Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:22][C:21](=O)[O:20][C:18](=[O:19])[CH2:17]2)=[CH:12][CH:11]=1>>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:21]1[CH2:22][CH:16]([C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=1)[CH2:17][C:18]([OH:20])=[O:19]
Reactant: Nc1ccccc1S
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Product: O=C(O)CC(Cc1nc2ccccc2s1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.55, starting from 2-aminothiophenol and 3-(4-chlorophenyl)glutaric anhydride, 4-(2-benzothiazolyl)-3-(4-chlorophenyl)-butanoic acid was obtained as colourless solid.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:2].[ClH:16].[CH2:17]([OH:19])[CH3:18]>C(Cl)(Cl)Cl>[ClH:16].[CH2:17]([O:19][C:1](=[NH:2])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=1)[CH3:18]
Reactant: CS(=O)(=O)Nc1cccc(OCC#N)c1
Reactant: CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)COc1cccc(NS(C)(=O)=O)c1
Reaction time: 16 h

Procedure:
N-(3-Cyanomethoxyphenyl)-methanesulfonamide (1.0 g) was dissolved in a mixture of 20 ml of chloroform and 0.25 ml of absolute ethanol (EtOH). The reaction mixture was cooled in an ice bath and saturated with hydrogen chloride gas. The mixture was slowly allowed to come to room temperature and stirred for 16 hours. The solvent was evaporated leaving 1.1 g of 2-(3-methanesulfonylaminophenoxy)-acetimidic acid ethyl ester hydrochloride. ##STR67##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N:11]1([CH:16]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH:17]([CH3:19])[CH3:18])[CH:15]=[CH:14][N:13]=[CH:12]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH:16]([N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)[CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)C(c1ccc(N)cc1)n1ccnc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(C)C(c1ccc(NC(=O)Nc2ccc(F)cc2)cc1)n1ccnc1
Yield: 32.4 %

Procedure:
4-Fluorophenylisocyanate (0.017 mol) was added to a solution of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.014 mol) in dry THF (100 ml) and the mixture was stirred and refluxed for 2 hours. The mixture was cooled, the precipitate was filtered off and recrystallized from 2-propanone and CH3OH, yielding 1.6 g (32%) (±)-N-(4-fluorophenyl)-N′-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]urea (compound 740).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1.[OH-:37].[K+].O>C(O)C>[NH2:1][C:2]1[C:7]([C:8](=[O:37])[NH2:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:3]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C#N)C1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C(N)=O)C1
Temperature: 70 °C
Reaction time: 60 h
Yield: 73 %

Procedure:
To a stirred suspension of tert-butyl 3-{2-amino-6-[2-(benzyloxy)phenyl]-3-cyano-4-pyridinyl}-1-piperidinecarboxylate (0.300 g, 0.619 mmol), which was obtained in the step (1) of Example 1-1, in ethanol (10 mL) was added a solution of potassium hydroxide (0.695 g, 12.381 mmol) in ethanol (20 mL). The reaction mixture was stirred at 70° C. for 60 hrs. After cooled to room temperature, the reaction mixture was poured into water and the resulting solid was filtrated and dried under reduced pressure to give tert-butyl 3-{2-amino-6-[2-(benzyloxy)phenyl]-3-carbamoyl-4-pyridinyl}-1-piperidinecarboxylat as a white amorphous. (0.226 g, yield; 73%).
Reaction SMILES: I[CH2:2][CH2:3][C@H:4]([O:11][C:12]1[C:20]2[S:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:23][NH2:24].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>O1CCCC1.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[S:19]1[C:20]2[C:12]([O:11][C@H:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][CH2:2][NH:24][CH3:23])=[CH:13][CH:14]=[CH:15][C:16]=2[CH:17]=[C:18]1[C:21]#[N:22]
Reactant: N#Cc1cc2cccc(O[C@@H](CCI)c3ccccc3)c2s1
Reactant: CN
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CNCC[C@H](Oc1cccc2cc(C#N)sc12)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of 7-{[(1S)-3-iodo-1-phenylpropyl]oxy}-1-benzothiophene-2-carbonitrile (222 mg, 0.5 mmol) in tetrahydrofuran (2 mL) was added 40% aqueous methylamine (0.83 mL) and the solution was stirred at room temperature for 16 hours. The solvent removed in vacuo and the residue purified by flash chromatography with a gradient of 0–15% methanol in dichloromethane. To a solution of free base (155 mg, 0.48 mmol) in methanol (1 mL) and added a warm solution of fumaric acid (40 mg, 0.48 mmol) in methanol (1 mL). The solvent removed in vacuo, and the solid residue triturated with diethyl ether (5 mL), then dried in a vacuum oven at 40° C. for 1 h to give the title compound (0.20 g, 85%); δH (300 MHz, DMSO) 8.40 (1H, s, 3-ArH), 7.61–7.52 (1H, m, ArH), 7.49–7.23 (6H, m, ArH), 7.05–6.98 (1H, m, ArH), 6.43 (2H, s, CHCO2H), 5.85–5.75 (1H, m, CHO), 3.05–2.90 (2H, m, 1-CH2), 2.52 (3H, s, NHCH3) and 2.46–2.07 (2H, m, 2-CH2).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:16]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:16]([N:19]1[CH2:24][CH2:23][CH:22]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:21][CH2:20]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCC(O)CC1
Reactant: O=C1NCCn2c1cc1cc(O)ccc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 205.2 %

Procedure:
To the suspension of 1.0 g (4.9 mmol) 8-hydroxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one in 70 ml tetrahydrofuran, a solution of 0.92 g (0.64 mmol) 1-isopropyl-piperidin-4-ol (commercially available) in 25 mL tetrahydrofuran, and 2.4 mL (2.0 g, 9.9 mmol) tributylphosphine were added. Another 20 mL tetrahydrofuran was added, and then the suspension was cooled to 0° C. Within 60 min., 2.5 g (9.9 mmol) 1,1′-(azodicarbonyl)dipiperidine was added under stirring and the reaction was allowed to reach room temperature. After 16 hours the suspension was filtered and the filtrate was evaporated. The residue was flash-chromatographed two times on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) to give 0.43 g (26%) of the product as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[NH:14][C:13]2=O)=[C:4]([F:24])[CH:3]=1.P(Cl)(Cl)([Cl:27])=O>N1C=CC=CC=1>[Cl:27][C:13]1[N:12]([C:5]2[CH:6]=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=2[F:24])[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=1
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with phosphorus oxychloride and pyridine within 20 minutes at 30°-35° C. and thereafter for 1 hour at 70° C. there is obtained 2-chloro-1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 101°-103° C.;
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[OH:25])[CH:20]=[O:21])[CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8])[CH:20]=[O:21])[CH3:15]
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (30.0 g), 3-ethoxy-4-hydroxybenzaldehyde (22.9 g), potassium carbonate (21.01 g) and N,N-dimethylformamide (300 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-ethoxy-4-[[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy]benzaldehyde as brown crystals (31.20 g, yield 69%). Recrystallization from ethyl acetate-hexane gave pale-yellow needle. melting point: 159-160° C.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[NH2:21][C@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1>>[N:24]12[CH2:23][C@@H:22]([NH:21][C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:9]4[O:8][C:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[N:11][C:10]=34)=[O:18])[CH:27]([CH2:28][CH2:29]1)[CH2:26][CH2:25]2
Reactant: O=C(O)c1cccc2oc(N3CCCCC3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(N3CCCCC3)nc12

Procedure:
Following general procedure GP-C1, a mixture of 2-(piperidin-1-yl)benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-(piperidin-1-yl)benzoxazole-4-carboxamide which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:10]([C:12]1[C:13](=[O:26])[N:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:19])[N:16]([CH3:18])[N:17]=1)=[O:11].C(N(CC)CC)C.[CH2:34]([S:37](Cl)(=[O:39])=[O:38])[CH2:35][CH3:36]>ClCCl>[CH2:34]([S:37]([O:1][C:2]1[N:6]([CH:7]([CH3:8])[CH3:9])[N:5]=[CH:4][C:3]=1[C:10]([C:12]1[C:13](=[O:26])[N:14]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15](=[O:19])[N:16]([CH3:18])[N:17]=1)=[O:11])(=[O:39])=[O:38])[CH2:35][CH3:36]
Reactant: CC(C)n1ncc(C(=O)c2nn(C)c(=O)n(-c3ccccc3)c2=O)c1O
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)Oc1c(C(=O)c2nn(C)c(=O)n(-c3ccccc3)c2=O)cnn1C(C)C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
0.85 g (2.60 mmol) of 6-(5-hydroxy-1-isopropyl-1H-pyrazol-4-yl carbonyl)-2-methyl-4-phenyl-1,2,4-triazine-3,5 (2H, 4H)-dione was dissolved in 20 ml of dichloromethane. To the solution, 0.27 g (2.60 mmol) of triethylamine and 0.37 g (2.60 mmol) of 1-propane sulfonyl chloride were added at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residues were purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 0.71 g of the target compound (yield 63%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:11][C:12](=[CH2:15])[CH2:13]Cl>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:13][C:12]([CH3:15])=[CH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=C(C)CCl
Reactant: CC(=O)N1CCC(O)CC1
Product: C=C(C)COC1CCN(C(C)=O)CC1

Procedure:
This compound was prepared similarly to Example E, starting from N-acetyl-4-hydroxypiperidine and 2-methylallyl chloride, and was distilled and used directly in the next stage. It had a b.p. of 128° C. @ 1 mm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Br-].[CH2:12]([Zn+])[CH:13]([CH3:15])[CH3:14]>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:12]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Brc1ccc2occc2c1
Reactant: CC(C)C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1ccc2occc2c1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
5-bromobenzofuran (500 mg, 2.56 mmol) was dissolved in THF solution of isobutylzinc(II)bromide (0.5M, 15 mL, 7.40 mmol) in a microwave reaction tube. Pd(PtBu3)2 (65 mg, 0.128 mmol, 0.05 eqv.) was added to this solution. The mixture was purged with N2 gas for 3-5 min and heated at 100° C. for 30 min under microwave irradiation. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with 1N HCl aqueous solution, brine, filtered through Celite. The filtrate was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (ISCO system, 5% EtOAc in hexanes) to give 0.331 g desired product (74% yield): 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.35 (d, 1H), 7.07 (d, 1H), 6.70(s, 1H), 2.59 (d, 2H), 1.9 (m, 1H), 0.9 (d, 6H).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[C:3]1([CH3:26])[CH3:25].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:25][C:3]1([CH3:26])[CH2:2][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]1[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1ccc([N+](=O)[O-])cc1)N2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc([N+](=O)[O-])cc1)N2
Yield: 81.6 %

Procedure:
To a solution of methyl 4-hydroxy-3,3-dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (61 mg 0.18 mmol) and triethylsilane (0.06 mL, 0.34 mmol) in dichloromethane (10 mL) was added dropwise a solution of trifluoroacetic acid (0.04 mL, 0.51 mol) in dichloromethane (5 mL) below 0° C. Upon completion of addition, the resultant mixture was stirred at room temperature for 24 h, then was quenched with sodium bicarbonate solution and separated. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to afford 50 mg of methyl 3,3-dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid Yield: 78%. Methyl-3,3-dimethyl-2-(4-nitrophenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (110 mg, 0.32 mmol) was dissolved in methanol/water Solution, iron powder (25 mg, 3.2 mmol) was added. The reaction mixture was heated to reflux for 2 hrs The mixture was filtered, the filtration was concentrated and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=4:1) to afford 95 mg of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a yellow solid. (yield: 96%). MS (ESI+APCI) M+1=311.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:34]=1[C:35](Cl)=[O:36]>CC#N>[C:1]([O:5][C:6]([CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:35](=[O:36])[C:34]3[C:33]([Cl:32])=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:42])=[CH:19][CH:20]=2)[CH2:10]1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(O)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(OC(=O)c3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.6 %

Procedure:
To a solution of 3-[2-(4-hydroxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (0.39 g; 1.27 mmol) and N-ethyldiisopropylamine (0.65 mL, 3.81 mmol) in CH3CN (5 mL) was added 2,6-dichlorobenzoyl chloride (0.44 ml; 3.0 mmol), at 0° C. Subsequently, the mixture was allowed to warm to RT and was stirred for 2 days at room temperature. The resulting mixture was partitioned between Et2O and 5% aqueous NaHCO3 solution. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O to afford 2,6-dichloro-benzoic acid 4-[4-(2-tert-butoxycarbonyl-ethyl)-morpholin-2-yl]-phenyl ester (0.51 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15])[CH3:11].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:14]([CH3:16])([CH3:15])[C:13]([O:12][CH2:10][CH3:11])=[O:18]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1Br
Temperature: 120 °C

Procedure:
A mixture of 2-bromo-4-chlorophenol (250 mg; 1.21 mmol) and ethyl-2-bromoisobutyrate (450 μl; 3.0 mmol) in DMF (5 mL) was treated with K2CO3 (250 mg, 1.81 mmol) and heated at 120° C. for 4.5 hours. Water was added and the reaction mixture was extracted 3 times with EtOAc. The combined organic phases were dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica), eluting with heptane containing increasing amounts of EtOAc. The title compound was obtained as a yellow sticky solid (320 mg; 83%).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:14][CH2:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([C:24]2[NH:33][C:32](=[O:34])[C:31]3[C:26](=[CH:27][C:28]([O:37][CH3:38])=[CH:29][C:30]=3[O:35][CH3:36])[N:25]=2)=[CH:19][C:18]=1[CH3:39].O>CN(C)C=O>[CH3:36][O:35][C:30]1[CH:29]=[C:28]([O:37][CH3:38])[CH:27]=[C:26]2[C:31]=1[C:32](=[O:34])[NH:33][C:24]([C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([O:16][CH2:15][CH2:14][N:6]3[C:7](=[O:9])[CH2:8][N:4]([CH:1]([CH3:3])[CH3:2])[C:5]3=[O:10])=[C:18]([CH3:39])[CH:19]=1)=[N:25]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Reactant: CC(C)N1CC(=O)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4C(=O)CN(C(C)C)C4=O)c(C)c3)nc2c1
Reaction time: 0.17 h

Procedure:
To a solution of 1-isopropyl-imidazolidine-2,4-dione (0.10 g, 0.70 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in mineral oil, 31 mg, 0.77 mmol) and the reaction mixture was stirred for 10 minutes. Then, 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.32 g, 0.73 mmol) was added. The reaction mixture was stirred at 55° C. for 16 hours, then poured into water (100 mL). The solid was filtered and dried. The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with 2:1 ethyl acetate and dichloromethane) to give the title compound as a white solid. Yield: 0.09 g (26.0%). MP 219-221° C. 1H NMR (400 MHz, DMSO): δ 9.64 (s, 1H), 7.69 (s, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 4.42 (m, 1H), 4.02 (m, 2H), 3.98 (m, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.85 (s, 2H), 2.32 (s, 6H) 1.22 (d, J=6.4 Hz, 6H). MS (ES+) m/z: 495.16 (M+1).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][C:5]=2[C:6](=[O:10])[C:7]=1[CH:8]=[O:9].CN(C)C=O.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[C:23]#[CH:24]>C(N(CC)CC)C>[CH2:15]([C:12]1[CH:13]=[CH:14][C:4]2[O:3][C:2]([NH:1][CH:24]=[CH:23][C:22]([O:26][CH2:27][CH3:28])=[O:25])=[C:7]([CH:8]=[O:9])[C:6](=[O:10])[C:5]=2[CH:11]=1)[CH3:16]
Reactant: C#CC(=O)OCC
Reactant: CCc1ccc2oc(N)c(C=O)c(=O)c2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=CNc1oc2ccc(CC)cc2c(=O)c1C=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A mixture consisting of 2.17 g of 2-amino-6-ethyl-4-oxo-4H-1-benzopyran-3-carboxaldehyde, 25 ml of dimethylformamide, 5 g of ethyl propiolate and 0.1 ml of triethylamine was stirred at 90° C. for one hour and then the mixture was allowed to stand at room temperature. The resulting crystals were collected by filtration and recrystallized from acetone to obtain 1.65 g of ethyl 3-(6-ethyl-3-formyl-4-oxo-4H-1-benzopyran-2-yl)aminoacrylate as colorless needles melting at 201°-203° C.
Reaction SMILES: [CH2:1]([C:9]1[N:10]=[C:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14]3[N:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([C:33]2([NH:37]C(=O)OC(C)(C)C)[CH2:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>ClCCl.O1CCOCC1>[CH2:1]([C:9]1[N:10]=[C:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14]3[N:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([C:33]2([NH2:37])[CH2:34][CH2:35][CH2:36]2)=[CH:29][CH:28]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CCc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(CCc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (1-(4-(2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.042 g) in dichloromethane (2 mL) was added 4.0 M HCl in dioxane (0.18 mL). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was treated with aq. saturated sodium bicarbonate (10 mL). The mixture was extracted with dichloromethane (2×10 mL). The combined extracts were concentrated under reduced pressure and the crude product was purified by preparative HPLC (YMC PACK ODS-AM; AM12S05-1020WT; 100×20 mm ID; CAN/0.1% TFA, 30 mL/min) The product, 1-(4-(2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutanamine was obtained as a yellow solid (0.010 g, 29%). M.p.: 158-160° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.62 (br. s, 1 H), 8.56 (br. s, 3H), 8.12 (dd, JA=4.8 Hz, JB=1.6 Hz, 1H), 7.91 (dd, JA=7.6 Hz, JB=1.6 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.40-7.36 (m, 1H), 7.32-7.22 (m, 3H), 7.21-7.05 (m, 6H), 6.82 (dd, JA=8.0 Hz, JB=1.6 Hz, 1H), 6.76 (dd, JA=7.6 Hz, JB=4.0 Hz, 1H), 3.05-2.97 (m, 2H), 2.91-2.83 (m, 2H), 2.64-2.46 (m, 4H), 2.22-2.10 (m, 1H), 1.87-1.75 (m, 1H); LCMS: 484 [M+H].
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]([C:12]1[CH:22]=[CH:21][C:15]([CH:16]=[CH:17][C:18]([OH:20])=O)=[CH:14][CH:13]=1)=[O:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:47][CH2:48][C@@H:49]1[O:53][C:52](=[O:54])[N:51]([C:55]2[CH:60]=[CH:59][C:58]([C:61]3[S:62][CH2:63][C:64](=[O:67])[NH:65][N:66]=3)=[C:57]([F:68])[CH:56]=2)[CH2:50]1>CN(C=O)C>[F:68][C:57]1[CH:56]=[C:55]([N:51]2[CH2:50][C@H:49]([CH2:48][NH:47][C:18](=[O:20])[CH:17]=[CH:16][C:15]3[CH:14]=[CH:13][C:12]([CH:10]=[O:11])=[CH:22][CH:21]=3)[O:53][C:52]2=[O:54])[CH:60]=[CH:59][C:58]=1[C:61]1[S:62][CH2:63][C:64](=[O:67])[NH:65][N:66]=1
Reactant: NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1ccc(C=CC(=O)NC[C@H]2CN(c3ccc(C4=NNC(=O)CS4)c(F)c3)C(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N,N-Diisopropylethylamine (0.169 ml, 0.972 mmol) is added to 4-formylcinnamic acid (0.057 g, 0.324 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.129 g, 0.340 mmol) in DMF (2 ml) and is stirred for 20 minutes at room temperature. 2-[4-(5(S)-aminomethyl-2-oxo-oxazolidin-3-yl)-2-fluorophenyl]-4H-[1,3,4]thiadiazin-5-one (0.100 g, 0.308 mmol) is added and stirring is continued at room temperature overnight. The reaction mixture is partially evaporated under vacuum and the residue is diluted with water (5 ml). The resulting precipitate is filtered and dried under vacuum to give crude product used directly in the next step (0.076 g, 51%). MS (m/z): [M+H]+=483.