Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH:9]=[CH:8]2)[CH:2]=[CH2:3].[H-].[Na+].[CH2:18](Br)[CH:19]=[C:20]([CH3:22])[CH3:21]>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([O:15][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH:9]=[CH:8]2)[CH:2]=[CH2:3]
Reactant: CC(C)=CCBr
Reactant: C=CCOc1ccc2[nH]c(=O)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2nc(OCC=C(C)C)ccc2c1
Yield: 34.9 %

Procedure:
10.2 Grams of 6-allyloxy-2(1H)-quinolinone was dissolved in 100 ml of dimethylformamide, then 2.2 g of 60% oily sodium hydride and 9.1 g of prenyl bromide were added thereto by the procedures similar to those employed in Reference example 7 and reacted. Then, thus obtained reaction mixture was treated and oily mixture was obtained. This mixture was subjected to separation and refining by means of a silica gel flush column chromatography in which a mixture of ethyl acetate:n-hexane (1:10 to 1:2) was used as an eluent. Colorless to light yellow oily product, which was obtained by concentrating the second eluate portion under reduced pressure, was allowed to stand at room temperature, then it was crystallized. There was obtained 4.7 g (34.9%) of 6-allyloxy-2-prenyloxy-quinoline by recrystallization from n-hexane. Colorless needle-like crystals (recrystallized from n-hexane)
Reaction SMILES: [NH3:1].C([O:4][C:5]([CH:7]([NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1)[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)=O)C>C(O)C>[C:5]([CH:7]([NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1)[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)(=[O:4])[NH2:1]
Reactant: N
Reactant: CCOC(=O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Solvent: CCO
Product: NC(=O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 32 %

Procedure:
20 ml of a 10% solution of ammonia in ethanol was added to 200 mg of 4-(α-ethoxycarbonyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was stirred at room temperature for 3 days. The crystal thus precipitated was recovered by filtration. Thus, 60 mg of the title compound was obtained.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([O:13][C:14](=O)[C:7]3=[CH:6][CH:5]=[CH:4]2)=[O:12])[CH:10]=1.CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[OH:12][CH2:11][C:9]1[CH:10]=[CH:1][CH:2]=[C:3]2[C:8]=1[C:7]([CH2:14][OH:13])=[CH:6][CH:5]=[CH:4]2
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OCc1cccc2cccc(CO)c12
Temperature: 95 °C

Procedure:
A 12-L 4-neck flask equipped with a thermocouple, an overhead stirrer, a 2-L addition funnel, and a condenser under N2 was charged with 1,8-naphthalic anhydride (200 g, 1.0 mol) in toluene (2.5 L) at room temperature. The reaction mixture was agitated while adding DIBAL-H (1.5 M in toluene, 2.664 L, 4 mol) via the addition funnel over 1.5 h. The solution was then heated to 95° C. overnight, cooled to 15° C. and then slowly diluted with ethyl acetate (2.2 L) and H2O (2 L) followed by addition of concentrated HCl (320 mL). The resulting suspension was stirred for 30 min at room temperature, filtered, and air dried on the filter for 2 h. The resultant material was in 95% ethanol (1.2 L), stirred at 70° C. for 2 h, and filtered to yield a wet solid which was air dried overnight on the filter and then dried at 70° C. in a vacuum oven to yield (8-hydroxymethyl-naphthalen-1-yl)-methanol as a solid;
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOc1ccc2ccccc2c1

Procedure:
172.8 g (1.2 mol) 2-naphthol (98%) is added to a solution of 48 g (1.2 mol) sodium hydroxide (99%) in 1 l ethanol in a 4 l three-neck flask with stirrer, cooler and thermometer, after it has dissolved 417 g (1.25 mol) n-octadecylbromide are added and the reaction mixture is heated for 14 hours under reflux. After addition of a further 1 l ethanol the hot solution is aspirated over a Seitz filter to remove inorganic material and the weakly pink coloured filtrate is brought to crystallization by placing it in an ice bath for 30 minutes. After aspiration of the almost colourless crystals, the filter cake is washed in portions with ca 700 ml ethanol and after drying over diphosphorus pentoxide, 371.9 g (93.7% of the theoretical yield) 2-naphthyl-octadecyl-ether are obtained as colourless crystals, Fp 64°-68° C.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1.CCN(CC)CC.CS(Cl)(=O)=O.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C.O>[N:32]1([CH2:2][CH2:3][C:4]2[CH:19]=[CH:18][C:7]([O:8][C:9]3[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=3)=[CH:6][CH:5]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: C1CCNCC1
Reactant: NC(=O)c1ccc(Oc2ccc(CCO)cc2)nc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(Oc2ccc(CCN3CCCCC3)cc2)nc1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
Dissolve 6-[4-(2-hydroxy-ethyl)-phenoxy]-nicotinamide (100 mg, 0.38 mmol) under N2 atmosphere in dry DMF (4 mL). Add Et3N (108 μL, 0.77 mmol) then cool the mixture at 0° C., add MsCl (29 μL, 0.38 mmol), allow the mixture to warm to room temperature. After 1 hour add piperidine (76 μL, 0.77 mmol) and heat the mixture at 90° C. for 1 hour. Cool to ambient temperature and pour into water. Extract the aqueous layer with EtOAc. Dry the organic layer over MgSO4. Eliminate the solvent. Purify by flash chromatography on silica gel (eluent: CHCl3/5% EtOH/0.5% NH4OH) to give the title compound (65 mg, 55%). Electrospray MS M+1 ion=326, 1H-NMR (CDCl3, 400 MHz): 8.58 (d, 1H, J=2.4 Hz), 8.14 (dd, 1H, J=2.4 and 8.5 Hz), 7.25-7.23 (m, 2H), 7.07-7.03 (m, 2H), 6.93 (d, 1H, J=8.5 Hz), 6.12 (bs, 2H), 2.88-2.80 (m, 2H), 2.68-2.65 (m, 2H), 2.53-2.44 (m, 4H), 1.67-1.59 (m, 4H), 1.51-1.43 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)=[O:21])=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]2[CH:26]=[CH:25][S:24][CH:23]=2)=[O:21])=[CH:17][C:18]=1[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc2cc(Br)ccc12
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc2c(C)noc2c1
Yield: 49.3 %

Procedure:
Example 5 was prepared in a similar manner to Example 4 using 6-bromo-3-methyl-1,2-benzisoxazole (11 mg) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-thiopheneamide (Intermediate 15, 17 mg) to give an oil (8.5 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:12]1([C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([CH3:11])[CH:4]=2)=[O:8])[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Cc1cc(C(=O)O)ccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)ccc1O
Yield: 35 %

Procedure:
The title compound is prepared from 4-hydroxy-3-methyl-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 35% of theory; LC (method 4): tR=1.92 min; Mass spectrum (ESI+): m/z=313 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:47]2[CH2:52][CH:51]3[CH:49]([CH:50]3[C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH:48]=2)O1>>[NH2:32][C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:47]2[CH2:52][CH:51]4[CH:49]([CH:50]4[C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH:48]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCOC(=O)C1C2C=C(B3OC(C)(C)C(C)(C)O3)CC21
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 86.6 %

Procedure:
The titled compound was prepared in 86.6% yield following the method described in step 1 for the preparation of Example 1 described above, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate as the reactants. MS: m/e 543.5 (M−16)+, 2.87 min. 1H NMR (400 MHz, CHLOROFORM-d) δ 5.84-5.72 (m, 1H), 5.47-5.32 (m, 1H), 4.72 (s, 1H), 4.59 (s, 1H), 4.24-3.99 (m, 2H), 3.09-2.74 (m, 1H), 2.67-2.40 (m, 3H), 2.26-2.10 (m, 1H), 2.09-1.92 (m, 3H), 1.69 (s, 3H), 1.67-1.65 (m, 1H), 1.64-1.31 (m, 9H), 1.29-1.22 (m, 5H), 1.17-1.05 (m, 4H), 1.02 (s, 6H), 0.98-0.93 (m, 7H), 0.82 (m, 3H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O.[CH3:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>C(#N)C>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:7]1[CH2:6][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CN1CCCC1
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: C1CCNCC1

Procedure:
A stock solution of 1 molar piperidine acetate was prepared by mixing one equivalent of glacial acetic acid in an appropriate volume of water and slowly adding one equivalent 1-methylpyrrolidine. The pH of the stock solution is 7. The stock solution was diluted in an appropriate volume of water or acetonitrile to working concentration.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].C([Li])CCC.[C:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>O1CCCC1>[Cl:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[C:24]1([OH:27])[CH2:25][CH2:26][N:22]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:23]1
Reactant: Clc1cccc(Br)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2Cl)C1

Procedure:
Preparation according to Example 23: 1-bromo-2,3-dichlorobenzene (2.1 g, 9.23 mmol) in dry tetrahydrofuran (40 mL), n-butyllithium (2.5 M in tetrahydrofuran, 3.7 mL, 9.23 mmol), 1-N-boc-3-pyrrolidinone (1.13 g, 6.15 mmol) in dry tetrahydrofuran (10 mL). Purified by flash column chromatography on silica gel (isooctane/ethyl acetate, 4:1 to 1:1). Yield: 1.23 g. MS m/z (rel. intensity, 70 eV) 230 (25), 196 (46), 172 (19), 57 (bp), 56 (29).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:13]([C:24]3[CH:28]=[CH:27][N:26]([Si](C(C)C)(C(C)C)C(C)C)[CH:25]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:13]([C:24]3[CH:28]=[CH:27][NH:26][CH:25]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cc[nH]c2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
305 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)-6-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]pyrimidine-2,4-diamine was dissolved in 3 ml of tetrahydrofuran, and 0.86 ml of 1M tetrabutylammonium fluoride/tetrahydrofuran solution was added under ice water cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was added with water. The solution was subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 199 mg of the objective compound as pale brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH:11](C)[O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1([CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: [H][H]
Reactant: COC1(/C=C/C(C)OCc2ccc3ccccc3c2)CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC1(CCCOCc2ccc3ccccc3c2)CCOCC1
Yield: 66.7 %

Procedure:
4-methoxy-4-[3-methyl-3-((napth-2yl)methoxy)-trans-prop-1-enyl]tetrahydropyran (320 mg, 1.02 mmol), prepared as in Example 3, was hydrogenated over palladium on calcium carbonate, poisoned with lead, with hydrogen (1 atm) in ethyl acetate at ambient temperature for 18 hours. After flushing the reaction solution with nitrogen, the solution was filtered through a pad of celite. The filter cake was thoroughly rinsed with ethyl acetate. The combined flltrates were concentrated in vacuo and chromatographed on silica gel (14 g, 15% ethyl acetate:hexanes) to provide the title compound (214 mg, 66%) as a colorless oil. 1H NMR (300 MHz, CDCl3); 7.75-7.87 (4H, m), 7.43-7.53 (3H, m), 4.67 (2H, s), 3.68 (4H, d,d, J=8,3 Hz), 3.52 (2H, t, J=6 Hz), 3.17 (3H, s), 1.49-1.78 MS (M+H)+ =315, (M+NH4 )+ =332. Analysis calc'd for C20H26O3 : C, 76.40; H, 8.33; Found: C, 76.30; H, 8.12.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN2C(=O)C(CCO)Oc3ccccc32)cc1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 4-methoxybenzyl chloride, in 48% overall yield after flash chromatography eluting with EtOAc/hexane, mp 80°-82° C.; IR (KBr) 3496, 1660, 1515, 1501, 1412, 1250, 1057, 754 cm-1 ; 1H NMR (CDCl3) 8 2.00 (v br s, 1H), 2.16-2.37 (m, 2H), 3.77 (s, 3H), 3.91 (t, J=6.1 Hz, 2H), 4.82 (dd, J=7.5, 5.6 Hz, 1H), 5.09 (s, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.91-7.00 (m, 4H), 7.18 (d, J=8.7 Hz, 2H); MH+ at m/z=314; Anal. Calc'd for C18H19 NO4 : C, 68.99; H, 6.11; N, 4.47. Found: C, 69.22; H, 6.10; N, 4.35.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)#[N:2]>O>[C:1]([CH2:3][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][O:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)#[N:2]
Reactant: N#CC=C1c2ccccc2COc2ccccc21
Solvent: O
Product: N#CCC1c2ccccc2COc2ccccc21
Reaction time: 8 h

Procedure:
A saturated mercury II chloride solution is prepared in 150 ml. dry ether. After the addition of 12 g. aluminium fillings, one leaves the solution to stand for 3 - 5 minutes and, after shaking up twice, decants. The aluminium amalgamated in this manner is now washed several times with absolute ether and finally covered with 300 ml. ether in a stirring apparatus. Subsequently, one mixes with 12 g. 11-(cyanomethylene)-6,11-dihydro-dibenzo-[b,e]-oxepine (0.051 mol), prepared according to C, and adds 12 ml. water thereto in the course of 5 hours, with vigorous stirring. The reaction mixture is then left to stand overnight. The inorganic components are filtered off with suction, the filtrate evaporated in a vacuum and one obtains 11.5 g. (95.5% of theory) of practically pure reduction product of m.p. 85° - 86°. After recrystallising once from a petroleum fraction of m.p. 100° - 140° C., the melting point increases to 87° - 89°. The UV-spectrum shows the absence of the cross-conjugated double bond.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O.[OH-].[Li+].Cl.O>C(OCC)(=O)C>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1cc(C(=O)OCC)ccc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)c1cc(C(=O)O)ccc1O
Temperature: 25 °C

Procedure:
The title compound of Example 1 (500 mg) was heated at reflux for 24 hours with 230 mg of lithium hydroxide monohydrate. The reaction mixture was cooled to room temperature, then added to 20 ml of 1N HCl with stirring, followed by the addition of 10 ml of water and 10 ml of ethyl acetate. The mixture was filtered and the solid recrystallized from dimethylformamide to give the title compound, m.p. ca. 170° C. ##STR12##
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:10][CH:9]=2)[O:5][N:4]=1>ClCCCl>[CH3:2][C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)[O:5][N:4]=1
Reactant: Cc1noc(-c2cnc(N3CCN(C(=O)OC(C)(C)C)CC3)s2)n1
Agent: Cl
Solvent: ClCCCl
Product: Cc1noc(-c2cnc(N3CCNCC3)s2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.8 %

Procedure:
A satd ethanolic HCl soln (4 ml) was added to a solution of 220 mg (0.63 mmol) of tert-butyl 4-[5-(3-methyl-[1,2,4]-oxadiazol-5-yl)thiazol-2-yl]-piperazine-1-carboxylate [Precursor BBB62] in DCE (10 ml). After stirring at RT 5 min, the reaction solution was concentrated in vacuo. The residue was taken up in DCM and washed successively with a 1% strength aq. NaOH soln and water. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. 152 mg (0.61 mmol, 96%) of 1-[5-(3-methyl-[1,2,4]-oxadiazol-5-yl)thiazol-2-yl]piperazine were obtained here.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[C:10]([C:12]1([NH:15][C:16]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]([N:26]2[CH2:39][CH2:38][C:29]3[NH:30][C:31]4[C:32]([OH:37])=[CH:33][CH:34]=[CH:35][C:36]=4[C:28]=3[CH2:27]2)=[O:25])=[O:17])[CH2:14][CH2:13]1)#[N:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:10]([C:12]1([NH:15][C:16]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]([N:26]2[CH2:39][CH2:38][C:29]3[NH:30][C:31]4[C:32]([O:37][CH2:3][CH2:4][N:5]5[CH2:9][CH2:8][CH2:7][CH2:6]5)=[CH:33][CH:34]=[CH:35][C:36]=4[C:28]=3[CH2:27]2)=[O:25])=[O:17])[CH2:14][CH2:13]1)#[N:11]
Reactant: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(O)cccc4c3C2)CC1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(OCCN5CCCC5)cccc4c3C2)CC1
Temperature: 25 °C
Reaction time: 45 h

Procedure:
Following on from Example 34, 1-(2-chloroethyl)pyrrolidine hydrochloride (82.0 mg, 0.48 mmol) was added to (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-hydroxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (131 mg, 0.32 mmol) and potassium carbonate (134 mg, 0.97 mmol) in DMF (5 mL) at 25° C. under air. The resulting solution was stirred at room temperature for 45 hours, to yield after purification a cream solid. (6.00 mg, 3.7%).
Reaction SMILES: [N:1]([C:4]([CH3:27])([CH:10]1[NH:14][CH:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:12]([CH3:26])([CH3:25])[S:11]1)[C:5]([O:7]CC)=[O:6])=[N+:2]=[N-:3].[OH-].[Na+].Cl>C(O)C>[CH3:27][C:4]([N:1]=[N+:2]=[N-:3])([CH:10]1[NH:14][CH:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C:12]([CH3:25])([CH3:26])[S:11]1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C)(N=[N+]=[N-])C1NC(C(=O)OCc2ccccc2)C(C)(C)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)SC(C(C)(N=[N+]=[N-])C(=O)O)NC1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl α-azido-α-methyl-4-benzyloxycarbonyl-5,5-dimethyl-2-thiazolidine acetate (3.92 g.) in ethanol (20 ml.) is slowly added 20 ml. of 0.5 N sodium hydroxide solution. The solution is stirred at room temperature overnight, then acidified with 20 ml. of 0.5 N hydrochloric acid. The product is extracted into ethyl acetate and the solution dried over anhydrous sodium sulfate and evaporated leaving α-methyl-α-azido-4-benzyloxycarbonyl-5,5-dimethyl-2-thiazolidineacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)(Cl)Cl)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH2:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[C:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=[O:20]
Reactant: O
Reactant: Clc1ccc(C(Cl)(Cl)c2ccc(Cl)c(Cl)c2)cc1Cl
Product: O=C(c1ccc(Cl)c(Cl)c1)c1ccc(Cl)c(Cl)c1

Procedure:
reacting said bis(3,4-dichlorophenyl) dichloromethane with water to form 3,3',4,4'-tetrachlorobenzophenone;
Reaction SMILES: [Na].[Br:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([OH:10])=[CH:5][C:4]=1[CH3:11].Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1>C(OCC)(=O)C.[Cu]>[Br:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([O:10][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[CH:5][C:4]=1[CH3:11]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: Cc1cccc(Br)n1
Agent: [Cu]
Agent: [Na]
Solvent: CCOC(C)=O
Product: Cc1cccc(Oc2cc(C)c(Br)c(C)c2)n1
Temperature: 185 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of sodium hydroxide (0.23 g, 5.81 mmol) in methanol (50 mL) was added 4-bromo-3,5-dimethylphenol (1.17 g, 5.81 mmol) and the mixture was left standing at room temperature for 10 min. and concentrated to dryness to give 4-bromo-3,5-dimethylphenol sodium salt (1.30 g). Then, a mixture of the obtained 4-bromo-3,5-dimethylphenol sodium salt (1.30 g), 2-bromo-6-methylpyridine (1.0 g, 5.81 mmol) and copper powder (11 mg, 0.17 mmol) was stirred at 185° C. for 1 hr. The reaction mixture was cooled, diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=5/1) to give the title compound (1.25 g, yield 74%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][CH:9]=1.[C:16]([O-])([O-])(OCC)[CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([C:16]([CH3:17])=[N:15][N:14]=2)[N:13]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: NNc1ncc(-c2ccccc2Cl)nn1
Product: Cc1nnc2ncc(-c3ccccc3Cl)nn12

Procedure:
A mixture of 4.45 g. of 6-(o-chlorophenyl)-3-hydrazino-1,2,4-triazine and 50 ml. of ethyl orthoacetate is treated as described in Example 16, giving the desired product as yellow crystals, m.p. 172°-175° C.