Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>CCO>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccs2)CC1
Yield: 69.2 %

Procedure:
A mixture of 5 g of tert-butyl 1-piperazinecarboxylate, 4.4 g of 2-bromo-1,3-thiazole and 7.4 g of K2CO3 in 50 ml of EtOH is refluxed for 4 days. Water is added to the reaction mixture, the EtOH is evaporated off under vacuum, the resulting aqueous phase is extracted with EtOAc, the organic phase is washed with saturated K2CO3 solution and with saturated NaCl solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture (98/2; v/v). 5 g of the expected product are obtained after precipitation from a cold DCM/hexane mixture and filtration by suction, m.p.=114–116° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:15]=1[C:16]([NH:18][NH2:19])=[O:17]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:19][NH:18][C:16](=[O:17])[C:15]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:14]=1[NH2:13]
Reactant: NNC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])cc1C(=O)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 76 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-amino-5-nitrobenzohydrazide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 69 mg of the title compound (76%) as a yellow powder in 98.8% purity by HPLC (Rt: 4.22, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:20])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:9]([Cl:19])[CH:8]=1)=[O:5].[C:21](OCC)(OCC)(OCC)[CH3:22]>>[Cl:19][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:20])[N:1]=[C:21]2[CH3:22])[CH:12]=[CH:11][C:10]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: C/C(N)=C/C(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(Cl)c2)c(C)n1
Temperature: 150 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
A mixture of (Z)-3-amino-N-(3-chloro-4-morpholinophenyl)but-2-enamide (2.0 g, 6.76 mmol) and triethyl orthoacetate (20 mL) was stirred at 150° C. for 12 h. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (1.63 g, 76%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[N:2]1C(=O)CC[C:3]1=O.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[CH3:18]>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][C:3]#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)c(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CC#N)c(C)c1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
Under argon atmosphere, a mixture of N-bromosuccinimide (17.8 g) and 2,2′-azobisisobutyronitrile (492 mg) was added to a solution of 1,2-dimethyl-4-methoxybenzene (13.6 g) in carbon tetrachloride (200 ml). The mixture was refluxed for 6.5 hours. The reaction mixture was cooled with ice-bath. An insoluble matter was removed by filtration, and washed with carbon tetrachloride. A combined filtrate was concentrated. The residue was dissolved into N,N-dimethylformamide (100 ml) and sodium cyanide (9.86 g) was added to the mixture. The mixture was stirred over night at room temperature. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:n-hexane=1:6→1:4) to give the title compound (11.78 g) having the following physical data.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:11][C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:11][C:10]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2oc(CCC(=O)O)nc2-c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)CCc1nc(-c2ccccc2)c(-c2ccc(O)cc2)o1
Temperature: 0 °C

Procedure:
5-(4-methoxyphenyl)-4-phenyl-2-oxazolepropanoic acid (18.5 g, 0.056 m) dissolved in 700 ml dichloromethane was treated with boron tribromide (275 ml of 1M in dichloromethane) at 25° C. for twenty hours. The solution was poured into 1 l of ice and water and extracted with 2×500 ml of diethyl ether. The organic extracts were washed with water and extracted with 2×500 ml 1N sodium hydroxide. The basic aqueous solution was acidified with 12N hydrochloric acid to pH 2 and extracted with diethyl ether. The ether solution was washed with brine, dried over anhydrous MgSO4 and evaporated. Thin layer chromatography on silica gel 60 with methylisobutylketone:CHCl3 :acetic acid 50:50:1 revealed two products detectable with U.V. and Bray's phenol spray. Comparative TLC demonstrated that the less polar product corresponded to metabolite II and the more polar product corresponded to metabolite III of Janssen et al. The two products were separated by HPLC on silica gel with methylene chloride:ethyl acetate:acetic acid 80:20:1. The appropriate fractions were pooled and evaporated. 9.0 Grams of the title and major product were obtained which were crystallized from 100 ml of hot ethyl acetate by chilling. Yield: 5.1 g, m.p. 175°-176°.
Reaction SMILES: [C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(Cl)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[C:22]([Cl:28])[N:21]=1)OC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([O:19][C:20]2[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[C:22]([Cl:28])[N:21]=2)[O:19][C:20]2[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[C:22]([Cl:28])[N:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Oc1nc(Cl)c(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Clc1cc(Cl)c(O[Si](Oc2nc(Cl)c(Cl)cc2Cl)(c2ccccc2)c2ccccc2)nc1Cl

Procedure:
In the manner described in Examples 1-7, diphenyldichlorosilane was reacted with about two moles of methyl 3,5,6-trichloro-2-pyridyl carbonate in the presence of tetrabutylammonium chloride to produce a good yield of diphenyl bis(3,5,6-trichloro-2-pyridyloxy)silane, a crystalline solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCOCC1
Temperature: 60 °C
Yield: 32.9 %

Procedure:
In the manner described in Example 21C, 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.38 mmol) from Example 21B was reacted with morpholine (99 μL, 1.14 mmol), diisopropylethyl amine (199 μL, 1.14 mmol), and tetrabutyl ammonium iodide (140 mg, 0.38 mmol). After heating at 60° C. overnight the reaction was cooled to room temperature, and 10 mL of water added. The resulting precipitate was collected by filtration and purified by HPLC on a phenyl-hexyl reverse phase column eluting with an acetonitrile/water gradient 35-55% over 60 minutes. The major peak was collected, neutralized to pH-8 with saturated sodium bicarbonate and extracted twice with ethyl acetate. The extracts were combined, dried with magnesium sulfate, and concentrated to a solid. The solid was triturated with 20:1 methanol water and the solid removed by filtration and dried to give 72 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.99 (s, 1H), 8.55 (s, 1H), 7.58 (m, 2H), 7.39 (m, 2H), 7.26 (m, 1H), 6.99 (m, 1H), 6.47 (s, 1H), 4.25 (m, 2H), 3.99 (s, 3H), 3.58 (m, 4H), 2.5-2.35 (m, 6H), 1.97 (m, 2H), 1.30 (s, 9H). LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([C:17]([O:19]CC)=[O:18])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([C:17]([OH:19])=[O:18])[C:10]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1C(c2ccccc2)=C1c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1C(c2ccccc2)=C1c1cccc(Cl)c1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
Ethyl 2-(3-chloro-phenyl)-3-phenyl-cycloprop-2-ene-1-carboxylate (0.55 g, 1.84 mmol) and potassium hydroxide (0.5 g, 9.25 mmol) were dissolved in methanol (20 cm3) and heated to reflux for 2 hours. The mixture was cooled to room temperature and the solvent evaporated. The residue was partitioned between water (30 cm3) and ethyl acetate (30 cm3). The aqueous layer was separated and washed with ethyl acetate (2×30 cm3) before being acidified to pH =1 with dilute hydrochloric acid and extracted with dichloromethane (3×40 cm3). The combined dichloromethane extracts were dried (MgSO4), evaporated, and washed with heptane to give the cyclopropene acid 0.21 g, 42%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[C:22]#[CH:23]>CN(C=O)C.[Cu]I.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>[CH2:26]([O:25][C:21](=[O:24])[C:22]#[C:23][C:10]1[C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([C@@H:12]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]2[OH:14])[CH:9]=1)[CH3:27]
Reactant: C#CC(=O)OCC
Reactant: Nc1ncnc2c1c(I)cn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2ncnc(N)c12
Temperature: 55 °C
Yield: 63.7 %

Procedure:
To a solution of the product from Step 5 (61 mg, 0.156 mmol) in DMF (2 mL) were added CuI (6 mg, 0.032 mmol) and TEA (45 μL, 0.323 mmol). The mixture was degassed with argon under sonication for 2-3 minutes and Pd(PPh3)4 (18 mg, 0.016 mmol) was added and the resulting mixture was heated at 55° C. for 15 min. Ethyl propiolate (4×5 μL, 0.197 mmol) was added to the reaction mixture at 55° C. in 30 minutes intervals. The crude mixture was concentrated and purified on silica gel with CH2Cl2/MeOH (100/1, 50/1, 25/1) as the eluents to afford 36 mg (64%) of the target compound.
Reaction SMILES: [CH3:1][C@@:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6]C(=O)N[C:3]1=[O:8].[OH2:15].N>C(OCC)(=O)C>[NH2:6][C@:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:1])[C:3]([OH:15])=[O:8]
Reactant: O
Reactant: C[C@@]1(c2ccccc2)NC(=O)NC1=O
Agent: N
Solvent: CCOC(C)=O
Product: C[C@@](N)(C(=O)O)c1ccccc1
Temperature: 160 °C

Procedure:
22 g (0.115 mol) of (+)-(5S)-5-methyl-5-phenylhydantoin, 100 ml of water and 100 ml of 28% aqueous ammonia are introduced successively into a 1 liter autoclave. The medium is heated at 160° C. for 15 hours. After cooling to room temperate, the solution is concentrated under reduced pressure. The white solid obtained is treated with 100 ml of ethyl acetate for 2 hours and then filtered and dried under vacuum at 80° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH3:20].[C:22]1(C)C=C(C)C=C(C)C=1Cl>CN(C=O)C>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9](=[O:21])[C:3]2[C:2](=[CH:7][C:6]([OH:8])=[CH:5][CH:4]=2)[O:1][CH:22]=1
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)c(OC)c1
Reactant: Cc1cc(C)c(Cl)c(C)c1
Solvent: CN(C)C=O
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)c(OC)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
BF3—OEt2 complex (14 ml, 112 mmol) was gradually added to a solution of 1-(2,4-dihydroxy-phenyl)-2-(2,4-dimethoxy-phenyl)-ethanone (8.1 gm, 28 mmol) in DMF at 0° C. The resulting solution was stirred for 30 min. Mesityl chloride (6.5 ml, 84 mmol) was then gradually added to it at 50° C. The solution was then heated up to 110° C. for 5 hours. The mixture was then concentrated. The residue was treated with ice and the solid obtained was purified with silica gel column chromatography using hexane-chloroform as the eluent to give 3-(2,4-dimethoxy-phenyl)-7-hydroxy-chromen-4-one (5.9 gm, 70%) as white solid.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)([OH:15])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[ClH:1].[F:25][C:22]([F:23])([F:24])[C:18]1[CH:17]=[C:16]([C:11]2([OH:15])[CH2:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH:21]=[CH:20][CH:19]=1
Reactant: [H][H]
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: OC1(c2cccc(C(F)(F)F)c2)CCCNC1
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A solution of gaseous hydrogen chloride in ethyl acetate was added dropwise to a solution of 64 g of 1-benzyl-3-(3-trifluoromethyl-phenyl)-piperidine-3-ol in 100 ml of ethyl acetate until the pH was acidic and the mixture was vacuum filtered. The recovered product was washed with ethyl acetate and was dried under reduced pressure to obtain 62.5 g of 1-benzyl-3-(3-trifluoromethyl-phenyl)-piperidine-3-ol hydrochloride which sublimed towards 240° C. A suspension of 60 g of the said hydrochloride in 2.4 liters of ethanol was admixed with 12 g of activated carbon containing 10% by weight of palladium hydroxide and 4.2 liters of hydrogen was bubbled therethrough at 20° C. in 2 hours. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was crystallized from 100 ml of methanol and the mixture was vacuum filtered at 5° C. The recovered product was washed with iced methanol and dried at 35° C. to obtain 43.6 g of 3-(3-trifluoromethyl-phenyl)-piperidine-3-ol hydrochloride melting at 210° C.
Reaction SMILES: [CH3:1][N:2]([CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[C:3]([C:5]1[CH:13]=[CH:12][C:8]2=[N:9][O:10][N:11]=[C:7]2[CH:6]=1)=[O:4].Cl.[NH2:22][OH:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:23][N:22]=[C:17]1[CH2:18][CH2:19][CH:14]([N:2]([CH3:1])[C:3]([C:5]2[CH:13]=[CH:12][C:8]3=[N:9][O:10][N:11]=[C:7]3[CH:6]=2)=[O:4])[CH2:15][CH2:16]1
Reactant: NO
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C(=O)c1ccc2nonc2c1)C1CCC(=NO)CC1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
N-Methyl-N-(4-oxocyclohexyl)-[2,1,3]-benzoxadiazole-5-carboxamide (0.41 g, 1.5 mmol) was dissolved in chloroform (10 ml), hydroxylamine hydrochloride (0.63 g) and triethylamine (1.6 ml) were added, and the mixture stirred overnight. Evaporation of the solvent and chromatography of the residue on silica gel, eluting with chloroform/ethyl acetate (3:2), gave a white solid (0.37 g). Mp=197-198° C., 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H); 7.93 (d, J=9.0 Hz, 1H); 7.86 (m, 1H); 7.43 (d, J=9.0 Hz, 1H); 4.90-4.70 and 3.80-3.35 (m, 1H); 2.99 and 2.88 (s+s, 3H); 2.80-1.50 ppm (s, 8H).
Reaction SMILES: [N:1]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][C:2]=12.[F:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:5]3[C:4](=[O:8])[N:3]4[CH2:9][CH2:10][CH2:11][C:2]4=[N:1][C:6]3=[O:7])[CH2:21][CH2:20]2)=[O:18])=[CH:28][CH:29]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCO)CC1
Reactant: O=c1nc2n(c(=O)[nH]1)CCC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)nc3n(c2=O)CCC3)CC1

Procedure:
In the manner described in Example 1-2), 7,8-dihydro-2H,6H-pyrrolo[1,2-a]-1,3,5-triazine-2,4(3H)-dione prepared in 1) above and 4-(4-fluorobenzoyl)-1-(2-hydroxyethyl)piperidine were condensed in N,N-dimethylformamide in the presence of triphenylphosphine and diethyl azodicarboxylate to obtain the entitled compound as a caramel-like substance.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([O:23][CH3:24])[CH:15]=1>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][C:16]=2[O:23][CH3:24])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(Cl)ccc1C(=O)O
Product: COc1cc(Cl)ccc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-chloro-2-methoxybenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl)=[O:20])([CH3:17])([CH3:16])[CH3:15].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:14]([O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1nc2c(N)cccn2c1C=O
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)OC(C)(C)C)c1CNc1cccn2c(C=O)c(C)nc12

Procedure:
Starting from 8-amino-3-formyl-2-methylimidazo[1,2-a]pyridine (4.0 g), 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (7.0 g), sodium iodide (4.1 g) and sodium carbonate (6.1 g) in acetone (250 ml) analogously using the process of Example B1 gives, after chromatography on silica gel (eluent toluene/dioxane 9:1) and recrystallization from diisopropyl ether, 7.3 g (81%) of the title compound of m.p. 210-212° C.
Reaction SMILES: O.C(OC([NH:12][C@@H:13]([C:17]([NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:21]=1[C:22]([OH:24])=[O:23])=[O:18])[CH:14]([CH3:16])[CH3:15])=O)C1C=CC=CC=1>[Pd].CO>[CH3:29][C:25]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([NH:19][C:17](=[O:18])[C@@H:13]([CH:14]([CH3:15])[CH3:16])[NH2:12])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(NC(=O)[C@H](NC(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Cc1cccc(NC(=O)[C@H](N)C(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
10% Pd-C (70 mg) was added to a 1% water-containing methanol solution (30 ml) of 2-(N-benzyloxycarbonyl-D-valyl)amino-6-methylbenzoic acid (669 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for two hours. After the catalyst was filtered off, the filtrate was concentrated to obtain 6-methyl-2-(D-valylamino)benzoic acid (347 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[NH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1>C(O)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][CH:14]1[NH:13][CH2:7][CH:6]([OH:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: Clc1ccccc1OCC1CO1
Reactant: NC1CCc2ccccc2C1
Solvent: CCO
Product: OC(CNC1CCc2ccccc2C1)COc1ccccc1Cl
Yield: 31.7 %

Procedure:
A solution of 1-(2-chlorophenoxy)-2,3-epoxypropane (2.65 g) prepared by the method described in British Patent 767,991, and 2-aminotetralin (2.1 g) in ethanol (70 ml) is heated to the reflux temperature for 5 hours. Ethanol is then evaporated off and the thus obtained residue is chromatographed on a silica gel column eluting with ethyl acetate. The residue which is obtained upon evaporation to dryness of the combined fractions is crystallized from ethyl acetate (10 ml) yielding 1.5 g of N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(2-chlorophenoxy)propanamine; m.p. 98°-101° C.
Reaction SMILES: N1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)CCCC1.Cl.ClCC[CH2:20][N:21]([CH3:23])[CH3:22]>>[CH3:20][N:21]([CH3:23])[CH2:22][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCOc1ccc(N)cc1
Temperature: 75 °C
Reaction time: 1.3 h

Procedure:
The title compound is prepared as described in Example 1 for 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine but using 1-chloro-3-dimethylamino-propane hydrochloride. After a 1.3 h stirring at 75° C. (oil bath temperature) and usual work-up, purification of the crude material by silica gel (157 g) column chromatography (CH2Cl2/MeOH, 50/50) provides the title compound as a dark brown oil: ES-MS: 195.0 [M+H]+; Rf=0.13 (CH2Cl2/EtOH, 50/50).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].Cl[C:20]1[CH:25]=[N:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][N:21]=1.[H-].[Na+].Cl>CN(C=O)C>[CH3:29][O:28][C:26]([C:23]1[CH:22]=[N:21][C:20]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[CH:25][N:24]=1)=[O:27]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C(=O)OC)cn3)cc(C)c21
Temperature: 25 °C
Yield: 61.5 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (2 g, 8 mmol) and methyl 2-chloro-5-pyrazinecarboxylate (1.95 g, 12 mmol) in DMF (40 mL) at 0° C. was added NaH (0.8 g, 20 mmol). The reaction mixture was allowed to warm up to room temperature slowly and heated at 50° C. for 1 h. The reaction mixture was cooled down and acidified to pH 3 with 6N HCl, extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, DCM/MeOH=9:1) affording the title compound (1.9 g, 61%) as a light yellow solid. 1H NMR (CDCl3) δ 8.82 (s, 1H), 8.53 (s, 1H), 7.38 (d, 1H), 7.07 (d, 1H), 5.69 (dd, 1H), 4.10 (q, 2H), 4.02 (s, 3H), 3.06 (dd, 1H), 2.43 (m, 1H), 2.39 (s, 3H), 1.23 (t, 3H).