Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]2[CH3:19])=[CH:12][CH:11]=1>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]2[CH3:19])=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2n1C
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)C(=O)c1c(C(=O)OCC)n(C)c2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A solution of 7.1 ml (63.6 mmol) of ethyl chlorooxoacetate in 100 ml of 1,2-dichloroethane is cooled to 0° C. 7.0 ml (63.6 mmol) of titanium tetrachloride are added in small portions and the mixture is stirred for 30 min at 0° C. A solution of 7.4 g (35.3 mmol) of ethyl 6-chloro-1-methyl-1H-indole-2-carboxylate is added and the mixture is stirred for 3 h at room temperature. The mixture is poured onto water and the organic phase is separated by settling, washed with dilute sodium hydroxide solution, dried over sodium sulphate and concentrated under reduced pressure to produce an oil which is purified by chromatography on a silica column (eluant: cyclohexane/dichloromethane: 2/8). 9.51 g (29.4 mmol) of compound are isolated in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:14][O:13]1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CCO>[N:15]1([CH2:14][C@H:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[OH:13])[CH2:20][CH2:19][N:18]([CH2:14][C@H:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[OH:13])[CH2:17][CH2:16]1
Reactant: C1CNCCN1
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c([C@H](O)CN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
To a 20 mL microwave tube charged with 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (980 mg, 5.15 mmol) and piperazine (200 mg, 2.3 mmol) was added a stir bar and EtOH (16 mL). The tube was sealed and heated in a microwave apparatus to 150° C. for 90 minutes. The crude product was adsorbed onto silica gel, and purified by flash chromatography (MeOH-DCM 0˜7% gradient). After removal of solvents, 5,5′-{piperazine-1,4-diylbis[(1S)-1-hydroxyethane-2,1-diyl]}bis(4-methyl-2-benzofuran-1(3H)-one) was collected (560 mg).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:13])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+].CCO>O>[I:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH2:5][NH:4]2)=[CH:8][CH:9]=1
Reactant: CC(=O)N1CCc2ccc(I)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Ic1ccc2c(c1)NCC2
Yield: 63.6 %

Procedure:
1-Acetyl-6-iodoindoline (1.06 g, 3.7 mmol), NaOH (1.16 g, 29 mmol), EtOH (8 mL), and H2O (6 mL) were heated at 90° C. overnight. The reaction mixture was then partitioned between H2O and EtOAc. The organic layer was extracted into aqueous HCl. The aqueous layer was in turn basified with NaOH, and was extracted with EtOAc. The organic layer was dried and concentrated. Hexane trituration yielded 6-iodoindoline (577 mg, 64%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:37]2)=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[S:37])[NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][CH:16]=1
Reactant: CC(C)(C)NC(=O)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)NC(=S)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1
Temperature: 25 °C

Procedure:
Combine 7-chloro-6-(4-tert-butylcarbamoyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (53 mg, 0.13 mmol) with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (53 mg, 0.13 mmol) in anhydrous 1,4-dioxane (1 mL) in a sealed tube and heat at 100° C. for 2 h. Cool the reaction mixture to room temperature, concentrate in vacuo and purify the residue by SCX chromatography to obtain 7-chloro-6-(4-tert-butylthiocarbamoyl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil. Purify by reverse phase preparative HPLC [Zorbax SB-Phenyl 21.2×250 mm, 5 micron, 22 mL/min of 0.1% aqueous HCl/acetonitrile (9:1 to 1:9) over 30 min, detector at 230 nm].
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].I[CH3:27].[H-].[Na+].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH3:27])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (1.44 mmol) of Compound 27 obtained in Example 27 was dissolved in 30 ml of dimethylformamide under argon atmosphere and the solution was cooled on ice. 0.27 ml of iodomethane and 63 mg of sodium hydride (60% oil dispersion) were added, the mixture was stirred at the same temperature for 1 hour and the temperature was raised to room temperature to stir for additional 2 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent was distilled off and the tan residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2) to give 2-[4-(N-acetyl-N-methylamino)-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:11](=[O:21])(=[O:20])[C:12]3[CH:19]=[CH:18][S:17][C:13]=3[N:14]([CH3:16])[N:15]=2)=[O:9])=[CH:4][CH:3]=1.CN(C=O)C.[Br:29]N1C(=O)CCC1=O>C(Cl)Cl>[Br:29][C:18]1[S:17][C:13]2[N:14]([CH3:16])[N:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[S:11](=[O:21])(=[O:20])[C:12]=2[CH:19]=1
Reactant: CN1N=C(C(=O)NCc2ccc(Cl)cc2)S(=O)(=O)c2ccsc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1N=C(C(=O)NCc2ccc(Cl)cc2)S(=O)(=O)c2cc(Br)sc21

Procedure:
A solution containing N-(4-chlorobenzyl)-1-methyl-1H-thieno[2,3-e][1,3,4]-thiadiazine-3-carboxamide 4,4-dioxide (Preparation 56, 0.14 g) and anhydrous DMF (2 mL) is stirred under nitrogen while adding N-bromosuccinimide (0.074 g) in one portion. This solution is stirred overnight at room temperature before diluting with CH2Cl2 (50 mL) and washing with water (60 mL). The organic portion is separated and washed with brine, dried over Na2SO4, filtered, and concentrated to give a brown oil. Physical characteristics: MS (ESI+) m/z 448 (M+H)+, 450.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:25][C:23]([F:24])([F:26])[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCc2ccc(C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(CCCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
4-[3-(4-Trifluoromethylphenyl)propyl]piperidine-1-carboxylic acid tert-butyl ester (13.45 g, 36.2 mmol) prepared in Reference Example 360 was dissolved in dichloromethane (50 ml). Trifluoroacetic acid (25 ml, 324 mmol) was added thereto and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and adjusted to a pH of 10 using a 5 N sodium hydroxide aqueous solution. The mixture was subjected to extraction with dichloromethane 4 times. The result was dried over anhydrous sodium sulfate and then concentrated to afford the title compound as a pale brown oil (10.2 g, quant).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[Cl:15])O1.[Cl:17][C:18]1[N:23]=[C:22]([NH2:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:19]=1I>>[Cl:17][C:18]1[C:19]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[Cl:15])=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[C:22]([NH2:24])[N:23]=1
Reactant: Nc1nc(Cl)c(I)cc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccncc2Cl)OC1(C)C
Product: Nc1nc(Cl)c(-c2ccncc2Cl)cc1[N+](=O)[O-]
Yield: 22 %

Procedure:
Following the same procedure as in Intermediate 1 (step a), but using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-chloropyridine, 6-chloro-5-iodo-3-nitropyridin-2-amine (Intermediate 5—step a) was transformed into the title compound as a white solid (205 mg, 22%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[CH:10](Cl)([CH2:12][CH3:13])[CH3:11].[K]>C1(C)C=CC=CC=1>[CH3:11][CH:10]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:12][CH3:13]
Reactant: CCC(C)Cl
Reactant: Cc1ccc(CCl)cc1
Agent: [K]
Solvent: Cc1ccccc1
Product: CCC(C)Cc1ccc(C)cc1
Temperature: 50 °C

Procedure:
0.05 Mol of p-methyl benzyl chloride and 0.05 mol of sec.-butyl chloride were dissolved in 100 ml. of toluene. The solution obtained was added dropwise to a toluene solution containing 0.1 mol of potassium metal with thorough stirring while obtaining the temperature of the solution at 20° to 30°C. After the addition, the temperature of the solution was raised to 50°C. with thorough stirring to complete the reaction. After the reaction, the product became black violet, and a white powder was precipitated. The resultant product containing the unreacted matter and by-products was distilled to afford 3-methyl-4-(p-tolyl) butane. The resulting product was used in the following Examples.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14](/[C:16](=[CH:19]\[CH3:20])/[CH:17]=O)[CH3:15]>C1C=CC=CC=1.O>[CH2:19](/[C:16](=[CH:14]\[CH3:15])/[CH:17]=[CH:5]/[C:3]#[N:4])[CH3:20]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: C/C=C(/C=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: C/C=C(/C=C/C#N)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a mixture of sodium hydride (60% in oil, 7.5 g) and dry benzene (200 ml) was added dropwise diethyl cyanomethylphosphonate (30 g) with stirring at 0° C. under dry nitrogen atmosphere. After stirring for 60 minutes at room temperature, a solution of (E)-2-ethyl-2-butenal (16.6 g) in dry benzene was added thereto at 0° C. with stirring. The resulting mixture was allowed to stand at room temperature for 60 minutes and diluted with water and then extracted with ethyl acetate. The extract was washed successively with water and brine, and then dried over magnesium sulfate. Removal of the solvent gave an oil which was purified by distillation under reduced pressure to give (E,E)-4-ethyl-2,4-hexadienenitrile (8.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:23][NH2:24].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:24][CH2:23][C:22]2[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:20]([C:19]([F:18])([F:32])[F:33])[CH:21]=2)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: COC(=O)C1CC(=O)CN1Cc1ccccc1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Reaction time: 3 h
Yield: 62.9 %

Procedure:
Benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (100 mg, 0.428 mmol) and 3,5-bis-trifluoromethyl-benzylamine (125 mg, 0.514 mmol) were dissolved in dry DCM (2 mL), acetic acid (0.1 mL) and NaBH(OAc)3 (180.6 mg, 0.856 mmol) was then added. After stirred for 3 hours the reaction mixture was diluted with DCM, washed with saturated NaHCO3 (cautiously), dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography to afford the title product 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid methyl ester 124 mg (63%) as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3S[C:8]=2[C:17]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[Mn]([O-])(=O)(=O)=O.[K+].[S:29]([O-:33])(O)(=O)=[O:30].[Na+]>O>[C:1]1([C:7]2[NH:12][C:11]3[CH:10]=[CH:16][CH:15]=[CH:14][C:13]=3[S:29](=[O:33])(=[O:30])[C:8]=2[C:17]#[N:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)([O-])O
Reactant: N#CC1=C(c2ccccc2)Nc2ccccc2S1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC1=C(c2ccccc2)Nc2ccccc2S1(=O)=O
Reaction time: 2 h

Procedure:
A mixture of 3-phenyl-4H-1,4-benzothiazine-2-carbonitrile (0.10 g, prepared according to Liso et al., J. Heterocycl. Chem. 18, 279 (1981), Liso et al., Synthesis 1983, 755) and acetic acid (6 ml) was added to a stirred solution of potassium permanganate (88 mg) in water (10 ml) at ambient temperature. After 2 h, 3 h and 18 h additional amounts (25 mg, 40 mg and 40 mg) of potassium permanganate were added. Then a 40% solution of sodium hydrogensulfate (200 μl) was added. After stirring for ½ h the mixture was filtered through celite. The filtrate was extracted with ethyl acetate (2×25 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give a solid. Trituration with ethyl acetate (2 ml), filtration and drying gave the title compound as light yellow crystals. Yield 34 mg (38%); mp 286-289° C.; 1H-nmr(DMSO) δ (ppm): 12.21 (br, 1H), 8.07-7.97 (m, 1H), 7.84-7.5 (m, 8H); IR(KBr) ν (cm−1): 3298 (NH), 2198 (C≡N), 1598, 1554, 1514, 1476, 1433, 1301, 1171, 1154, 1136; MS m/e (rel. intensity): 282 (25 %, M+), 250 (4%), 218 (100%), 190 (15%), 115 (10%), 77 (10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:22][CH:23]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CC(C)(C)c1ccc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of example 3.1 using 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (2 mmol) and 4-tert-butyl-benzoyl chloride (2 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[CH:22][C:23]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:30])C=CC=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[F:29][C:26]([F:27])([F:28])[O:25][C:23]1[CH:22]=[CH:21][C:20]2[C:10]3([CH2:17][O:18][C:19]=2[CH:24]=1)[C:11]1[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:8][C:9]3=[O:30]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Yield: 74.7 %

Procedure:
To a suspension of 1′-(diphenylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (6.00 g, 12.3 mmol) in methanol (100 mL) and acetic acid (1.00 mL) was added 10% palladium on carbon (0.65 g, 0.62 mmol), and the mixture was hydrogenated at ambient temperature under 130 psi of hydrogen for 5 days. The reaction mixture was filtered over celite and the filtrate was concentrated in vacuo to dryness. The residue was subjected to flash chromatography eluting with 30% ethyl acetate in hexane to give the title compound (2.95 g, 75%) as a white solid: mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ 9.19 (S, 1H), 7.29-6.92 (m., 4H), 6.86-6.64 (m, 3H), 5.03 (d, 1H), 4.75 (d, 1H); 13C NMR(75 MHz, CDCl3) δ 179.9, 161.9, 150.6, 132.3, 129.4, 127.4, 125.6, 124.3, 124.2, 123.8, 120.5, 114.1, 110.7, 104.3, 80.8, 58.2; MS (ES+) m/z 322 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][CH2:17][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1>C(NCC)C.CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]3[CH2:19][CH2:18][CH2:17][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:30]#[C:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(I)c2[C@@H]2CCCN12
Reactant: C#Cc1cccc(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1cccc(C#Cc2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)c1

Procedure:
2.0 g (5 mmol) (S)-8-chloro-11,12,13,13a-tetrahydro-1-iodo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one was heated to boiling under reflux for 9 hours with 0.73 g (5.6 mmol) of 3-methoxyphenylacetylene, 65 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 65 mg of copper(I) iodide in 20 ml of diethylamine and 20 ml of N,N-dimethylformamide. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with methylene chloride/methanol (99:1). By crystallization from methylene chloride and ethyl acetate there was obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-[(m-methoxyphenyl)ethynyl]-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 204°-205°.
Reaction SMILES: NC1C=CC=CC=1.[C:8]([C:12]1[CH:13]=[C:14]([CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])[C:15]([O:17][CH2:18][CH2:19][C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([NH2:30])[CH:24]=1)=[O:21])=[O:16])([CH3:11])([CH3:10])[CH3:9].[CH2:39]([O:43][C:44]1[CH:49]=[CH:48][C:47]([C:50](=[O:57])[CH2:51][C:52](OCC)=[O:53])=[CH:46][CH:45]=1)[CH2:40][CH2:41][CH3:42]>C1(C)C(C)=CC=CC=1>[C:35]([C:32]1[CH:31]=[C:14]([CH:13]=[C:12]([C:8]([CH3:10])([CH3:11])[CH3:9])[C:33]=1[OH:34])[C:15]([O:17][CH2:18][CH2:19][C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([NH:30][C:52](=[O:53])[CH2:51][C:50]([C:47]2[CH:48]=[CH:49][C:44]([O:43][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:45][CH:46]=2)=[O:57])[CH:24]=1)=[O:21])=[O:16])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)c1cc(C(=O)OCCC(=O)Oc2ccc(Cl)c(N)c2)cc(C(C)(C)C)c1O
Reactant: CCCCOc1ccc(C(=O)CC(=O)OCC)cc1
Solvent: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: CCCCOc1ccc(C(=O)CC(=O)Nc2cc(OC(=O)CCOC(=O)c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)ccc2Cl)cc1
Reaction time: 5 h
Yield: 82.2 %

Procedure:
A solution of the aniline from (c) (19.8 g, 44.2 mmole) and the β-ketoester from (e) (13.0 g, 44.2 mmole) in xylene (160 ml) were heated under reflux, using a Dean & Stark apparatus, for 5 hours. Over the final hour, the volume of the mixture was reduced to 75 ml by distillation. 60-80 petroleum ether (300 ml) was added with cooling and the solid collected by filtration. The product was isolated as a brown solid (24.2 g, 82%). m.p. 94-96%.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[F:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1F
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccccc1F
Yield: 68.6 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.48 g, 10 mmol), 2-fluoroaniline (1.45 ml, 15 mmol) and 1,4-dioxan (10 ml) were stirred at room temperature overnight then heated at reflux for 30 minutes. The hydrochloride salt was filtered off, converted to free base and recrystallised from aqueous ethanol to give 3-butyryl-4-(2-fluorophenylamino)-8-methylquinoline (2.21 g), m.p. 109°-111°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].Cl.[CH3:13][C:14]1[S:15][CH:16]=[C:17]([C:19]([N:21]2[CH2:26][C:25]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[O:24][CH2:23][CH2:22]2)=[O:20])[N:18]=1>C(N(CC)CC)C.C(#N)C>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][C:25]2([O:24][CH2:23][CH2:22][N:21]([C:19]([C:17]3[N:18]=[C:14]([CH3:13])[S:15][CH:16]=3)=[O:20])[CH2:26]2)[CH2:27][CH2:28]1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCCCCCCCCBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCCCCCCCCO)CC3)C2)cs1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
9-Bromononan-1-ol (0.29 g) was added to a suspension of (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride (example 1, step f) (0.4 g) in a mixture of triethylamine (0.41 mL) and acetonitrile (10 mL). The resulting mixture was stirred for 16 h at 50° C. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (30 mL) and saturated sodium bicarbonate solution (30 mL). The layers were separated and the aqueous extracted with ethyl acetate (2×30 mL). The combined organic solutions were washed with brine (30 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in methanol (10 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (10 mL) and eluted with 3M ammonia in methanol solution (100 mL). The eluent was evaporated in vacuo to give the subtitled compound a yellow oil. Yield 0.32 g.
Reaction SMILES: [N+:1]([O-:4])([O-])=O.[Na+].C(O)(=O)C(O)=O.[N:12]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[N+:13]=[N-:14].CCCCCC>C(Cl)Cl>[N:20]([CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:12]=[N+:13]=[N-:14])[N:1]=[O:4])=[N+:21]=[N-:22]
Reactant: O=[N+]([O-])[O-]
Reactant: [N-]=[N+]=NCCNCCN=[N+]=[N-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: [N-]=[N+]=NCCN(CCN=[N+]=[N-])N=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84 %

Procedure:
A suspension of sodium nitrate (13.4 g; 0.194 mol), oxalic acid (24.4 g; 0.194 mol) and N,N-bis(2-azidoethyl)amine LI (15 g; 0.097 mol) in DCM (300 mL) was stirred vigorously at r.t. for 2.5 h. Silica gel (20 g) and hexane (200 mL) was added to the reaction mixture and the resulting suspension was filtered. The solids were washed (1:1 hexane/DCM, 200 mL). The solvent was evaporated under reduced pressure to afford N,N-bis(2-azidoethyl)-N-nitrosoamine LII (15 g; 0.081 mol; 84% yield).