH3:7])[CH3:6])[CH3:2].I[C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]#[C:19][C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=2)=[CH:11][C:10]=1[CH3:20])[CH3:7])[CH3:2]
Reactant: C#CCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC#Cc2ccc(OC(F)(F)F)cc2)cc1C

Procedure:
In analogy to the procedure described in example 13B], 2-(4-but-3-ynyloxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 16A]) and 1-iodo-4-trifluoromethoxy-benzene gave the title compound as a light yellow viscous oil.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=3)=[CH:4][C:3]=2[O:2]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CO>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:5][CH2:10][N:11]([CH3:23])[CH3:12])[CH:27]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(/C=C/c1cccc(O)c1)N1CCc2c([nH]c3ccccc23)C1c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCOc1cccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)c1
Yield: 41.3 %

Procedure:
To a solution of Example 58 (0.25 g, 0.57 mmol) in 50 mL of DMF was added K2CO3 (0.24 g, 3 equiv.) and an excess of dimethylaminodiethyl chloride (about 15 equiv.). The resulting mixture was heated at 60° C. for four hours until disappearance of the starting material (tlc monitoring, DCM:MeOH (90:10). A new compound was formed (Rf=0.20). After evaporation of DMF, the residue was taken up in 150 mL of DCM, washed with 2×50 mL of water, dried over Na2SO4 and recrystallized from EtOH:H2O. to give the title compound (0.06 g, 22%) as yellow crystals.