Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[CH2:14]([O:21][C:22]([NH:24][CH2:25][C@H:26]([NH:30][C:31]([O:33]C(C)(C)C)=O)[C:27]([OH:29])=[O:28])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(=O)O[C:41](=[O:42])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12>ClCCl.Cl.C1(C)C=CC=CC=1>[CH2:14]([O:21][C:22]([NH:24][CH2:25][C@H:26]([N:30]1[C:31](=[O:33])[C:39]2=[CH:47][CH:46]=[CH:45][CH:44]=[C:40]2[C:41]1=[O:42])[C:27]([OH:29])=[O:28])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(NC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of (2S)3-benzyloxycarbonylamino-2-tert-butoxycarbonylaminopropionic acid dicyclohexylamine salt (3 g, 5.8 mmol) in dichloromethane (200 ml) was washed four times with 1M HCl solution, dried (MgSO4) and concentrated. The resulting oil was dissolved in dry dichloromethane (35 ml), cooled to 0° C. and treated with trifluoroacetic acid (35 ml). This solution was stirred at 0° C. for 1.5 h then evaporated to dryness. Dichloromethane (50 ml) was added to the residue then removed under vacuum. This process repeated six times to afford a white solid. The white solid was suspended in toluene (50 ml), treated with powdered phthalic anhydride (940 mg, 6.35 mmol) and refluxed for 18 h. The resulting solution was concentrated to afford an oil which was purified by flash chromatography (2-10% methanol/dichloromethane) to afford 266, 2.01 g (94%) as a white powder: IR (KBr) 3600-2500br, 1776, 1714, 1530, 1469, 1455, 1392, 1263, 1131, 722; 1H NMR (CDCl3) δ 7.83 (2H, m), 7.72 (2H, m), 7.29 (5H, m), 5.41 (1H, m), 5.03 (2H, s), 3.90 (2H, m); MS (ES−), 367 (M−1).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH2:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:24]>N1C=CC=CC=1>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:28]4[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CCN1CCNCC1
Solvent: c1ccncc1
Product: CCN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4CC)CC1
Yield: 70.4 %

Procedure:
1-Ethyl-8-(4-ethyl-1-piperazinyl)-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 1.6 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 2.3 g of 1-ethylpiperazine in 16 cm3 of pyridine. 1.4 g of 1-ethyl-8-(4-ethyl-1-piperazinyl)-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 287°-288° C., solvated by 1.6% of water.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>[C].[Pd].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:14][CH:15]=1
Reactant: O=C1CCCCC1=Cc1ccc(F)cc1
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Oc1ccccc1Cc1ccc(F)cc1
Temperature: 250 °C
Reaction time: 7 h
Yield: 73 %

Procedure:
In a 100-ml, four-necked flask equipped with a magnetic stirrer, a reflux condenser and a thermometer were placed 22.6 g (0.1 mole, calculated based on a purity of 89%) of the 2-(4-fluorobenzylidene)cyclohexanone produced in Example 6 and 40 ml of diphenyl ether in this order. The flask inside was purged with nitrogen. Thereto was added 2.0 g (10 wt. %, 0.94 mmole as palladium) of 5% palladium carbon (a product of Wako Pure Chemical Industries, Ltd.). The system was made vacuum using an aspirator and then returned to ordinary pressure using nitrogen; this operation was repeated three times. Then, the system was stirred at 250° C. for 7 hours and cooled to room temperature. 100 ml of toluene was added to the system. Filtration was conducted to remove the palladium carbon. The filtrate was extracted with 100 ml of a 10% aqueous sodium hydroxide solution, and this operation was repeated twice. The aqueous layer was washed with 30 ml of toluene. To the resulting aqueous layer was added 35% hydrochloric acid until the aqueous layer became acidic, after which the aqueous layer was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous sodium chloride solution in this order. The ethyl acetate layer was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove ethyl acetate, to obtain 14.8 g of a red oil. Yield: 73% The purity of the intended product in the oil was 77% as measured by gas chromatography.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10](C2C(O)=CC=CC=2)[C:11](O)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:22](=[O:25])([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][Br:35]>CC(C)=O>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:3]2[CH:4]=[CH:5][C:22]([O:25][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][Br:35])=[CH:1][CH:2]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C([O-])[O-]
Reactant: BrCCCCCCBr
Reactant: CCCCCCOc1ccc(O)c(-c2ccccc2O)c1
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCOc1ccc(-c2ccc(OCCCCCCBr)cc2)cc1
Yield: 76.9 %

Procedure:
A solution of 4'-(hexyloxy)biphenol (8.10 g, 30 mmol), potassium carbonate (8.30 g, 60 mmol), 1,6-dibromohexane (22.0 g, 90 mmol) and acetone (80 mL) was heated to reflux for 24 h. One-half the acetone was removed by distillation and the mixture was poured into tetrahydrofuran:ether, 1:1 (600 mL), and washed with water. The solution was dried over magnesium sulfate and concentrated to a solid. The solid was recrystallized from tetrahydrofuran-ether to give 4'-(hexyloxy)-4-(6-bromohexyloxy)biphenyl (5.0 g, 38%): mp 103-105° C.; NMR 7.4(d, 4H), 6.85(d, 4H), 3.92(t, 4H), 3.4(t, 2H), 2.0-1.2(m, 16H), 0.9(t, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[N:16]=[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][N:10]2[N:9]=1.N1CCCCC1CC1N=C2C=CC=CN2N=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:66][C:67]1[CH:72]=[CH:71][C:70]([C:73]2[S:77][C:76]([CH3:78])=[N:75][C:74]=2[C:79](O)=[O:80])=[CH:69][CH:68]=1>CN(C=O)C>[F:66][C:67]1[CH:68]=[CH:69][C:70]([C:73]2[S:77][C:76]([CH3:78])=[N:75][C:74]=2[C:79]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][C:8]2[N:16]=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[O:80])=[CH:71][CH:72]=1
Reactant: C1CCC(Cc2nc3n(n2)CCCC3)NC1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccn2nc(CC3CCCCN3)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3ccccn3n2)c(-c2ccc(F)cc2)s1

Procedure:
The mixture of 2-piperidin-2-ylmethyl-5,6,7,8-tetrahydro-[1,2,4]-triazolo[1,5-a]pyridine and 2-piperidin-2-ylmethyl-[1,2,4]-triazolo[1,5-a]pyridine, D34 (0.220 g) was treated with HATU (0.380 g), N,N-diisopropylethylamine (1.0 ml) and 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (0.240 g) in dry DMF, according to the procedure described in Example 60. The crude product was chromatographed (silica gel, 4% methanol-diethyl ether) to afford 1-[5-(4-fluoro-phenyl)-2-methylthiazol-4-yl]-1-(2-[1,2,4]-triazolo[1,5-a]pyridin-2-ylmethylpiperidin-1-yl)-methanone as a colourless foam (0.070 g) (Mass spectrum (API+): found 436 (MH+): C23H22FN5OS requires 435). Continued elution (10% methanol-diethyl ether) afforded 1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(5,6,7,8-tetrahydro-[1,2,4]-triazolo[1,5-a]pyridin-2-ylmethyl)-piperidin-1-yl]-methanone as a colourless foam (0.230 g)
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18](O)=[C:17](O)[CH:16]=3)[CH:10]=[N:9]2)=[C:5]([CH3:26])[O:4][N:3]=1.[C:27](=[O:30])([O-])[O-:28].[Cs+].[Cs+].Br[CH:34](Br)C>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:14]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]4[O:28][CH:27]([CH3:34])[O:30][C:17]=4[CH:16]=3)=[O:25])[CH:10]=[N:9]2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COc1cc(C(=O)Nc2cnn(Cc3c(C)noc3C)c2)cc(O)c1O
Reactant: O=C([O-])[O-]
Reactant: CC(Br)Br
Agent: [Cs+]
Product: COc1cc(C(=O)Nc2cnn(Cc3c(C)noc3C)c2)cc2c1OC(C)O2
Yield: 25 %

Procedure:
Prepared as in Example 4-92 from N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-3,4-dihydroxy-5-methoxybenzamide (Example 4-73), cesium carbonate and 1,1-dibromoethane. Yield 25%. MS M+H calculated 385.1, found 385.1.
Reaction SMILES: Cl[C:2]([O:5][C:6](Cl)=[O:7])(Cl)Cl.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=1[NH2:20].[CH2:21]1COCC1>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=1[NH:20][C:6](=[O:7])[O:5][CH2:2][CH3:21]
Reactant: COc1cccc([N+](=O)[O-])c1N
Reactant: C1CCOC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: CCOC(=O)Nc1c(OC)cccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
17.1 mL (0.141 mol) trichloromethylchloroformate are added dropwise at reflux temperature to a solution of 23.8 g (0.142 mol) 2-methoxy-6-nitro-phenylamine in 300 mL THF and then the mixture is stirred for 4 hours at this temperature. The solvent is distilled off and the residue is stirred with isopropanol, during which time a yellow solid is precipitated. Yield: 25.0 g (73%); mass spectroscopy: [M+H]+=241.
Reaction SMILES: [C:1]1([CH:7]([C:11](Cl)=[O:12])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N)C.[O:17]1CCCC1.[CH2:22]([N:24](CC)[CH2:25][CH3:26])[CH3:23].Cl>C(OCC)(=O)C.C(Cl)Cl>[CH2:22]([N:24]([CH2:25][CH3:26])[C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]([OH:12])=[O:17])[CH3:23]
Reactant: C1CCOC1
Reactant: O=C(Cl)C(C(=O)Cl)c1ccccc1
Reactant: CCN(CC)CC
Agent: CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)C(C(=O)O)c1ccccc1
Reaction time: 8 h

Procedure:
The phenylmalonic acid dichloride (8.99 g) obtained in Reference Example 1a) was added dropwise to a mixture of ethylamine/tetrahydrofuran (2M, 45.5 mL), triethylamine (13.9 mL) and methylene chloride (80 mL) at −20° C. The reaction temperature was elevated to room temperature, and the mixture was stirred overnight. After addition of 3N hydrochloric acid, the reaction solution was diluted with ethyl acetate, and the organic phase was washed successively with saturated brine, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over sodium sulfate, and then concentrated to give a solid. The solid was washed with ethyl acetate-hexane to give the title compound (4.85 g) as a white powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:13][NH:12][C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][N:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(#N)C>CCOCC.CCOC(C)=O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([OH:25])[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(C2CC(=O)NN=C2c2cccc(C(F)(F)F)c2)n1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CSc1nccc(-c2cc(O)nnc2-c2cccc(C(F)(F)F)c2)n1
Temperature: 90 °C

Procedure:
Compound 6 (1.92 g, 5.26 mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.78 g, 21.0 mmol), and acetonitrile (30 mL) were combined under argon and heated at 90° C. for 1 h. The solution was cooled and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (methylene chloride:methanol:ammonium hydroxide 95:5:0.5) to give a solid. Trituration with.Et2O EtOAc gave Compound 69: 1.60 g (4.4 mmol, 83%)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([NH:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([F:63])([F:62])[C:58]([F:59])([F:60])[F:61])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41])=[O:14]
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Reactant: NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1)c1cccc2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 5-chloronaphthalene-1-carboxylic acid (176 mg, 0.849 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg, 0.849 mmol) and 1-hydroxybenzotriazole monohydrate (130 mg, 0.849 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(2,2,3,3,3-pentafluoropropyl)phenyl]-1-propanol (318 mg, 0.809 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The mixturewas filtered using a glass filter filled with silica gel, and the filtrate was washed with ethyl actate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give 5-chloro-N-{(1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]ethyl}-1-naphthamide (330 mg, 70%) as colorless crystals.
Reaction SMILES: ClC1C=C(C2C=C(C(O)=O)OC=2C2C=CC=C(C#N)C=2)C=C(F)C=1.[Br:25][C:26]1[CH:27]=[C:28]([C:38]([O:40]CC)=[O:39])[O:29][C:30]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1>>[Br:25][C:26]1[CH:27]=[C:28]([C:38]([OH:40])=[O:39])[O:29][C:30]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1
Reactant: CCOC(=O)c1cc(Br)c(-c2cccc(Cl)c2)o1
Agent: N#Cc1cccc(-c2oc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)c1
Product: O=C(O)c1cc(Br)c(-c2cccc(Cl)c2)o1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 20A starting with the compound from Example 5A. Instead of using ethyl acetate, the crude product is extracted with dichloromethane and reacted further without chromatographic purification. 447 mg (98% of theory) of the title compound are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[CH3:22])=[O:16])[N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]=12)=[O:5])C.O.[OH-].[K+].Cl>CO>[CH3:22][C@H:18]1[CH2:19][CH2:20][CH2:21][N:17]1[C:15]([C:8]1[N:9]2[C:10]([CH2:11][O:12][CH2:13][CH2:14]2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=1)=[O:16]
Reactant: CCOC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Temperature: 80 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester (Comp. No. 6c) (762 mg, 2.49 mmol) in methanol (10 ml) was added water (4 ml) and 2 N aqueous potassium hydroxide (6 ml, 12 mmol). The mixture was stirred for 3 h at 80° C., then cooled down to 25° C. and acidified with excess 10 M aqueous hydrochloric acid. After extraction (3 times with dichloromethane), the combined organic layers were dried over sodium sulfate and the solvents evaporated to give 595 mg (86%) 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid as a white solid. LC/MS (method 2): Rt=0.98 min; m/z=279.06 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][NH:5][C:6](=[O:20])[CH2:7][NH:8][C:9](=[O:19])[CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[OH-].[Na+].Cl>O1CCCC1.O>[C:15]([O:14][C:12]([NH:11][CH2:10][C:9]([NH:8][CH2:7][C:6]([NH:5][CH2:4][C:3]([OH:21])=[O:2])=[O:20])=[O:19])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)NCC(=O)O
Reaction time: 16 h

Procedure:
Add to a solution of t-butoxycarbonyl-glycyl-glycyl-glycine methyl ester (4.1 g.) in tetrahydrofuran (30 ml.) and water (30 ml.) dropwise with stirring 1 N sodium hydroxide (13.6 ml.). Stir the reaction mixture for 16 hours, acidify to pH 3 with dilute hydrochloric acid and then evaporate to dryness under reduced pressure. Suspend the residue in acetone, filter and evaporate the filtrate to dryness to afford the title product (m.p. 115°-120° C.).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][CH3:24])[CH:19]=2)[CH:14]([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[CH2:13]1.Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O>[C:36]([CH2:35][O:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][CH3:24])[CH:19]=2)[CH:14]([C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][O:33][C:27]=3[CH:26]=2)[CH2:13]1)([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)CBr
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)CC2c1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)OCC)CC2c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a slurry of sodium hydride (5 mg, 0.21 mmol) in dimethylformamide (0.5 ml) was added (1RS, 3RS)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (0.058 g, 0.14 mmol) at ice-bath temperature under argon. After stirring for 15 min, ethyl bromoacetate (50 μl, 0.2 mmol) was added and the solution stirred for 1 h at room temperature. The product was partitioned between ethyl acetate and 3M aq HCl. The organic extract was washed with water, sat. aq. NaHCO3 solution and finally brine. After drying (MgSO4 anhydrous) filtration and evaporation followed by chromatography gave (1RS, 3RS)-3-(2-carboethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (0.041 g). The product was dissolved in hot ethanol (10 ml) and 1M aq. NaOH added (1 ml). The mixture was refluxed for 1 h then cooled, acidified with 6M-aqueous HCl and extracted with ethyl acetate. After evaporation the residue was crystallized from ethyl acetate/hexane to give the title compound (0.035 g, 93%). m.p. 177°-178° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1ncccn1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ncccn2)c1=O
Temperature: 50 °C
Reaction time: 120 h
Yield: 36 %

Procedure:
To a stirred solution of 100 mg (0.348 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 5 ml of ethanol, 430 mg (4.524 mmol) of 2-aminopyrimidine was added. The resulting mixture was stirred at 50° C. during five days and the final product was collected by filtration and washed with diethylether to yield the title compound (42 mg, 35.6% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=1
Reactant: Clc1cnccn1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc(-c2cnccn2)cc1
Temperature: 80 °C
Yield: 71.7 %

Procedure:
A mixture of 2-chloropyrazine (0.230 ml, 2.62 mmol), 4-(hydroxymethyl)phenylboronic acid (517 mg, 3.41 mmol), tetrakis(triphenylphosphine)palladium (0) (303 mg, 0.262 mmol) and 2 M potassium phosphate aqueous solution (2.62 ml, 5.24 mmol) in dioxane (10 mL) was heated at 80° C. overnight under nitrogen. The mixture was cooled down, poured into water and extracted with ethyl acetate. The combined organic layers were dried and concentrated. The residue was purified by preparative HPLC to give the title compound (350 mg) as an off-white solid. LCMS m/z=187.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 4.79 (s, 2H), 7.52 (d, J=8.1 Hz, 2H), 8.02 (d, J=8.1 Hz, 2H), 8.51 (d, J=2.5 Hz, 1H), 8.63 (dd, J=2.4 and 1.6 Hz, 1H), 9.03 (d, J=1.6 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C@:32]([OH:36])([C:34]#[CH:35])[CH3:33])[N:28]=1>>[F:25][C:3]1[C:2]([C:35]#[C:34][C@@:32]([OH:36])([C:29]2[N:28]=[C:27]([CH3:26])[O:31][N:30]=2)[CH3:33])=[CH:24][C:6]2[C:7]3[N:8]([C:12]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Product: Cc1nc([C@](C)(O)C#Cc2cc3c(cc2F)OCCn2c-3nc(C(N)=O)c2CN2CCCC2)no1
Yield: 10.4 %

Procedure:
10-bromo-9-fluoro-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol similarly to as described in General Procedure F with non-critical modifications to afford 9.8 mg (10.4%) of 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-3-(pyrrolidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. M+1=481.2.
Reaction SMILES: [CH3:1][SiH:2]([CH3:26])[O:3][CH:4]([C:20]([CH3:25])([CH3:24])[CH:21]([CH3:23])[CH3:22])[C@H:5]1[N:10]2[C:11]3[CH:12]=[CH:13][C:14]([OH:18])=[CH:15][C:16]=3[CH:17]=[C:9]2[C:8](=[O:19])[NH:7][CH2:6]1.[CH:27]([N:30]1[CH2:35][CH2:34][CH:33](O)[CH2:32][CH2:31]1)([CH3:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>>[CH3:1][SiH:2]([CH3:26])[O:3][CH:4]([C:20]([CH3:24])([CH3:25])[CH:21]([CH3:22])[CH3:23])[C@H:5]1[N:10]2[C:11]3[CH:12]=[CH:13][C:14]([O:18][CH:33]4[CH2:34][CH2:35][N:30]([CH:27]([CH3:29])[CH3:28])[CH2:31][CH2:32]4)=[CH:15][C:16]=3[CH:17]=[C:9]2[C:8](=[O:19])[NH:7][CH2:6]1
Reactant: CC(C)N1CCC(O)CC1
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)[C@@H]1CNC(=O)c2cc3cc(O)ccc3n21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C(O[SiH](C)C)C(C)(C)C(C)C)CNC2=O)CC1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 1, from (S)-4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-8-hydroxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butyl-azodicarboxylate, to give the desired product as a light yellow foam (40%).