Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2.[S:23]1[CH:27]=[C:26]([CH2:28][C:29](O)=[O:30])[N:25]=[CH:24]1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:29](=[O:30])[CH2:28][C:26]4[N:25]=[CH:24][S:23][CH:27]=4)[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2
Reactant: O=C(O)Cc1cscn1
Reactant: Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1
Product: O=C(Cc1cscn1)Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 6 from rac-N2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine and 4-thiazole acetic acid (CAS 7504-44-1); MS: m/e=419.1 (M+H+).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.[Br:17][C:18]1[CH:19]=[C:20](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[C:21]([F:24])=[N:22][CH:23]=1>C(O)CC.O.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>[Br:17][C:18]1[CH:19]=[C:20]([C@@H:25]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[OH:12])[C:21]([F:24])=[N:22][CH:23]=1
Reactant: CC(C)(C)OCl
Reactant: CC(C)(C)OC(N)=O
Reactant: Fc1cccc(/C=C/c2cc(Br)cnc2F)c1
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](c1cc(Br)cnc1F)[C@H](O)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of tert-butyl carbamate (363 mg, 3.10 mmol) in propanol (10 mL) was added sodium hydroxide (122 mg, 3.05 mmol) in water (4 mL) followed by tert-butyl hypochlorite (331 mg, 3.05 mmol). After 5 min the solution was cooled to 0° C. and treated with a solution of (DHQD)2PHAL (38.9 mg, 0.050 mmol) in propanol (4 mL). To this solution was added a solution of (E)-5-bromo-2-fluoro-3-(3-fluorostyryl)pyridine (296 mg, 1.0 mmol) in propanol (10 mL). To this solution was added potassium osmate dihydrate (14.73 mg, 0.040 mmol) in one portion. The reaction turned light orange and was allowed to stir at 0° C. for 1 hr. The ice bath was then removed and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with a 10% solution of sodium thiosulfate and stirred for 30 min. The reaction was then extracted with diethylether (3×). The combined organic extracts were combined washed with water, then brine. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The crude residue was purified by silica gel chromatography 25% EtOAc/75% Hexanes to 50%/50% EtOAc/Hexanes to afford tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-(3-fluorophenyl)-2-hydroxyethylcarbamate (223 mg, 0.520 mmol, 52.0% yield) along with its regioisomer as an inseparable mixture. LC/Mass spec. (Analytical HPLC method 2): RT=2.11 min. Mass=453.14 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[CH:19]3[CH2:21][CH2:20]3)[C:9]2=[O:12])=[CH:4][C:3]=1[OH:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(N[S:40]([C:43]([F:46])([F:45])[F:44])(=[O:42])=[O:41])C=CC=CC=1>C1COCC1>[F:44][C:43]([F:46])([F:45])[S:40]([O:22][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[C:9](=[O:12])[N:8]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]1[CH2:20][CH2:21]1)[CH2:7][CH2:6]2)(=[O:42])=[O:41]
Reactant: O=C1c2cc(Cl)c(O)cc2CCN1c1cnccc1C1CC1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1c2cc(Cl)c(OS(=O)(=O)C(F)(F)F)cc2CCN1c1cnccc1C1CC1
Yield: 66.7 %

Procedure:
7-Chloro-6-hydroxy-2-(4-cyclopropylpyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (90A: 180 mg, 0.57 mmol) was reacted with KHMDS (0.71 mL, 0.71 mmol) in THF (10 mL) and N-phenyl trifluoromethanesulfonamide (226 mg, 0.630 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 170 mg of the product (66.6% yield).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[NH2:27][C:28]1[CH:39]=[CH:38][C:31]([CH2:32][C:33]2[N:34]=[CH:35][NH:36][CH:37]=2)=[CH:30][CH:29]=1.N1CCCCC1.O>CN(C=O)C>[NH:36]1[CH:37]=[C:33]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([NH:27]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:39][CH:38]=2)[N:34]=[CH:35]1
Reactant: Nc1ccc(Cc2c[nH]cn2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(Cc2c[nH]cn2)cc1)c1ccccc1

Procedure:
Prepared by reacting 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone with 1.45 equivalents of 4-(4-amino-benzyl)-1H-imidazole in DMF (100° C., for 2 hours), subsequent treatment with 5 equivalents of piperidine (20° C., 1 hour) and precipitation with water.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].[NH:22]1[C:30]2[C:25](=CC=C[CH:29]=2)[C:24]2(COC3C=C4C(=[CH:41][C:31]2=3)CCO4)C1=O.ClCC1C=NC(OC)=NC=1>>[N:22]1[CH:41]=[CH:31][CH:24]=[CH:25][C:30]=1[CH2:29][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: COc1ncc(CCl)cn1
Product: O=C1N(Cc2ccccn2)c2ccccc2[C@@]12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using (3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (2-bromomethyl)pyridine hydrobromide to replace 5-(chloromethyl)-2-methoxypyrimidine, (3R)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (77%) as a colorless solid: mp 154-156° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ8.53-8.51 (m, 1H), 7.82-7.77 (m, 1H), 7.38-7.13 (m, 4H), 7.05-6.99 (m, 1H), 6.98-6.92 (m, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 5.10 (d, J=16.4 Hz, 1H), 5.00 (d, J=16.4 Hz, 1H), 4.86 (d, J=9.3 Hz, 1H), 4.75 (d, J=9.3 Hz, 1H), 4.49 (t, J=8.7 Hz, 2H), 2.98 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.0, 161.0, 160.4, 155.2, 149.2, 142.4, 137.0, 132.2, 128.5, 123.4, 122.8, 122.6, 121.5, 120.6, 119.7, 119.2, 109.2, 92.3, 79.7, 72.0, 56.8, 44.7, 28.2; MS (ES+) m/z 371.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])[CH:5]=[O:6].[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:38](=[O:43])[CH2:39][O:40][CH2:41][CH3:42])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC>>[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:38](=[O:43])[C@@H:39]([O:40][CH2:41][CH3:42])[C@H:5]([OH:6])[C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[C:2]([CH3:1])[CH:3]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: Cc1cc(C=O)ccc1OCCc1nc(-c2ccccc2)oc1C
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c(C)c1

Procedure:
In analogy to the procedures described in examples 11 a] to 11 c], 3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (example 114 b]) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R) -2-ethoxy-3-hydroxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid. The enantiomeric excess was judged according to chiral HPLC (Chiralpak-AD) to be 99.3%.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21]Cl)=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21][N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:25][CH:26]([CH3:28])[CH3:27])=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CNCC(C)C
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CC(C)CN(Cc1nnc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)o1)CC(C)C
Yield: 86.8 %

Procedure:
1.09 g (3 mmol) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature overnight with 0.97 g (7.5 mmol) of diisobutylamine and 15 ml of N,N-dimethylformamide. After evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.19 g (86%) of 7-chloro-3-(5-diisobutylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 181°-182°, which was converted into the hydrochloride of m.p. 161°-163°.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]=[CH:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[CH3:1][N:2]([CH3:9])[CH:3]=[C:4]([C:20](=[O:21])[C:19]1[CH:23]=[C:24]([F:28])[C:25]([Cl:27])=[CH:26][C:18]=1[Cl:17])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C=CN(C)C
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C(=CN(C)C)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 89.1 %

Procedure:
First a solution of 12.9 g of methyl 3-dimethylaminoacrylate in 25 ml of dioxane is added dropwise, and then 10.5 g of triethylamine are added to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 80 ml of anhydrous dioxane, while cooling in ice and stirring. The mixture is stirred at room temperature for 3 hours, heated at 50°-60° C. for 1 hour, and the solvent is removed by distillation in vacuo and the residue is taken up in methylene chloride/H2O. The phases are separated, and the aqueous solution is again extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate, and the methylene chloride is removed in vacuo. The crystalline residue is recrystallized from methanol/water. 28.5 g of methyl 3-dimethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate of melting point 107°-109° C. are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[N:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=O)=[CH:10][CH:9]=1.Cl.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH:25]1([CH2:28][NH:29][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[N:21][C:13]=2[O:12][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:23][CH:22]=2)[CH2:27][CH2:26]1
Reactant: NCC1CC1
Reactant: O=C(O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC1CC1)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reaction time: 0.08 h

Procedure:
To a 100 mL round-bottomed flask was added 2-(4-(pyridin-2-ylamino)phenoxy)nicotinic acid (0.333 g, 1.08 mmol), cyclopropylmethanamine hydrochloride (0.116 g, 1.08 mmol), and TEA (0.4500 mL, 3.25 mmol) in DMF to stir for 5 min. EDC (0.2314 g, 1.19 mmol) and HOBT (0.1870 g, 1.19 mmol) was then added and allowed to stir overnight. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (1×10 mL), saturated sodium chloride (1×10 mL), saturated sodium bicarbonate (1×10 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (25M), eluting with a gradient of 1% to 5% methanol in DCM, to provide N-(cyclopropylmethyl)-2-(4-(pyridin-2-ylamino)phenoxy)nicotinamide. MS (ESI, pos. ion) m/z: 361.1 (M+1). IC50 (uM) 0.831.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8]([CH:10]1[CH2:12][CH:11]1[C:13](Cl)=[O:14])=[O:9])[CH3:6].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C(Cl)Cl>[CH2:22]([C:16]1[CH:17]=[CH:18][C:19]([C:13]([CH:11]2[CH2:12][CH:10]2[C:8]([O:7][CH2:5][CH3:6])=[O:9])=[O:14])=[CH:20][CH:21]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCc1ccccc1
Reactant: CCOC(=O)C1CC1C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCc1ccc(C(=O)C2CC2C(=O)OCC)cc1
Temperature: 0 °C
Yield: 60.3 %

Procedure:
Aluminum chloride (6.93 g) is added in one portion to a solution of 2-ethoxycarbonyl-cyclopropane carboxylic acid chloride (4.17 g) and 1-phenyloctane (4.49 g) in methylene chloride (100 ml). After the initial exothermic reaction subsides, the mixture is heated under reflux for 16 hours. The mixture is cooled and poured into ice water (500 ml) containing conc. hydrochloric acid (50 ml). The product is extracted with ether (3×200 ml). The extract is dried over MgSO4 and then evaporated under reduced pressure. The residue is chromatographed on silica gel (hexane/ether) to provide ethyl 2-(4-n-octylbenzoyl)cyclopropane carboxylate as an oil (4.7 g). This ester is heated under reflux in aqueous 2N NaOH (36 ml) for 24 hours. The reaction mixture is diluted with water (100 ml), acidified and extracted with ether (3×50 ml). The extract is dried (MgSO4) and evaporated. The residue is crystallized from petroleum ether (40°-60°) to provide 2-(4-n-octylbenzoyl) cyclopropane carboxylic acid (1.88 g), m.p. 45°-47° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12](=[O:20])[N:11]2[CH:21]=1.[H-].[Na+].[C:24](Cl)(=[O:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[C:24]([N:13]1[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[C:10]2=[N:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:21][N:11]2[C:12]1=[O:20])(=[O:26])[CH3:25].[C:24]([O:20][C:12]1[N:11]2[CH:21]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:9]=[C:10]2[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1nc2c(c3nc(-c4ccccc4F)cn13)CCCC2
Product: CC(=O)n1c2c(c3nc(-c4ccccc4F)cn3c1=O)CCCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(2-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (283 mg) and 50% sodium hydride (144 mg) in DMF (5 mL) was stirred at room temperature for 15 min. Acetyl chloride (1 mL) was added and stirring was continued for 30 min. The reaction was diluted with ethyl acetate and washed with water. After drying over magnesium sulfate, the solvent was removed in vacuo and he residue was subjected to flash chromatography on silica gel with 30% ethyl acetate in hexane as the eluent to afford 6-Acetyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 47) and 5-Acetoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 48) as white solids.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:11][N:12](C)C=O>O>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:11]#[N:12])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: Nc1ccc(I)cc1CO
Reactant: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N)c(CO)c1
Temperature: 25 °C

Procedure:
2-Amino-5-iodobenzyl alcohol (12 g.) and cuprous cuyanide (5.4 g.) in dry dimethylformamide (10 ml.) were heated on a steam-bath for 30 hours, then cooled to ambient temperature and poured into a solution of ferric chloride (10 g.) in water (100 ml.). This mixture was exhaustively extracted with ether (14×60 ml.), the extracts were combined and dried, and the solvent was evaporated. The residue was chromatographed on a column of "Merck 7734" silica, and elution with ether yielded the required 4-amino-3-hydroxymethylbenzonitrile as a buff-coloured solid.
Reaction SMILES: C(O[CH:6]([N:10]([CH3:12])C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH:13]1[N:17]2[C:18]3[CH2:29][C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:19]=3[NH:20][C:21](=[O:22])[C:16]2=NC=1.O>CN(C)C=O.CO>[CH3:16][N:17](/[CH:18]=[C:29]1\[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:19]2[NH:20][C:21](=[O:22])[C:6]3[N:7]([CH:8]=[CH:12][N:10]=3)[C:9]\1=2)[CH3:13]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CN(C)/C=c1\c2ccccc2c2[nH]c(=O)c3nccn3c12
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
6.3 g of t-butoxybis(dimethylamino)methane are added dropwise over 5 minutes at a temperature in the region of 25° C. to a suspension of 5.5 g of 5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 100 ml of dimethylformamide. After stirring for 30 minutes at the same temperature, the mixture is poured into 500 ml of distilled water and extracted 5 times with 1.5 litres in total of chloroform. The organic extracts are combined, washed with 250 ml of distilled water, dried over anhydrous magnesium sulphate and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 60° C. The product obtained (4.5 g) is suspended in 25 ml of methanol, filtered, washed twice with 20 ml in total of methanol and dried under reduced pressure (15 mmHg; 2 kPa) at 20° C. The product obtained (4.5 g) is dissolved in 45 ml of boiling dimethylformamide and, after cooling, the solution is stored for 4 hours at a temperature in the region of 5° C. The crystals are separated out by filtration, washed successively with 10 ml of dimethylformamide, 10 ml of acetone and dried to dryness under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 4 g of 10-[(E)-dimethylaminomethylene]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, melting at 293° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 3.35 (s, 6H: --N(CH3)2); 7.18 and 7.28 (2t, J=7.5 Hz, 2H: --H7 and --H8); 7.48 and 7.92 (2d, J=7.5 Hz, 1H each: --H6 and --H9); 7.63 and 8.50 (2s broad, 1H each: --H of the imidazole); 8.09 (s, 1H: =CH--N); 12.30 (cplx, 1H: --NH--)].
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].C([Li])CCC.CCCCCC.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].[C:31]1([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[C:10]([C:39]2([OH:46])[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:38]2)=[CH:9][N:8]=[C:7]1[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CC(c2ccccc2)c2ccccc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c(C2(O)CC(c3ccccc3)c3ccccc32)cnc1[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of imidazole-1-sulfonic acid dimethylamide (1.96 g, 0.0112 mol, prepared according to D. J. Chadwick and R. I. Ngochindo J. Chem. Soc. Perkin Trans. I (1984) 481) in dry tetrahydrofuran (90 ml) under nitrogen was cooled to −78° C. and treated dropwise with 15% n-butyllithium in hexane (8.2 ml, 0.01393 mol). After 30 minutes tert-butyldimethylsilyl chloride (2.1 g, 0.01393 mol) in dry tetrahydrofuran (5 ml) was added and the mixture was allowed to warm to room temperature. After 1.5 hr the mixture was again cooled to −78° C. and treated with 15 % n-butyllithium in hexane (8.5 ml, 0.01360 mol). After 30 minutes 3-phenyl-1-indanone (3.40 g, 0.01633 mol) in dry tetrahydrofuran was added and the mixture was allowed to warm to room temperature during the night. The mixture was quenched with saturated sodium carbonate solution and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed twice with water, dried, filtered and concentrated under reduced pressure. Purification was done by flash chromatography (elution with a heptane—ethyl acetate gradient).
Reaction SMILES: [FH:1].[C:2]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C:23](=[CH:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])(=[O:4])[CH3:3].[Br:29]N1C(=O)CCC1=O.N>O.CN(C)C=O>[C:2]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@:23]([Br:29])([C@@H:24]([F:1])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])(=[O:4])[CH3:3]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reactant: F
Reactant: O=C1CCC(=O)N1Br
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(Br)[C@@H](F)C[C@@]21C
Reaction time: 3 h

Procedure:
At -78° C., 20 ml. of hydrogen fluoride is combined with 8 ml. of dimethylformamide, and 6 g. of 17-acetoxy-4,9(11)-pregnadiene-3,20-dione (J. Org. Chem. 26 1961!: 866) and 4 g. of N-bromosuccinimide are added to the reaction mixture. The latter is allowed to stand for 3 hours at -30° C. and then introduced into a mixture of water, ice, and a 25% ammonia solution. The precipitate is filtered off, washed with water, taken up in ethyl acetate, and dried over sodium sulfate. After chromatography of the crude product on silica gel with 19-21.6% acetone/hexane, the yield is 3.0 g. of 17-acetoxy- 9-bromo-11β -fluoro-4-pregnene-3,20-dione; m.p. 180°-182° C. (under decomposition).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([S:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:17])=[O:16])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[Cl:24]N1C(=O)CCC1=O>ClCCCl.CO>[Cl:24][C:10]1[C:5]2[N:6]([C:2]([CH3:1])=[N:3][N:4]=2)[C:7]2[CH:13]=[C:12]([CH3:14])[N:11]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:8]=2[CH:9]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCCl
Solvent: CO
Product: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Temperature: 60 °C

Procedure:
A suspension of 1,7-dimethyl-6-(phenylsulfonyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (2.0 g, 6.1 mmol, from Step 4) and N-chlorosuccinimide (0.91 g, 6.8 mmol, Aldrich) in 1,2-dichloroethane (40 mL) was heated at 60° C. overnight. Flash chromatography, eluting with a gradient from 0-5% MeOH/DCM (0.5% NH4OH), afforded an orange solid which was refluxed in 10 mL MeOH for 15 minutes. The product was isolated by filtration. Yield: (2.2 g, 80%). 1H NMR (500 MHz, d6-DMSO) δ 8.23 (s, 1H), 8.01-7.96 (m, 2H), 7.80-7.74 (m, 1H), 7.68-7.61 (m, 2H), 7.22 (s, 1H), 2.86 (s, 3H), 2.62 (s, 3H); LCMS (M+H)+: 361.