Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[CH2:27]([O:34][C:35](=[O:48])[CH2:36][C@H:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35](=[O:48])[CH2:36][C@H:37]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38][I:20])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CI)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of polymer bound triphenyl phosphine (18.25 g, 54.76 mmol) in DCM (100 ml) is treated with iodine (12.2 g, 48.1 mmol) and the reaction mixture stirred at ambient temperature for 15 minutes. Imidazole (3.72 g, 54.7 mmol) is added and the reaction mixture stirred for a further 15 minutes. A solution of (S)-3-tert-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (6.76 g, 21.9 mmol) in DCM (100 ml) is added. The suspension is stirred at reflux for 1.5 hours, then filtered through Celite™ filter material, washing through with DCM. The combined organic phase is washed with an aqueous solution of 10% sodium thiosulphate, water and brine, then dried over magnesium sulphate and evaporated. The crude product is chromatographed over flash silica using 8% ethylacetate in iso-hexane as eluent to afford (S)-3-tert-butoxycarbonylamino-4-iodo-butyric acid benzyl ester. [M-BOC] 320.12
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:24][NH2:25].O>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:25][CH3:24])=[N:6][CH:7]=1
Reactant: CN
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(-c2cccc(NCc3cccc(F)c3)n2)c(Cl)cn1

Procedure:
A mixture of 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (Intermediate B) (15 mg, 0.045 mmol) was added DMSO (0.4 ml) and methyl amine 40% in water (200 μl, 2.293 mmol) in a microwave tube was microwaved at 145° C. for 900 seconds and the reaction progress was followed by LCMS. Most of the amine was removed under vacuum, 0.5 ml of DMSO was added, filtered and purified by prep LC. After lyapholization 13.9 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 343.0 (MH+), retention time=0.67 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 2.97 (s, 3H) 4.62 (s, 2H) 6.81 (d, J=8.50 Hz, 1H) 6.91-7.02 (m, 3H) 7.09 (d, J=9.96 Hz, 1H) 7.17 (d, J=7.62 Hz, 1H) 7.27-7.39 (m, 1H) 7.69 (dd, J=8.50, 7.33 Hz, 1H) 8.03 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][C@@H:18]3[C:23]#[CH:24])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N:37]=[N+:38]=[N-:39])(C)C.[ClH:40]>C1(C)C=CC=CC=1.CCOCC>[ClH:40].[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][C@H:18]3[C:23]2[NH:39][N:38]=[N:37][CH:24]=2)[CH:4]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:8]=1
Reactant: C#C[C@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@@H]3N[C@@]2(c2ccccc2)C[C@H]3c2cnn[nH]2)cc(C(F)(F)F)c1

Procedure:
(1R*,2R*,5S*,6R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-6-ethynyl-1-phenyl-8-azabicyclo[3.2.1]octane (Example 98; 136 mg, 0.3 mmol) and trimethylsilylazide (0.1 ml, 0.8 mmol) in toluene were heated in a sealed tube at 130° C. for 48 hours. The mixture was allowed to cool and quenched with methanol and water. The mixture was concentrated in vacuo, and the residue purified by flash column chromatography, eluting with 5% methanol/dichloromethane. The debenzylated product was treated with 1.0 eq HCl in ether and the title compound isolated as a white crystalline solid (20 mg, 13%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][NH2:20])=[CH:6]2.C(N(CC)CC)C.[C:28](Cl)(=[O:32])[CH2:29][CH2:30][CH3:31].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][NH:20][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])=[CH:6]2
Reactant: CCCC(=O)Cl
Reactant: COc1ccc2c(c1)C=C(CN)C(c1ccccc1)O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NCC1=Cc2cc(OC)ccc2OC1c1ccccc1

Procedure:
A solution of 0.45 g (1.7 mmol) of the amine obtained in Step C of Example 42 in 15 ml of anhydrous dichloromethane is cooled to 0° C.; 0.7 ml (5.1 mmol) of triethylamine and also 0.26 ml (2.55 mmol) of butyryl chloride are then added to the medium. Stirring is maintained for 30 minutes; the reaction mixture is then adjusted to an acid pH with a 1N hydrochloric acid solution. The aqueous phase is extracted with dichloromethane; the organic phase is then washed with a saturated solution of sodium hydrogen carbonate. The residue obtained after evaporation of the solvent in vacuo is passed over a silica column (eluant: AcOEt/PE: 60/40) to yield the title amide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:13]O)[CH2:9][N+:8]([O-:21])=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:6]=2[CH:29]=1.C=O.O.[C:33]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:33]=[N:13][C:12]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[C:10]3[CH2:9][N+:8]([O-:21])=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:6]=2[CH:29]=1
Reactant: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2NC(C(=NO)N2CCOCC2)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: O
Solvent: CCO
Product: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-n2cnc(N3CCOCC3)c2C1

Procedure:
A mixture of 3 g (7.1 mmole) of 7-chloro-5-(2-fluorophenyl)-2,3-dihydro-N-hydroxy-α-(4-morpholinyl)-1H-1,4-benzodiazepine-2-methanimine 4-oxide, 0.6 g (20 mmole) of paraformaldehyde, 100 ml of ethanol and 250 mg of paratoluene sulfonic acid hydrate was heated to reflux for 16 hours. The crude product obtained after the usual workup was chromatographed over 60 g of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The clean fractions of product were combined and evaporated. The residue was crystallized from ether and recrystallized from ethyl acetate/hexane for analysis to yield end product as yellow crystals with mp 200°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:21])[C:7]3[C:15](=[O:16])[N:14]([CH2:17][CH2:18][OH:19])[N:13]=[C:12]([OH:20])[C:8]=3[NH:9][C:10]=2[CH:11]=1.Br.[C:23](O)(=[O:25])[CH3:24]>O>[C:23]([O:19][CH2:18][CH2:17][N:14]1[C:15](=[O:16])[C:7]2[C:6](=[O:21])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:10]=3[NH:9][C:8]=2[C:12]([OH:20])=[N:13]1)(=[O:25])[CH3:24]
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCO)c(=O)c12
Reactant: CC(=O)O
Agent: Br
Solvent: O
Product: CC(=O)OCCn1nc(O)c2[nH]c3cc(Cl)ccc3c(=O)c2c1=O
Temperature: 25 °C
Yield: 86 %

Procedure:
An orange suspension of 7-chloro-4-hydroxy-2-(2-hydroxyethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (0.250 g, 0.81 mM) in a 30% solution of hydrobromic acid in glacial acetic acid (5 mL) was gently refluxed for 16 hours under nitrogen. The mixture was cooled to room temperature and diluted with water (20 mL) to form a precipitate. The collected solids were washed with water and methanol and then dried to give the title compound (0.242 g, 86%) as a tan solid, mp=307-309° C.; MS(CI): 350 (M+H).
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[F:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1B(O)O>>[F:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[NH:2][CH3:3]
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OB(O)c1ccncc1F
Product: CNc1cnccc1-c1ccncc1F

Procedure:
The title compound was prepared in analogy to example 69, intermediate, from (4-bromo-pyridin-3-yl)-methyl-amine (example 25, intermediate b) and 3-fluoropyridine-4-boronic acid (CAS RN 458532-97-3). Brown solid (92%). MS (ESI): m/z=204.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([OH:17])=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:23]3[CH2:24][CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC1CCCNC1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCC(C)C2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
A mixture of 2-(1, 2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (50 mg, 0.205 mmol), 3-methyl piperidine (19 mg, 0.205 mmol), DCC (46 mg, 0.22 mmol), and DMAP (27 mg, 0.22 mmol) in dry DCM (2.0 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator afforded 34.2 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(3-methylpiperidin-1-yl)ethanone as TFA Salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% Bin 30 min, injection vol. 5 mL).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:30])[CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH3:25])=[C:12]2[CH2:26][C:27]([NH2:29])=[O:28].O>CO>[NH2:29][C:27](=[O:28])[CH2:26][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([NH:8][CH2:7][CH2:6][C:5]([OH:30])=[O:4])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]=1[CH3:25]
Reactant: COC(=O)CCNc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(CC(N)=O)c2cc(NCCC(=O)O)ccc2n1Cc1ccccc1
Reaction time: 1 h
Yield: 19.2 %

Procedure:
One mL of 1N NaOH was added to a solution of 110 mg (0.3 mmol) of 3-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]amino]propanoic acid methyl ester (Example 26) in 5 mL of MeOH, stirred 1.0 hour, then 1 mL of 1N NaOH was added and the mixture stirred 0.5 hour. Water was added, then 2 mL of 1N HCl, and the mixture extracted with EtOAc. This was dried (MgSO4) and concentrated at reduced pressure to give 21 mg (20% yield) of 3-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]amino]propanoic acid.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[C:17]([CH3:19])[C:15]([NH2:16])=[C:14]([CH3:20])[CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:22][CH2:23][CH2:24][CH2:25]Br.C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:1]12([O:11][C:12]3[CH:13]=[C:14]([CH3:20])[C:15]([N:16]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[C:17]([CH3:19])[CH:18]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: BrCCCCBr
Reactant: Cc1cc(OC23CC4CC(CC(C4)C2)C3)cc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(OC23CC4CC(CC(C4)C2)C3)cc(C)c1N1CCCC1
Yield: 111.2 %

Procedure:
A mixture of 1.8 g (6.63 mmoles) of 4-(1-adamantyloxy)-2,6-dimethylaniline, 1.43 g (6.63 mmoles) of 1,4-dibromobutane, and 2.01 g (14.6 mmoles) of K2CO3 in 25 ml deaerated absolute ethanol is refluxed for forty-five hours, cooled, and evaporated. The residue is taken up in CH2Cl2 (125 ml) and water (125 ml). The CH2Cl2 layer is washed with water, and the combined aqueous layers are extracted with CH2Cl2 (50 ml.). The combined organic layers are dried and concentrated to give 2.4 g of a brown oil, which is chromatographed by HPLC on a 2.54 cm×109 cm column at 40 psi eluting with 0.5% acetone in CH2Cl2 and then 0.75% acetone in CH2Cl2 to give 0.45 g in the first liter eluted from the column. This solid in 1 ml of CH2Cl 2 and 5 ml of ether is treated with 3.5 N HCl in ether. The hydrochloride is filtered, washed with ether, and dried to give 0.38 g of white solid, m.p. 184.4-185.6 (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:21](=O)[CH:20](Br)[CH2:19][CH2:18][CH2:17][C:7]=2[N:8](C(OC(C)(C)C)=O)[CH:9]=1)=[O:4].Cl.[C:25]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)(=[NH:27])[NH2:26].C([O-])(O)=O.[Na+].CO>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:21]3[N:26]=[C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[NH:27][C:20]=3[CH2:19][CH2:18][CH2:17][C:7]=2[NH:8][CH:9]=1)=[O:4]
Reactant: N=C(N)c1ccncc1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1c[nH]c2c1-c1nc(-c3ccncc3)[nH]c1CCC2
Temperature: 25 °C
Yield: 53.2 %

Procedure:
To a solution of 4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole 1,3-dicarboxylic acid 3-methyl ester 1-tert-butyl ester(1.1 g, 3.6 mmol) in DMSO(20 mL) is added 1,3-dibromo-5,5-dimethylhydantoin(1.5 g, 5.4 mmol) portion wise with the aid of a cooling bath and the resulting mixture is stirred for 18 h at RT. Water is added and the reaction mixture is extracted with ether. The combined ether layers are washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (10% EtOAc/Hex to 25% EtOAc/Hex) to yield 915 mg of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a bright yellow oil (66%). 1H NMR (CDCl3) 1.59 (s, 9H), 1.72-1.84 (m, 1H), 2.12-2.25 (m, 2H), 2.43-2.58 (m, 1H), 3.05-3.14 (m, 1H), 3.40-3.49 (m, 1H), 3.80 (s, 3H), 4.75 (m, 1H), 7.79 (s, 1H) Step 2: A mixture of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester(467 mg, 1.2 mmol), 4-Amidinopyridine hydrochloride(953 mg, 6.1 mmol), and NaHCO3(813 mg, 9.7 mmol) in dioxane(20 mL) is refluxed for 20 h. After cooling to RT, MeOH(5 mL) is added and the mixture is filtered. The filtrate is concentrated in vacuo and the brown residue is purified by flash chromatography on silica gel (10% MeOH/CH2Cl2) to yield 197 mg of 2-Pyridin-4-yl-4,5,6,7-tetrahydro-3H-1,3,7-triaza-cyclopenta[e]azulene-9-carboxylic acid methyl ester as a yellow solid (53%). 1H NMR (CDCl3) 2.06 (quint, 2H), 2.98 (t, 2H), 3.04 (t, 2H), 3.91 (s, 1H), 7.46 (s, 1H), 7.76 (d, 2H), 8.28 (br s, 1H)8.56 (d, 2H)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[CH:15]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1)[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([CH2:28][CH:15](/[CH:14]=[CH:13]/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][CH2:2][O:45][C:42]2[CH:43]=[CH:44][C:39]([C:38]([F:37])([F:46])[F:47])=[CH:40][CH:41]=2)[CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCBr)Cc2ccc(C#N)cc2)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCOc2ccc(C(F)(F)F)cc2)Cc2ccc(C#N)cc2)cc1

Procedure:
A solution of 392 mg (0.72 mmol) of methyl 4-[(4E)-5-[2-(4-bromobutoxy)phenyl]-3-(4-cyanobenzyl)pent-4-en-1-yl]benzoate in 10 ml of dry acetonitrile is mixed with 174 mg (1.08 mmol) of 4-trifluoromethylphenol and 148 mg (1.08 mmol) of anhydrous potassium carbonate and then heated under reflux for 12 h. The mixture is subsequently filtered, and the filtrate is evaporated to dryness. 450 mg (0.61 mmol, purity 86%, 86% of theory) of a yellowish oil are isolated.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:33])[NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[CH:26]2)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][N:16]=[C:15]2[NH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[CH:26]2)=[O:33]
Reactant: Cc1cc2cc(Nc3ncnc4ccc(NC(=O)CCNC(=O)OC(C)(C)C)cc34)ccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2cc(Nc3ncnc4ccc(NC(=O)CCN)cc34)ccc2[nH]1
Yield: 85.2 %

Procedure:
150 mg of 2-[4-(2-methyl-1H-indol-5-ylamino)-quinazolin-6-ylcarbamoyl]-ethyl-carbamic acid t-butylester dissolved in 5 ml of methylene chloride was reacted with 5 ml of trifluoroacetic acid at room temperature for 4 hours. The residue obtained from distillation of the reacted solution under a reduced pressure was stirred in 50 ml of saturated aqueous sodium bicarbonate solution for 30 mins, filtered under a reduced pressure, and dried to obtain the title compound (100 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[C:16]1([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>C1C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:8][CH2:10][CH2:9][N:29]2[CH2:28][CH2:27][C:26]3([N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][NH:24][C:25]3=[O:32])[CH2:31][CH2:30]2)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(c1ccc(F)cc1[N+](=O)[O-])N1CC1
Solvent: c1ccccc1
Solvent: CO
Product: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 15 parts of 1-(4-fluoro-2-nitrobenzoyl)-aziridine, 12 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 8.8 parts of methanol and 56 parts of benzene is stirred first for 1.50 hours at reflux and further overnight at room temperature. The reaction mixture is evaporated. The residue is dissolved in trichloromethane and the solution is washed with water. Then there are added 8 parts of methanol and silica gel and the whole is stirred for 10 minutes. The silica gel is filtered off and the filtrate is evaporated. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and crystallized from 4-methyl-2-pentanone. It is filtered off and dried, yielding 13 parts of 4-fluoro-2-nitro-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro-[4,5]dec-8-yl)ethyl]benzamide; mp. 160° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([C:9]1[C:10](Cl)=[C:11]([CH:25]=[C:26]([F:29])[C:27]=1[Cl:28])[C:12]([C:14](=[CH:20][NH:21][CH:22]1[CH2:24][CH2:23]1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])#[N:8]>CN(C=O)C>[C:7]([C:9]1[C:27]([Cl:28])=[C:26]([F:29])[CH:25]=[C:11]2[C:10]=1[N:21]([CH:22]1[CH2:24][CH2:23]1)[CH:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:12]2=[O:13])#[N:8]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)c(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(Cl)c(F)cc2c1=O
Temperature: 42.5 °C
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
34.7 g of anhydrous K2CO3 (0.35 mol) was added to a solution of 64.2 g of ethyl 2-(3-cyano-2,4-dichloro-5-fluorobenzoyl)-3-cyclopropylaminoacrylate (0.173 mol) in 220 ml of DMF. The reacting mixture was stirred at 40-45° C. for 2.5 hours, and the reaction was monitored by TLC. The reactant was then poured into 800 ml of ice-water, filtered, washed with water (100 ml×2), and dried. The resultant solid was dissolved in 120 ml of 95% ethanol and then refluxed for 15 minutes, cooled, filtered and dried to afford 53.2 g of ethyl 8-cyano-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.159 mol) as a white solid, mp 196-199° C., in 90.1% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].I[CH2:13][CH3:14]>>[CH2:13]([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)[CH3:14]
Reactant: CCI
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Product: CCOC[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (1.5 g), in dimethylfomylamide (30 mL), 60% sodium hydride (0.50 g) was added portion-wise at 0° C. then warmed to ambient temperature. Iodoethane (3.5 mL) was added to the mixture at 0° C. then stirred for 16 h at room temperature. The reaction mixture was filtered then the filtrate was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O (×2) then brine and dried (MgSO4), filtered and evaporated. Purification was by column chromatography on silica gel using EtOAdEt2O (1:1) as eluent to give the subtitle compound as clear, colourless oil. Yield: 1 g
Reaction SMILES: [NH2:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[CH2:23]([O:25][C:26](Cl)=[O:27])[CH3:24]>N1C=CC=CC=1>[CH2:23]([O:25][C:26]([NH:1][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22])=[O:27])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: C[C@]12CCC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: c1ccncc1
Product: CCOC(=O)NC1=C2C=C[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CCC1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3.0 g of 4-aminoandrosta-4,6-dien-3,17-dione in 15 ml of dry pyridine, cooled to 0° to -5° C., 1.25 ml of ethylchlorocarbonate are added dropwise. The mixture is cooled and stirred for 30 minutes and then, after the temperature is left to rise to 20° C., it is quenched in 100 ml of water. The mixture is extracted several times with ethyl acetate, washed with aqueous sodium chloride solution until neutral and dried. The solvent is then distilled in vacuo to obtaind 3.2 g of crude which is purified by crystallization with warm ethyl acetate to yield 2.95 g of pure title compound,
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]2[N:16]([CH:17]=1)[C:15]([CH2:18]O)=[CH:14][S:13]2)([O-:3])=[O:2].S(Cl)([Cl:22])=O>ClCCl.CN(C=O)C>[Cl:22][CH2:18][C:15]1[N:16]2[CH:17]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[N:11]=[C:12]2[S:13][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1-c1cn2c(CO)csc2n1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1-c1cn2c(CCl)csc2n1
Reaction time: 0.08 h

Procedure:
To a stirred solution of [6-(2-Nitro-phenyl)-imidazo[2,1-b]thiazol-3-yl]-methanol (1.0 g, 3.63 mmol) in anhydrous dichloromethane (15 ml) was slowly added thionyl chloride (2 ml, 7.5 eq). The solution turned homogenous, followed by development of a yellow precipitate. After 5 minutes, a catalytic amount of DMF (1 drop) was added and the mixture was stirred for 1 hour, concentrated to dryness, chased with CH2Cl2 (2×) then Ether (1×), and dried under reduced pressure. 1.53 g of yellow solid was obtained, and assumed to be quantitative yield. (MS, M++H=294.0)