Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1)#[CH:2].[CH:13]1([C:16]2[CH:17]=[C:18]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[C:34](I)[CH:33]=3)[CH:19]=[CH:20][C:21]=2[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:15][CH2:14]1>>[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[C:2][C:36]2[CH:37]=[C:32]([CH:33]=[CH:34][C:35]=2[CH3:38])[C:31]([NH:30][C:18]2[CH:19]=[CH:20][C:21]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[C:16]([CH:13]3[CH2:15][CH2:14]3)[CH:17]=2)=[O:40])=[CH:4][N:5]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C3CC3)c2)cc1I
Reactant: C#Cc1cnnc2ccccc12
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C3CC3)c2)cc1C#Cc1cnnc2ccccc12

Procedure:
The title compound can be synthesized from 4-ethynylcinnoline and N-(3-cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1 (nitro reduction performed in a manner similar to that described for Example 10; 0.25M in MeOH/10% AcOH). 4-ethynylcinnoline is prepared from 4-bromocinnoline and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:14]([N:18]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)([CH3:17])([CH3:16])[CH3:15].Cl>>[CH:28]1([N:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23]([O:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:22][CH:21]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: CC(C)(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Agent: Cl
Product: COc1cc(Oc2ccc(C(=O)N(C3CCCCC3)C(C)(C)C)cc2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and p-bromobenzoic acid N-tert-butyl-N-cyclohexyl amide (1.35 g, 4.0 mmol) 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound.
Reaction SMILES: [Na+:1].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:18]([S:22]([O-:25])(=[O:24])=[O:23])=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]=1[S:26]([O-:29])(=[O:28])=[O:27])=[O:10])([O-])=O.[H][H]>[Pd].O>[Na+:1].[Na+:1].[NH2:3][C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:18]([S:22]([O-:25])(=[O:24])=[O:23])=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]=1[S:26]([O-:29])(=[O:28])=[O:27])=[O:10]
Reactant: O=C(Nc1ccc2c(S(=O)(=O)[O-])cccc2c1S(=O)(=O)[O-])c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: Nc1cccc(C(=O)Nc2ccc3c(S(=O)(=O)[O-])cccc3c2S(=O)(=O)[O-])c1

Procedure:
A mixture of 25.0 g of 2-(m-(nitrobenzamido)-1,5-naphthalenedisulfonic acid disodium salt (prepared as in Example 1), 250 ml of water and 2.0 g of 10% palladium on charcoal is hydrogenated in a Parr shaker for 31/2 hours at room temperature with an initial pressure of 42 pounds of hydrogen. During this time a total of 11.5 pounds of hydrogen is absorbed.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:14][CH2:13]1.[C:29](Cl)(=[O:33])[CH2:30][CH2:31][CH3:32]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][CH:15]([N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:16][CH2:17]1)[C:29](=[O:33])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC(=O)Cl
Reactant: CCC(=O)N(c1ccccc1)C1CCN(CCNc2c(C)cccc2C)CC1
Product: CCCC(=O)N(CCN1CCC(N(C(=O)CC)c2ccccc2)CC1)c1c(C)cccc1C

Procedure:
Using the same procedure but starting from 1-[2-(2,6-dimethyl phenylamino)-ethyl]-4-(N-phenyl N-propionylamino) piperidine and butyroyl chloride, 1-[2-(N-(2,6-dimethyl phenyl) N-butyrylamino)-ethyl]-4-(N-phenyl N-propionylamino) piperidine is produced.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[NH:10][C:11]1[C:12]([O:23][CH3:24])=[N:13][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:15][CH:16]=1.[OH-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[NH:10][C:11]1[C:12]([O:23][CH3:24])=[N:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1nc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A mixture of ethyl 3-[N′-(2-bromophenyl)ureido]-2-methoxy-6-pyridylacetate (2.90 g, 7.10 mmol), 0.25 N NaOH (56.8 ml, 14.2 mmol), and THF (50 ml) was stirred for 5 h. The mixture was neutralized with 1 N HCl and the resulting precipitate was collected by filtration. The residue was recrystallized from CHCl3—MeOH-hexane to give 3-[N′-(2-bromophenyl)ureido]-2-methoxy-6-pyridylacetic acid (2.40 g, 89%) as a colorless crystalline powder. mp 195-197 IC; 1H-NMR (DMSO-d6), δ3.59 (s, 2 H), 3.95 (s, 3 H), 6.88 (d, J=8.1 Hz, 1 H), 6.97-7.01 (m, 1 H), 7.33 (t, J=7.3 Hz, 1 H), 7.61 (d, J=8.1 Hz, 1 H), 7.95-7.97 (m, 1 H), 8.29 (d, J=8.1 Hz, 1 H), 8.81 (s, 1 H), 9.10 (s, 1 H), 12.35 (br s, 1 H); Anal. Calcd. for C15H14BrN3O4: C, 47.39; H, 3.71; N, 11.05. Found: C, 47.27; H, 3.59; N, 10.86.
Reaction SMILES: [OH:1][CH:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][CH:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[CH2:5][CH2:4][CH:3]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:22])[CH3:21]
Reactant: CCOC(=O)C1CCn2c(cc3ccccc32)C1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1CCn2c(cc3ccccc32)C1OC(C)=O
Temperature: 50 °C
Yield: 99556.3 %

Procedure:
A solution of 75 g (0.29 mmol) of ethyl 6,7,8,9-tetrahydro-9-hydroxypyrido[1,2-a]indole-8-carboxylate in 1000 ml of pyridine is treated dropwise within 10 minutes with 59.2 g (0.58 mol) of acetic anhydride. The reaction mixture is heated at 50° C. for 24 hours and the solvent is subsequently evaporated. The residue is taken up in a mixture of ethyl acetate and water (2:1, total 750 ml) and the organic phase is washed with 250 ml of water and twice with 100 ml of 1N hydrochloric acid each time, dried over anhydrous sodium sulfate and evaporated to dryness. In this manner, there are obtained 87 g (100%) of ethyl 9-acetoxy-6,7,8,9-tetrahydropyrido[1,2-a]indole-8-carboxylate as a pale yellow solid, m.p. 98°-100° C.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[O:25]1[C:30]2[CH:31]=[CH:32][C:33]([NH:35]N)=[CH:34][C:29]=2[O:28][CH2:27][CH2:26]1>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:35]([C:33]4[CH:32]=[CH:31][C:30]5[O:25][CH2:26][CH2:27][O:28][C:29]=5[CH:34]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NNc1ccc2c(c1)OCCO2
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccc2c(c1)OCCO2
Yield: 52 %

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and (2,3-dihydro-benzo[1,4]dioxin-6-yl)-hydrazine according to the method described for Example 91 in 52% yield. MS: M=439.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[N:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=2)=[O:10])[CH:7]=1.[CH:21]1(O)[CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH:26]2[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]2)=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[N:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=2)=[O:10])[CH:7]=1
Reactant: OC1C=CCCC1
Reactant: N#Cc1cnc(NC(=O)Nc2cc(Cl)ccc2O)cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)Nc2cc(Cl)ccc2OC2C=CCCC2)cn1
Yield: 11.9 %

Procedure:
A mixture of Example 1F (28.9 mg, 0.10 mmol), 2-cyclohexen-1-ol (9.8 mg, 0.10 mmol), di-tert-butylazocarboxylate (34.5 mg, 0.15 mmol), triphenylphosphine on polystyrene (3 mmol/g, 50 mg, 0.15 mmol) and THF (2 mL) in a capped 4-mL vial was shaken at room-temperature overnight and filtered. The resin was washed twice with THF (1 mL each) and the combined THF washes were concentrated. The concentrate was purified by preparative HPLC with acetonitrile/water containing 0.1% TFA to provide 4.4 mg (12%) of the desired product. MS (ESI(−)) m/z 368 (M−H)−; 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.05 (br s, 1H), 8.92 (s, 1H), 8.73 (s, 1H), 8.27 (d, J=2.5 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 7.06 (dd, J=8.9, 2.7 Hz, 1H), 6.01–6.08 (m, 1H), 5.85–5.92 (m, 1H), 4.97–5.04 (m, 1H), 1.89–2.19 (m, 3H), 1.73–1.85 (m, 2H), 1.56–1.68 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([CH3:19])[CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8].[Li].[OH-]>CO>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][O:9][C:7]([NH:6][CH2:5][CH:4]([CH3:19])[C:3]([OH:20])=[O:2])=[O:8])=[CH:16][CH:15]=1
Reactant: COC(=O)C(C)CNC(=O)OCc1ccc(OC)cc1
Agent: [Li]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(COC(=O)NCC(C)C(=O)O)cc1
Yield: 97.3 %

Procedure:
A solution of N-4-methoxybenzyloxycarbonyl α-methyl β-alanine methyl ester (2.81 g, 10.0 mmol) in 30 mL of 25% aqueous methanol was treated with lithium is hydroxide (1.3 equivalents) at room temperature for a period of 2 h. The solution was concentrated in vacuo and the residue taken up in a mixture of water and ether and the phases separated and the organic phase discarded. The aqueous phase was acidified with aqueous potassium hydrogen sulfate to pH=1.5 and then extracted three times with ether. The combined ethereal phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 2.60 g, 97% of N-4-Methoxybenzyloxycarbonyl α-methyl β-alanine (N-Moz-AMBA) which was purified by recrystallization from a mixture of ethyl acetate and hexane to give 2.44 g, 91% of pure product, mp 96–97° C., MH+=268. 1H NMR (D6-acetone/300 MHz) 1.16 (3H, d, J=7.2Hz), 2.70 (1H, m), 3.31 (2H, m), 3.31 (3H, s), 4.99 (2H, s), 6.92 (2H, 4, J=8.7 Hz), 7.13 (2H, d, J=8.7 Hz).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]([CH3:19])[CH2:11][CH2:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]([CH3:19])[CH2:11][CH2:12][CH:13]([OH:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCC(=O)CCN(C)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCC(O)CCN(C)Cc1ccccc1
Yield: 94.3 %

Procedure:
Add sodium borohydride (1.29 g, 34.1 mmol) to a stirred solution of 1-(benzyl-methyl-amino)-heptan-3-one (2.41 g, 10 mmol) and methanol (45 ml) at 0° C. under N2. Stir the reaction for 1 hr at 0° C. Quench the reaction with water at 0° C. and concentrate under reduced pressure. Dissolve the residue in ethyl acetate, wash with brine and dry over sodium sulfate. Filter off and concentrate to give the crude compound. Purify the compound by flash chromatography, eluting with 5% ethanol/0.5% ammonium hydroxide/chloroform to yield 2.22 g (91%) of 1-(benzyl-methyl-amino)-heptan-3-ol: mass spectrum (ion spray) m/z=236 (M+1); 1H NMR (CDCl3) δ 7.34-7.23 (m, 5H), 3.76-3.72 (m, 1H), 3.53 (dd, 2H), 2.80-2.73 (m, 1H), 2.59-2.53 (m, 1H), 2.21 (s, 1H), 1.68-1.62 (m, 1H), 1.57-1.29 (m, 7H), 0.91 (t, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=1)[O:9][C:10]1[N:11]=[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]3)=[C:24]([CH3:35])[CH:23]=2)[C:13]([C:18]([NH2:20])=[O:19])=[N:14][C:15]=1[CH2:16][CH3:17])(=[O:4])[CH:2]=[CH2:3].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.ClCCCl>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=1)[O:9][C:10]1[N:11]=[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH:31]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH2:30][CH2:29]3)=[C:24]([CH3:35])[CH:23]=2)[C:13]([C:18]([NH2:20])=[O:19])=[N:14][C:15]=1[CH2:16][CH3:17])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCC(=O)CC4)c(C)c3)c(C(N)=O)nc2CC)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCC(N5CCOCC5)CC4)c(C)c3)c(C(N)=O)nc2CC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-[3-(acryloylamino)phenoxy]-6-ethyl-3-{[3-methyl-4-(4-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide (200 mg), morpholine (35 μL), and 1,2-dichloroethane (1.94 mL) was added sodium triacetoxyborohydride (100 mg), followed by stirring at room temperature overnight. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution and water, followed by extraction with chloroform twice. The extract was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=100:0-99:1-97:3) to obtain 5-[3-(acryloylamino)phenoxy]-6-ethyl-3-({3-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (55 mg) as a solid.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]#[N:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][OH:22]>>[CH3:21][O:22][C:19]([C:10]1[C:11]2[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)=[NH:20]
Reactant: CO
Reactant: COc1cccc2c(C#N)cn(CC3CCCCC3)c12
Product: COC(=N)c1cn(CC2CCCCC2)c2c(OC)cccc12
Reaction time: 72 h

Procedure:
Hydrochloride gas was bubbled, for 30 mins, through a cooled (0° C.) solution of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbonitrile (prepared as described in Example 1; 3.15 g, 11.0 mmol) in methanol (200 ml). The resulting mixture was left to stand for 72 h before being concentrated, by two thirds, in vacuo. Crystallisation of the product was achieved on addition of diethyl ether, and the resultant solid was collected via filtration to give 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carboximidic acid methyl ester as the hydrochloride salt (3.82 g). 1-(Cyclohexyl)methyl-7-methoxy-1H-indole-3-carboximidic acid methyl ester hydrochloride salt (0.10 g, 0.297 mmol), hydrazine hydrate (0.289 ml, 5.94 mmol), aluminium chloride (39.6 mg, 0.297 mmol) and toluene (18 ml) were combined and the mixture was subjected to microwave irradiation for 60 min at 120° C. The resultant mixture was concentrated in vacuo, re-dissolved in toluene and concentrated in vacuo twice more. The obtained residue was suspended in a toluene/acetonitrile mixture (12/1) (19.5 ml) and chloroacetylchloride (0.118 ml, 1.49 mmol) added, before the mixture was subjected to microwave irradiation for 12 min at 120° C. The resultant mixture was concentrated in vacuo and re-dissolved in acetonitrile (3 ml). N-(2-methoxyethyl)isopropylamine (0.068 ml, 0.446 mmol), potassium carbonate (45.2 mg, 0.327 mmol) and sodium iodide (44 mg, 0.297 mmol) was added and the mixture was subjected to microwave irradiation for 5 min at 160° C. before being left to stand for 72 hours and then concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 2.5%-5% (v/v) methanol in dichloromethane to afford the title compound as a 1:1 hydrochloride salt (46 mg). 1H NMR (400 MHz, CD3OD): 0.95-1.12 (2H, m), 1.13-1.24 (3H, m), 1.50 (6H, s (br)), 1.55-1.73 (5H, m), 1.79-1.93 (1H, m), 3.34-3.50 (5H, m), 3.70-3.99 (6H, m), 4.24 (2H, d, J 6.4), 4.67 (2H, s (br)), 6.70 (1H, d, J 7.7), 7.16 (1H, t, J 7.7), 7.95 (1H, d, J 7.7), 8.02 (1H, s (br)); EsIMS: m/z 440.3 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[O:23])[CH:18]=[C:17]([Br:31])[CH:16]=2)([CH3:14])[N:13]=1)(C)(C)C.O1CCOCC1.[ClH:39]>>[ClH:39].[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[N:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=3)=[O:23])[CH:18]=[C:17]([Br:31])[CH:16]=2)([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cc(NC(=O)c3ncc(Br)cn3)c2)COC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(Br)cc(NC(=O)c3ncc(Br)cn3)c2)COCC(N)=N1

Procedure:
A solution of ((R)-5-{3-bromo-5-[(5-bromo-pyrimidine-2-carbonyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (22 mg, 0.039 mmol) in 4 M HCl in dioxane (0.8 ml, 80 eq.) was warmed to 40° C. for 24 hrs in a closed reaction vial. After completion volatiles were removed under reduced pressure to yield the title compound (hydrochloride salt) in the form of a colourless solid. 1H-NMR (500 MHz, DMSO-d6): 11.05 (s, 1H), 10.61 (s, 1H, NH+), 9.25 (s, 2H), 9.19 (s, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 7.44 (s, 1H), 4.59 (m, 2H), 3.91 (m, 2H), 1.63 (s, 3H); MS: 470 [(M+H)+].
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>O.CO>[CH2:19]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC[C@H](NCc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
A solution of Nδ-Boc-ornithine (7.0 g), 2M sodium hydroxide (20 ml), benzaldehyde (3.2 ml) and methanol (10 ml) was cooled to 0° C. and sodium borohydride (2.7 g) was added. After 1 hr at 0° C., the mixture was kept at 25° C. for 12 h. Water (100 ml) was added and the mixture extracted with ether (2×60 ml). The combined organic extract was washed with sat. sodium bicarbonate (ca. 150 ml) and water, and dried over anhydrous sodium sulfate. After concentration in vacuo, the desired product (4.5 g) was obtained as a white solid: 1H NMR (400 MHz, CD3OD) δ1.42 (s, 9H), 1.60 (m, 2H), 1.84 (m, 2H), 3.03 (m, 2H), 3.50 (t, J=7.4 Hz, 1H), 4.11 (d, J=11.9 Hz, 1H), 4.21 (d, J=11.9 Hz, 1H), 7.41 (m, 3H), and 7.49 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].CN(C=O)C.[H-].[Na+].Cl[CH2:20][S:21][C:22]#[N:23]>O>[NH2:6][C:5]1[CH:7]=[C:8]([S:11][CH2:20][S:21][C:22]#[N:23])[CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: N#CSCCl
Reactant: Nc1cc(S)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CSCSc1ccc([N+](=O)[O-])c(N)c1
Reaction time: 0.5 h

Procedure:
A solution of 3.4 g. of 2-nitro-5-mercaptoaniline in 20 ml. of DMF is treated with 0.5 g. of 100% sodium hydride, and 2.2 g. of chloromethylthiocyanate is added to the solution. After 30 minutes at 20°-25° C., the solution is diluted with water and extracted with chloroform. Removal of the chloroform leaves 1-amino- 2-nitro-5-(thiocyanatomethylthio)benzene.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:32]([NH:33][C:34](=[O:36])[CH3:35])=[C:13]3[C:14](=[O:31])[N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>O1CCCC1>[CH3:44][S:45]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:32]([NH:33][C:34](=[O:36])[CH3:35])=[C:13]3[C:14](=[O:31])[N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[N:11]2)=[CH:8][CH:9]=1)(=[O:47])=[O:46]
Reactant: COc1ccc(Cn2c(=O)c3c(NC(C)=O)n(-c4ccc(CCO)cc4)nc3c3ccccc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)c3c(NC(C)=O)n(-c4ccc(CCOS(C)(=O)=O)cc4)nc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of N-{2-[4-(2-hydroxyethyl)phenyl]-5-(4-methoxybenzyl)-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-3-yl}acetamide (3.2 g) and triethylamine (1.85 ml) in tetrahydrofuran (400 ml) was added dropwise methanesulfonyl chloride (0.77 ml) at 0° C. The mixture was stirred at room temperature for 5 hours, triethylamine (0.46 ml) and methanesulfonyl chloride (0.19 ml) were added thereto, and stirred again for 3 hours. The mixture was concentrated under reduced pressure, and to the residue was added ethyl acetate, washed with an aqueous sodium hydrogen carbonate solution, water, saturated brine, dried and concentrated under reduced pressure to obtain the target compound (3.5 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[C:10]3[CH:17]=[CH:18][CH:19]=[N:20][C:9]=3[S:8][CH2:7][C:6]2=1.Cl.N1C=CC=CC=1>>[CH3:16][N:12]1[C:11]2[C:10]3[CH:17]=[CH:18][CH:19]=[N:20][C:9]=3[S:8][CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([OH:2])[CH:4]=2
Reactant: COc1ccc2c(c1)c1c(n2C)-c2cccnc2SC1
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c2c(c3cc(O)ccc31)CSc1ncccc1-2
Temperature: 180 °C

Procedure:
A mixture of 8-methoxy-11-methyl-6,11-dihydro-5-thia-4,11-diaza-benzo[a]fluorene (100 mg, 0.355 mmoL) and pyridine HCl salt (410 mg, 3.55 mmoL) was sealed in a tube and heated to 180° C. for 2 hours. The reaction mixture was cooled and the residue was partitioned between water and EtOAc. The EtOAc layer was washed with saturated NaHCO3, water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, hexanes:EtOAc 1:1 as eluent) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]1[C:24]([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[CH:23][N:22]=[CH:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([C:24]2[O:20][CH:21]=[N:22][CH:23]=2)=[CH:33][CH:32]=1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(Cl)c1ccc(-c2cnco2)cc1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-oxazol-5-yl-benzoyl chloride. MS: 431.3 (M+H).