Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.O>CN(C)C=O>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: BrCCCCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2ccc(OCCCCCCBr)cc2)cc1
Yield: 54 %

Procedure:
40 g of 4-(4-hydroxyphenyl)benzonitrile, 42 g of potassium carbonate, and 250 g of 1,6-dibromohexane were mixed. The resultant mixture was then caused to react in dimethylformamide at 100° C. for 5 hours. After cooled, the resultant was poured into 1 L of water and extracted with chloroform. The resultant was purified by silica gel column chromatography, and then recrystallized from chloroform/hexane, to give the target compound (yielded amount 39 g, and yield 54%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15](#[N:18])[CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([Cl:8])=[CH:7][C:2]=1[O:17][CH2:16][C:15]#[N:18])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: N#CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 58.5 %

Procedure:
A solution of 1,5-dichloro-2,4-dinitrobenzene (5.0 g), glycolonitrile (1.81 g) and anhydrous potassium carbonate (2.19 g) in dimethylformamide (20 g) was stirred at 25° to 30° C. for 24 hours. After completion of the reaction, the reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml). The organic layer was washed with water, dried over magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and washed with ether to give crude crystals (4.16 g), which were recrystallized from methanol to give 2,4-dinitro-5-chlorophenoxyacetonitrile (3.18 g; yield, 58.5%). M.P., 117°-118° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[NH2:11][C:5]1[C:6]([C:8]([NH2:10])=[O:9])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(Cl)ccc1N

Procedure:
A solution of 6-chloro-3-nitropicolinamide (0.30 g, 1.49 mmol) in EtOAc (30 mL) is hydrogenated at 60 psi over 5% Pd-C (0.10 g) for 20 min. After removal of the catalyst by filtration the solution is concentrated to dryness to give 3-amino-6-chloropicolinamide as a yellow oil, which is used directly in the next step. It is dissolved in triethylorthoformate (30 mL) and the mixture is heated under reflux for 18 h. Petroleum ether (30 mL) is added to the cooled solution, and the resulting precipitate of crude 6-chloro-3H-pyrido[3,2-d)pyrimidin-4-one (0.27 g, 99%) is filtered off and dried in a vacuum oven.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35]OS(C)(=O)=O)=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].Cl.[CH3:42][NH:43][CH3:44].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:42][N:43]([CH2:35][C:3]1[C:2]([F:1])=[C:26]([NH:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:32])[CH3:31])[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]=1[F:34])[CH3:44]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(COS(C)(=O)=O)c(F)c3o2)cc1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)Cc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
800 mg (1.37 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methanesulfonyloxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 120 (1) was dissolved in 10 mL of dimethylformamide, 558 mg (6.85 mmol) of dimethylamine hydrochloride and 945 mg (6.85 mmol) of potassium carbonate were added and the mixture was stirred at room temperature for 45 minutes. Water was added to the reaction solution and the mixture was extracted once 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 sodium sulfate, and the solvent was distilled off under reduced pressure to give 727 mg of 7-dimethylaminomethyl-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 100%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH:14]([CH3:16])[CH3:15])[CH2:3]1.[CH3:17][Mg]Br>C1COCC1>[OH:1][C:2]1([CH3:17])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[C@H:4]([CH:14]([CH3:16])[CH3:15])[CH2:3]1
Reactant: C[Mg]Br
Reactant: CC(C)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC(C)(O)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2S)-4-oxo-2-(propan-2-yl)pyrrolidine-1-carboxylate (500 mg, 2.2 mmol) in THF (10 mL) at −78° C. was added methylmagnesium bromide (1.65 mL, 4.95 mmol) dropwise. The reaction was stirred at −78° C. for 2 hours before warming to room temperature and stirring for an additional 2 hours. The reaction was quenched by slowly adding saturated aqueous ammonium chloride at 0° C. The mixture was acidified with HCl (1N) and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-80% ethylacete/hexanes, linear gradient) to afford tert-butyl (2S)-4-hydroxy-4-methyl-2-(propan-2-yl)pyrrolidine-1-carboxylate.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[Cl:15][C:16]1[C:22]([Cl:23])=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1>C(O)C>[Cl:15][C:16]1[C:22]([Cl:23])=[CH:21][C:19]([NH:20][C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: O=C(Cc1ccccc1)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of phenylacetic acid (10 mmol) in SOCl2 (4 ml, apr. 50 mmol) was stirred for 16 h at room temperature, then evaporated and kept at 2 mm Hg for 0.5 h to remove residual SOCl2. A suspension of 4,5-dichloro-2-nitroaniline (1.035 g, 5 mmol) in ethanol-free CHCl3 (10 mL) was added to the residue and the mixture was stirred at 50° C. for 4 h. It was then cooled to room temperature and evaporated. The residue was treated with ether (100 mL). Precipitated crude product was filtered, washed with ether (5×20 mL) and dried on air to give the title compound. Yield 90%; mp 116°-118° C. (from EtOH); (Lit., 118° C., Ahmad, Yu., et al., Tetrahedron 21:861 (1965)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=1>CO.C1COCC1.[Ni]>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Br)cc23)cc1

Procedure:
24 g (58.4 mmol) of 2-[4-(6-bromo-3-nitro-quinolin-4-ylamino)-phenyl]-2-methyl-propionitrile (Example 1e) is shacked in 300 ml of MeOH-THF (1:1) under 1.1 bar of H2 in the presence of 8.35 g of Raney-Ni for 1 h. After completion of the reaction, the catalyst is filtered off and the filtrate is evaporated to dryness to give the title compound as a yellow foam. ES-MS: 381, 383 (M+H)+, Br pattern; analytical HPLC: tret=3.21 min (Grad 1).
Reaction SMILES: [Cl:1][CH2:2]C1C(C)=CC2OCOC=2C=1.[CH3:13][O:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=1[CH3:23]>>[CH3:13][O:14][C:15]1[C:16]([CH3:23])=[C:17]([C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])[CH2:2][Cl:1]
Reactant: Cc1cc2c(cc1CCl)OCO2
Reactant: COc1c(C)cc(C)cc1C
Product: COc1c(C)cc(C)c(CCl)c1C

Procedure:
3-Methoxy-2,4,6-trimethylbenzyl chloride was synthesized in the same fashion as for 5-chloromethyl-6-methylbenzo[d][1,3]dioxole (Example 7) except that 1-methoxy-2,4,6-trimethylbenzene was used instead of 5-methylbenzo[d][1,3]dioxole.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]([CH3:21])([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=O)[C:7]([NH2:9])=[O:8])([CH3:5])[CH3:4]>>[CH:3]([C:6]1([CH3:21])[N:10]2[C:18](=[O:19])[C:17]3[C:12]([C:11]2=[N:9][C:7]1=[O:8])=[CH:13][CH:14]=[CH:15][CH:16]=3)([CH3:5])[CH3:4]
Reactant: CC(C)C(C)(C(N)=O)N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21

Procedure:
Following the procedure described in Example 1 and sodium hydride as the base, but substituting (-)-α-isopropyl-α-methyl-1,3-dioxo-2-isoindolineacetamide for the racemic compound, the product (+)-3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2(3H),5-dione is obtained, melting point 137.5-139° C, [α]D25 +64.54 (THF, C 0.097).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16](=[O:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:31])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29]I)([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:19]([O:23][C:24](=[O:31])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[C:16](=[O:18])[CH3:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCCCCI
Reactant: CC(=O)c1c(O)cccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2-benzyloxy-6-hydroxyphenyl)-ethanone (100 mg, 0.41 mmol) and (4-iodobutyl)-carbamic acid tert-butyl ester (Example 123, step A) (150 mg, 0.5 mmol) in DMF (5 mL) is added K2CO3 (113 mg, 0.82 mmol) and the mixture is stirred at RT for 18 h. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (10:1) as eluent to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:33]=[N:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: COc1cncc(B(O)O)c1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: COc1cncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 5-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 64. LC-MS Method 2 tR=1.694 min, m/z=465.2; 1H NMR (CDCl3) 1.34 (m, 1H), 1.53 (m, 3H), 1.68 (m, 1H), 1.94 (m, 3H), 2.18-2.32 (m, 3H), 2.95 (m, 1H), 3.56 (m, 2H), 3.88 (s, 3H), 5.69 (m, 1H), 7.01 (m, 4H), 7.24 (m, 3H), 7.31 (m, 2H), 8.25 (m, 1H), 8.34 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 1.8 mmol of benzoyl chloride in 3 ml of DMF were added. The reaction solution was then stirred at RT for a further 20 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:17][CH2:16][C:15]4[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=4[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[C:22](=[N:28][Si](C)(C)C)=[N:23][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:17][CH2:16][C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[CH2:13][CH2:12]1)/[C:8]/2=[N:28]/[C:22]#[N:23]
Reactant: O=C1c2cc(Br)ccc2CC12CCc1ccccc1CC2
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\c2cc(Br)ccc2CC12CCc1ccccc1CC2
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
To a solution of 6′-bromo-5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-inden]-1′(3′H)-one (20 mg, 0.059 mmol) in DCM (2 mL) was added TiCl4 (44.7 mg, 0.235 mmol) dropwise, the mixture was stirred at 50° C. at Ar2 under microwave for 20 minutes, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (43.8 mg, 0.235 mmol) was added dropwise. The mixture was stirred at 60° C. at Ar2 under microwave for 10 minutes and repeated the same operation for one time and then poured into ice-water (10 mL). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude (Z)—N-(5′-bromo-5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-indene]-3′(1′H)-ylidene)cyanamide (20 mg, 4%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9](C(OC(C)(C)C)=O)[C:10]2[C:15]([C:16]=1[CH:17]([CH:19]1[C:23](=[O:24])[N:22]([C:25](OC(C)(C)C)=O)N(C3C4CC5CC(CC3C5)C4)[CH2:20]1)O)=[C:14]([Cl:42])[CH:13]=[C:12]([Cl:43])[CH:11]=2)=[O:7])(C)(C)C.Cl>C(O)C>[Cl:42][C:14]1[CH:13]=[C:12]([Cl:43])[CH:11]=[C:10]2[C:15]=1[C:16](/[CH:17]=[C:19]1/[C:23](=[O:24])[N:22]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:25][CH2:20]/1)=[C:8]([C:6]([O:5][CH3:1])=[O:7])[NH:9]2
Reactant: CC(C)(C)OC(=O)c1c(C(O)C2CN(C3C4CC5CC(C4)CC3C5)N(C(=O)OC(C)(C)C)C2=O)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: COC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1/C=C1\CCN(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 215.8 %

Procedure:
Intermediate 4 (700 mg) was suspended in ethanol (95%) (10 ml), hydrochloric acid (10 ml, 6 M) was added and the heterogeneous mixture refluxed for 10 h. The suspension was cooled to room temperature and the solid filtered, washed with further portions of 6 M hydrochloric acid and finally vacuum dried to yield the title compound (427 mg) as a white solid
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([CH3:12])[CH:5]=1.CS(O[CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)(=O)=O.O>CN(C=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([O:3][CH:18]2[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21]2)=[CH:5][C:6]=1[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Cc1cc(O)ccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1C=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A slurry of sodium hydride (60%, 0.12 g, 3.10 mmol) in DMF (4 ml) was cooled by an ice-bath. Under nitrogen, 4-hydroxy-2-methylbenzaldehyde in DMF (2 ml) was added. The mixture was stirred for 30 min and then tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate in DMF (4 ml) was added. The mixture was heated to 100° C. using an oil bath for 3 days and then cooled to RT. Water (100 ml) was added while stirring. The mixture was extracted trice with EtOAc. The combined organic solutions were dried (MgSO4) and then evaporated. The residue was purified by silica gel chromatography eluting with EtOAc/heptane (10:90). There was obtained 120 mg (20%) of partly purified 69A as an oil. 1H NMR (500 MHz, CDCl3): δ 1.46 (s, 9H), 2.64 (s, 3H), 4.01 (m, 2H), 4.33 (m, 2H), 4.94 (m, 1H), 6.60 (d, 1H), 6.66 (dd, 1H), 7.76 (d, 1H), 10.13 (s, 1H).
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].C(N1CCOCC1)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:3]
Reactant: CCOC(=O)Cl
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Agent: Br
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
2 g (0.0066 mol) of L-alanyl-L-proline ethylamide hydrobromide were suspended in 20 ml of dry tetrahydrofuran, 1.84 ml (0.0145 mol) of N-ethylmorpholine and 0.76 ml (0.0079 mol) of ethyl chloroformate were added and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated off and the residue dissolved in 100 ml of chloroform and washed successively with 2-N hydrochloric acid in brine, brine, saturated sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to an oil which soon crystallised. Recrystallisation from chloroform/petrol yielded 0.88 g (47%) of N-ethoxycarbonyl-L-alanyl-L-proline ethylamide of melting point 126°-128° C.; [α]D20 =-117.6° (c=1.02% in methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH:15]=O)[C:7]=2[N:17]=1.C([O-])(=O)C.[NH4+].[N+:23]([CH3:26])([O-:25])=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([CH:15]=[CH:26][N+:23]([O-:25])=[O:24])[C:7]=2[N:17]=1
Reactant: COc1ccc2c(n1)c(C=O)c1n2CCCC1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc2c(n1)c(C=C[N+](=O)[O-])c1n2CCCC1

Procedure:
550 mg (2.39 mmol) of the compound obtained in Step C dissolved in 25 ml of nitromethane are heated at 120° C. for 3 hours in the presence of 460 mg (5.97 mmol) of ammonium acetate. After returning to room temperature and evaporation to dryness, the reaction mixture is diluted in dichloromethane and washed with water. The organic phase is dried over magnesium sulphate, filtered and evaporated. After washing with a pentane/diethyl ether mixture, the title compound is obtained in the form of a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][OH:14])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][O:14][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)C(=N)NO
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A solution of {1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (2) (2.5 g, 10 mmol) in dichloromethane (125 ml) was treated with benzoic acid (1.36 g, 11 mmol), EDCI (2.14 g, 11 mmol), HOBT (1.37 g, 10 mmol) and triethylamine (1.35 ml, 11 mmol) and stirred at room temperature overnight. Reaction mixture was washed with saturated sodium bicarbonate solution and then water and dried over Na2SO4. Solvent evaporated under reduced pressure, crude purified by mplc eluting with 1% triethylamine in 2:3 v/v ethyl acetate and heptane mixture to give yellow solid (850 mg); MS: MH+ 352.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:30][CH2:31][C:32]2[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=2)=[CH:4][C:5]2[N:6]([CH:29]=1)[C:7](=[O:28])[C:8](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13](C=O)[CH2:12]1)[N:10]=2.C[O-:41].[Na+].O>CO>[F:1][C:2]1[C:3]([CH2:30][CH2:31][C:32]2[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=2)=[CH:4][C:5]2[N:6]([CH:29]=1)[C:7](=[O:28])[C:8](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:41])[CH2:12]1)[N:10]=2
Reactant: CC(C)c1csc(CCc2cc3nc(N4CCCC(C=O)C4)c(/C=C/C(=O)OC(C)(C)C)c(=O)n3cc2F)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)c1csc(CCc2cc3nc(N4CCCC(O)C4)c(/C=C/C(=O)OC(C)(C)C)c(=O)n3cc2F)n1
Temperature: 25 °C
Reaction time: 9 h
Yield: 65.4 %

Procedure:
The tert-butyl (E)-3-{7-fluoro-2-(3-formylpiperidino)-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (147 mg, 0.258 mmol) obtained in (L) was dissolved in methanol (3ml), added with sodium methoxide (33.6 mg, 0.618 mmol), and then stirred at room temperature for 9 hours. The reaction mixture was added with distilled water and extracted with chloroform (twice). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by preparative TLC (chloroform:methanol=100:5) to obtain the title compound (91.6 mg, 65%).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)C(C)C)(C)C>C1COCC1>[C:33]([N:30]1[CH2:31][CH2:32][CH:27]([C:19]2[N:20]3[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]3)=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:34]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 41.7 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (150 mg, 0.33 mmol) in THF (1.88 mL) was added acetyl chloride (26 μL, 0.36 mmol) and N,N-diisopropylethylamine (170 μL, 0.98 mmol). The reaction was stirred at rt for 17 h. The mixture was partitioned between EtOAc (25 mL) and H2O (25 mL). The layers were separated and the organic phase was washed with H2O (20 mL), brine, dried (Na2SO4) and concentrated. The crude material was purified by ISCO® chromatography using a gradient of 0 to 10% MeOH in EtOAc. The isolated compound was crystallized from EtOAc/hexanes to afford 64 mg (42%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.28-7.38 (m, 5 H), 7.13 (dd, 1 H), 6.59 (s, 1 H), 5.64 (s, 2 H), 4.48 (d, 1 H) 3.89 (s, 1 H), 3.32-3.41 (m, 3 H), 3.19 (s, 1 H), 2.67 (d, 1 H), 1.98-2.07 (m, 3 H), 1.66 (d, 1 H), 1.51 (s, 1 H); ES-MS m/z 466.4 [M+H]+, HPLC RT (min) 2.49.