Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]1[CH:7]([O:8]C(=O)C)[NH:6][C:5]1=O)[CH2:2][CH3:3].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1C=CC=CC=1>[CH2:1]([CH:4]1[CH:5]([S:22][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[NH:6][C:7]1=[O:8])[CH2:2][CH3:3]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CCCC1C(=O)NC1OC(C)=O
Solvent: c1ccccc1
Product: CCCC1C(=O)NC1Sc1ccc([N+](=O)[O-])cc1

Procedure:
3-Propyl-4-acetoxy azetidinone, 171 mg, is refluxed with 200 mg p-nitrophenyl thiol in 10 ml benzene for 6 hours. The solution is washed 3x with aqueous Na2CO3, dried with MgSO4, filtered and evaporated. The residue is chromatographed on silica gel, eluting with 10:1 CHCl3 -EtOAc, affording 3-propyl-4-p-nitrophenylthioazetidin-2-one.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:9]2)=CC=1.ClC(OCCCl)=O.CO>ClCCCl>[CH3:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][NH:8][CH2:9]2
Reactant: COCCOCCOc1cccc2c1CN(Cc1ccc(OC)cc1)C2
Agent: O=C(Cl)OCCCl
Solvent: CO
Solvent: ClCCCl
Product: COCCOCCOc1cccc2c1CNC2
Reaction time: 17 h

Procedure:
A solution of 2-(4-methoxy-benzyl)-4-[2-(2-methoxy-ethoxy)-ethoxy]-2,3-dihydro-1H-isoindole (45 mg, 0.13 mmol) in 1,2-dichloroethane (2 mL) was treated with -chloroethyl chloroformate (0.1 mL, 0.93 mmol). After 17 hours, methanol (5 mL) was added and the mixture stirred for 3 hours. The solvents were removed in vacuo to afford the title compound as a greenish-black solid, which was used without further purification. 1H NMR (methanol-d4) 7.36 (1H, t), 6.98 (2H, d), 4.60 (2H, s), 4.57 (2H, s), 4.23-4.21 (2H, m), 3.85-3.83 (2H, m), 3.69-3.67 (2H, m), 3.57-3.54 (2H, m), 3.36 (3H, s). MS: [M+H]+ 238.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[N:7]=[C:6]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:17][CH2:18]2)[CH:5]=[CH:4][N:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1nccc(N2CCN(Cc3ccccc3)CC2)n1
Temperature: 40 °C

Procedure:
A mixture of 9.9 g (0.0664 mol) of 2,4-dichloropyrimidine, 200 ml of water and 11.7 ml (0.0673 mol) of 1-(phenylmethyl)piperazine was heated to 40° C. for 2 hours in an ultrasound bath. After cooling the mixture was made alkaline with potassium carbonate and extracted thoroughly with ethyl acetate. The crude product obtained after working up in the usual way was purified by column chromatography over silica gel (30-60 μm) using FM2 and FM4 (2/1 v/v) as eluant. Working up the appropriate fractions yielded 7.4 g (38.6% of theory) of a colourless oil, Rf=0.51 (FM4; Macherey-Nagel POLYGRAMO® SIL G/UV254, ready-made films for TLC).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[C:15]1([CH:21]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[CH:21](=[N:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-aminoacetate hydrochloride (15.00 g, 116.00 mmol, 1.0 eq) in CH2Cl2 (150 mL) was added Et3N (20 mL, 143.3 mmol, 1.2 eq) and PhCHO (14.6 mL, 143.3 mmol, 1.2 eq) in turn. The reaction mixture was stirred at room temperature overnight, and concentrated in vacuo. The residue was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo to afford the crude product methyl 2-(benzylideneamino)acetate, which was used for the next step without further purification. To a solution of methyl 2-(benzylideneamino)acetate in MeOH (200 mL) at −5° C. was added NaBH4 (2.80 g, 72.8 mmol, 0.55 eq) slowly. The reaction mixture was stirred at −5° C. for 2 h. The reaction mixture was then quenched with water and extracted with EtOAc (100 mL×3). The combined organic phases were washed with water followed by brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) PE/EtOAc) to afford the title compound as colorless oil (21.30 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@@H:14]2[CH2:18][C@H:17]([O:19][CH2:20][CH2:21][OH:22])[C@@H:16]([OH:23])[C@H:15]2[OH:24])=[N:4][C:5]([S:9][CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[Cl:8].[N:25](OCCC(C)C)=O>C(OCC)(=O)C>[Cl:8][C:7]1[C:2]2[N:1]=[N:25][N:13]([C@@H:14]3[CH2:18][C@H:17]([O:19][CH2:20][CH2:21][OH:22])[C@@H:16]([OH:23])[C@H:15]3[OH:24])[C:3]=2[N:4]=[C:5]([S:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: CC(C)CCON=O
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@@H](O)[C@H]2O)n1
Solvent: CCOC(C)=O
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Temperature: 65 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a stirring solution of (1S,2S,3R,5S)-3-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (OLACINA; 0.38 g, 1 mmol) in ethyl acetate (7 mL) was added isopentyl nitrite (0.16 mL, 1.2 mmol). The reaction mixture was stirred for 1 h at 65° C. and then evaporated under reduced pressure to give a reddish powder which was recrystallized from a mixture of methyl tert-butyl ether/n-hexane to give CLTOL as a crystalline product (0.31 g, 80% yield): 99 area % by HPLC.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH:24]3[CH2:26][CH2:25]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[CH:24]1([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:30]=[N:29][C:28]([NH2:27])=[CH:33][CH:32]=4)[CH:7]=3)[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=2)[CH2:26][CH2:25]1
Reactant: FC(F)(F)c1ccc(-c2cc(-c3ccnc(Cl)c3)nc(C3CC3)c2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C4CC4)n3)ccn2)cn1

Procedure:
The title compound was prepared from 2′-chloro-6-cyclopropyl-4-(4-trifluoromethylphenyl)-[2,4′]bipyridinyl (example E.29) (0.300 g, 0.80 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.229 g, 1.17 mmol) according to the general procedure VI. Obtained as a white solid (0.060 g, 17%). MS (ISP) 433.1 [(M+H)+]; mp 172-174° C.
Reaction SMILES: [NH:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[Br:29][C@H:30]([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[Br:29][C@H:30]([CH3:34])[C:31]([N:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:32]
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Reactant: C[C@@H](Br)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Br)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylate and 1.5 liters of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine followed by 132 g of (2R)-2-bromo-propionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S,3aS,7aS)-1-[(2R)-2-bromopropionyl]octahydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:14][C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=2)[C:5]([O:8]C)=[N:6][CH:7]=1>Br.CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][C:13]=3[N:14]=2)[C:5]([OH:8])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1-c1nc2c([nH]1)CCCC2
Agent: Br
Solvent: CC(=O)O
Product: Oc1ncc(Br)cc1-c1nc2c([nH]1)CCCC2
Yield: 130.8 %

Procedure:
To a solution of 2-(5-bromo-2-methoxypyridin-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d]imidazole (0.8 g, 2.6 mmol) in HBr/AcOH (10 mL), was heated to 100° C. for 12 hours. The solvent was removed off and the resulting residue was washed with dichloromethane (2*20 mL), then dry to provide 5-bromo-3-(4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)pyridin-2-ol (1 g, yield 100%) as a solid. 1HNMR (400 MHz, DMSO) δ 13.87 (br, 2H), 8.40 (d, J=2.7 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 2.61 (s, 4H), 1.76 (s, 4H). MS (M+H)+: 294/296.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.Cl.[N:23]1([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][CH:35]([NH:38][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:36][CH2:37]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(Oc3ccccc3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3ccccc3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-phenoxy-1H-indole-2-carboxylic acid 129 (preparation see below) and amine 5.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[N+:13]([C:16]1[N:17]=[C:18]2[N:23]([CH:24]=1)[CH2:22][CH2:21][CH:20]([CH2:25][OH:26])[O:19]2)([O-:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:46][C:47]1[CH:52]=[CH:51][C:50](O)=[CH:49][CH:48]=1>C1COCC1>[I:46][C:47]1[CH:52]=[CH:51][C:50]([O:26][CH2:25][CH:20]2[O:19][C:18]3=[N:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][N:23]3[CH2:22][CH2:21]2)=[CH:49][CH:48]=1
Reactant: O=[N+]([O-])c1cn2c(n1)OC(CO)CC2
Reactant: Oc1ccc(I)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(I)cc1)CC2
Temperature: 25 °C
Reaction time: 32 h
Yield: 85.7 %

Procedure:
Diethylazodicarboxylate (0.070 mL, 0.45 mmol) was added dropwise to a suspension of oxazine alcohol 134 (see Example 2BB above) (251 mg, 1.26 mmol), triphenylphosphine (448 mg, 1.71 mmol), and 4-iodophenol (377 mg, 1.71 mmol) in anhydrous THF (3.0 mL) at 0° C. under N2, and the resulting mixture was stirred at room temperature for 32 h. The solvent was removed and the residue was chromatographed on silica gel. Elution with CH2Cl2 firstly gave foreruns, and then further elution with 0-2% EtOAc/CH2Cl2 gave a crude solid, which was further chromatographed on silica gel. Elution with 0-50% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 10% MeOH/CH2Cl2 gave 7-[(4-iodophenoxy)methyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (135) (433 mg, 86%) as a cream solid: mp (MeOH/CH2Cl2/hexane) 224-227° C.; 1H NMR [(CD3)2SO] δ 8.08 (s, 1H), 7.62 (dt, J=9.0, 2.7 Hz, 2H), 6.86 (dt, J=9.0, 2.7 Hz, 2H), 4.89 (m, 1H), 4.31 (dd, J=11.1, 3.4 Hz, 1H), 4.25 (dd, J=11.1, 5.8 Hz, 1H), 4.18 (ddd, J=12.6, 5.8, 3.0 Hz, 1H), 4.09 (ddd, J=12.5, 10.8, 5.2 Hz, 1H), 2.35-2.26 (m, 1H), 2.25-2.12 (m, 1H). Anal. (C13H12IN3O4) C, H, N.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[N:9][N:10]([CH3:13])[C:11]=1[NH2:12].[C:14](OC(=O)C)(=[O:16])C.C(O)=O>C(N(CC)CC)C.[Cl-].[Na+].O>[NH2:12][C:11]1[N:10]([CH3:13])[N:9]=[CH:8][C:7]=1[NH:6][CH:14]=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1ncc(N)c1N
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1ncc(NC=O)c1N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 4,5-diamino-1-methylpyrazole sulfuric acid salt (20 g) in triethylamine (29.2 ml) was stirred at 0° C. for 10 minutes. A mixture of acetic anhydride (9.87 ml) and formic acid (7.96 ml) was stirred at 40° C. for 30 minutes, cooled to 0° C., and added dropwise to the above solution at 0° C. The whole mixture was stirred at 0° C. for 2 hours. To the mixture was added brine, and the whole mixture was extracted with tetrahydrofuran. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give crude N-(5-amino-1-methyl-1H-pyrazol-4-yl)formamide, which was used in the next step without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:19])[CH:13]([CH3:18])[CH2:14][C:15]([OH:17])=O)=[CH:8][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[O:19][C:15](=[O:17])[CH:14]=[C:13]2[CH3:18])=[CH:10][CH:11]=1
Reactant: CC(CC(=O)O)C(=O)c1ccc(OCCCBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=CC(=O)OC1c1ccc(OCCCBr)cc1
Reaction time: 18 h

Procedure:
4-(3-Bromopropyloxy)-γ-oxo-β-methylbenzenebutanoic acid (30 g) in toluene (300 ml) was refluxed with p-toluenesulfonic acid (500 mg) under a Dean-Stark water separator for 18 hours. The mixture was filtered through basic alumina (20 g). The alumina was further washed with ethyl acetate and the combined eluants were reduced to dryness to provide the title compound as an oil.
Reaction SMILES: [Na].COS([O-])(=O)=O.CN(C)[C:10]1[CH2:14][CH2:13][CH2:12][N+:11]=1[CH3:15].[CH3:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:19]>C(O)C>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:18](=[O:19])[CH:17]=[C:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C1=[N+](C)CCC1
Reactant: COc1cccc(C(C)=O)c1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Product: COc1cccc(C(=O)C=C2CCCN2C)c1
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A solution of 10.35 g of sodium in 225 ml of ethanol is added dropwise at 90° (with stirring) in the course of one hour to a mixture of 107 g of 2-dimethylamino-1-methyl-1-pyrrolinium methyl sulfate and 45.1 g of 3-methoxyacetophenone; stirring is effected for a further 2 hours at this temperature, and the solvent is then largely distilled off under a vacuum. 300 ml of water and 300 ml of diethyl ether are added to the cooled residue, and thorough shaking is effected. The ethereal phase is collected, dried over sodium sulfate and concentrated. The crystalline residue is recrystallized from chloroform/cyclohexane to yield 41.8 g of the title compound (as yellowish crystals), m.p. 92° to 93°.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1(O)[CH2:31][CH2:30]CC[CH2:27][CH2:26]1.Cl>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:30][CH2:31][CH2:25][CH2:26][CH2:27][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: OC1CCCCCC1
Agent: [Ti]
Agent: Cl
Solvent: CCO
Product: O=C(OC1CCCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 0.25 h

Procedure:
A mixture of 10.35 g (30 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 50 g of cycloheptanol and 2 g of tetraethyl orthotitanate is heated to 130° for 8 hours, evaporated in vacuo, the residue is taken up in chloroform and the solution obtained is poured into about 20 percent hydrochloric acid. The mixture is stirred for 15 minutes, the chloroform phase is separated, washed successively with 2N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate/hexane there is obtained cycloheptyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 179°-180°.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][CH:39]=[C:9]23)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:20][CH:21]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][CH:39]=[C:9]23)[CH2:4][CH2:3]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ccnn12
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To a solution of 4-(trans-4-hydroxycyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propylpyrazolo[1,5-a]pyrimidin-5(4H)-one (0.20 g) in methylene chloride (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.24 g), and the mixture was stirred for 18 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.091 g, 45%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C@@H:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([O:10]C(C)(C)C)=[O:9])=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][C:4]([NH:6][C@@H:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([OH:10])=[O:9])=[O:5]
Reactant: COCC(=O)N[C@H](C(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from Example 55A (0.012 g, 0.038 mmol) in dichloromethane (0.2 mL) was treated with trifluoroacetic acid (0.2 mL), stirred at 25° C. for 1 hour and concentrated. The residue was azeotroped with toluene to give the title compound, which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([CH3:19])[CH:13]=1.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:21])=[O:20]
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(Br)c(C)c1
Product: Cc1cc(C(=O)Nc2ccccc2C(=O)O)ccc1Oc1ccccc1

Procedure:
In analogy to example 2,2-(3-Methyl-4-phenoxy-benzoylamino)-benzoic acid was prepared from 2-(4-bromo-3-methyl-benzoylamino)-benzoic acid methyl ester and phenol. MS (m/e): 346.3 (M−H−, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[S:9][CH:10]=1)=[O:5])C.O1CCCC1.[OH-].[Na+]>CO>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH:13]=1
Reactant: CCOC(=O)c1csc(Nc2cccnc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1csc(Nc2cccnc2)n1

Procedure:
2-(Pyridin-3-ylamino)-thiazole-4-carboxylic acid (165 mg) was prepared according to General Procedure C using 2-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester in methanol:tetrahydrofuran:2N NaOH (1:1:1, 1.5 mL). The solvents were evaporated and the compound was dried. The crude product was used without further purification.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([CH3:22])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=O)(C)(C)C.[ClH:23].O1CCOCC1>>[ClH:23].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:16]2[C:17]([CH3:22])=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: Cc1c(F)ccc2onc(OCCNC(=O)OC(C)(C)C)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(F)ccc2onc(OCCN)c12
Reaction time: 0.25 h
Yield: 98 %

Procedure:
3-(2-(N-t-butoxycarbonylamino)ethoxy)-5-fluoro-4-methyl-1,2-benzisoxazole (0.15 g) was dissolved in 4N hydrochloric acid/dioxane solution (1.4 ml) and stirred for 15 minutes. The reaction mixture was evaporated under reduced pressure and the precipitated crystals were filtered. The title compound (0.13 g, 98% yield) was obtained as a colorless powder by washing the crystals with ethyl acetate (3 ml).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)#[N:4].Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>>[C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]=[CH:18][N:17]=3)[C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)#[N:4]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Agent: [H-]
Agent: [Na+]
Product: COc1cc2c(C3C(=O)Nc4cc(C#N)ccc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.3 %

Procedure:
Sodium hydride (80 mg, 2.07 mmol) was added to a solution of 6-cyanooxindole (280 mg, 1.78 mmol), (prepared as described for the starting material in Example 57), in dry, degassed DMF (10 ml) and the suspension stirred for 15 minutes at ambient temperature. A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 5), in a dry, degassed mixture of DMF (2 ml) and THF (2 ml) was added dropwise and the reaction mixture was heated at 60° C. for 3 hours. The mixture was allowed to cool, the solvents were removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic phase was separated and the aqueous phase extracted with ethyl acetate (50 ml×3). The ethyl acetate fractions were combined, dried (MgSO4), the solvent removed by evaporation and the residue was purified by flash column chromatography eluting with methylene chloride/methanol (100/13). The purified product was triturated in boiling ether and the solid product collected by filtration to give 4-(6-cyanooxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (36 mg, 13%) as an orange solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:34]=[CH:33][C:29]([N:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=1)#[CH:25]>>[CH3:31][N:30]([CH3:32])[C:29]1[CH:33]=[CH:34][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:27][CH:28]=1
Reactant: C#Cc1ccc(N(C)C)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: CN(C)c1ccc(-c2cn(C3CCc4c(CC(=O)O)c5ccccc5n4C3)nn2)cc1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 4-ethynyl-N,N-dimethylaniline. MS (+ESI) m/z: 416.2.