Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1B([C@@H](NC(=O)[C@@H](NC(C2C=NC=CN=2)=O)CC2C=CC=CC=2)CC(C)C)[O:5][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:36])[CH3:35])[O:3]B1[C@@H](NC(=O)[C@@H](NC(C1C=NC=CN=1)=O)CC1C=CC=CC=1)CC(C)C.[C:82](O)(=[O:90])[C@H:83]([C@@H:85]([C:87]([OH:89])=[O:88])[OH:86])O.CCCCCCC>CC(C)=O>[OH:86][C@@H:85]([C@H:83]1[C:82](=[O:90])[O:3][B:4]([C@@H:32]([NH:37][C:38](=[O:56])[C@@H:39]([NH:47][C:48]([C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:49])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:33][CH:34]([CH3:35])[CH3:36])[O:5]1)[C:87]([OH:89])=[O:88]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)OB([C@H](CC(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)c2cnccn2)O1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CC(C)=O
Solvent: CCCCCCC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1cnccn1)B1OC(=O)[C@H]([C@H](O)C(=O)O)O1
Yield: 547 %

Procedure:
A mixture of N,N′,N″-(boroxin-2,4,6-triyltris{[(1R)-3-methylbutane-1,1-diyl]imino[(2S)-1-oxo-3-phenylpropane-1,2-diyl]})tripyrazine-2-carboxamide (0.180 g, 0.164 mmol) and D-tartaric acid (147.5 mg, 0.33 mmol) were mixed in acetone (4 mL). The mixture was heated to form a solution. The solution was cooled uncontrolled until the internal temperature was about 25° C. Heptane (8 mL) was added. The mixture was evaporated to yield (S)-2-hydroxy-2-((S)-2-((R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl)-5-oxo-1,3,2-dioxaborolan-4-yl)acetic acid (0.447 g) which also contained a dimeric species. MS (m/z) in CH3CN: [M+H] calculated for C23H28BN408, 499.2000. found, 499.2.
Reaction SMILES: FC1C=C([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][N:10]=2)C=CC=1O.C(O)C.[OH-].[K+].CC(CC)CCCCBr>C1(C)C=CC=CC=1.O>[CH2:15]([C:12]1[CH:13]=[CH:14][CH:9]=[N:10][CH:11]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCc1ccc(-c2ccc(O)c(F)c2)nc1
Agent: CCC(C)CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCc1cccnc1
Reaction time: 4 h
Yield: 134.4 %

Procedure:
To this 2-(m-fluoro-p-hydroxyphenyl)-5-octylpyridine (2 g, 0.007 mol) were added ethanol (20 ml), KOH (0.4 g, 0.007 mol) and optically active 5-methylheptyl bromide (1.4 g, 0.007 mol), followed by heating the mixture under reflux with stirring for 4 hours, cooling, adding water and toluene, transferring the mixture into a separating funnel, washing the resulting organic layer with 2N-NaOH aqueous solution, washing with water, distilling off the solvent under reduced pressure and recrystallizing the residue in a freezer to obtain the objective optically active (S)-2-p-5-methyl-heptyloxy-m-fluorophenyl)-5-octylpyridine (1.8 g).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][CH:5]=1.C[Si]([C:15]#[N:16])(C)C.CN(C)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:15]#[N:16])[CH:5]=1
Reactant: COc1cc[n+]([O-])cc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
4-Methoxypyridine-N-oxide hydrate (1 g, 6.99 mmol) dissolved in dichloromethane (4 ml) was added with trimethylsilyl cyanide (1 ml, 7.69 mmol) and subsequently added dropwise with N,N-dimethylcarbamoyl chloride (0.8 ml, 9.09 mmol) under ice cooling. The reaction solution was warmed to room temperature, stirred for 1 hour, and then added further with trimethylsilyl cyanide (0.2 ml, 1.40 mmol). The reaction solution was stirred for 19 hours, then added with 10% potassium carbonate (2 ml). The mixture was diluted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting crystals were washed with hexane to obtain 560 mg (60%) of the title compound as pink crystals without purification.
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:14])C.[OH:15]O>>[CH3:14][C:5]1[C:4](=[O:3])[C:13]2[C:8]([C:7](=[O:15])[CH:6]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CCOc1c(C)ccc2ccccc12
Reactant: OO
Product: CC1=CC(=O)c2ccccc2C1=O

Procedure:
2-Methyl-1,4-naphthoquinone was prepared in much the same manner as in Example 1, except that 18.6 g of 1-ethoxy-2-methylnaphthalene (86% content) was used in place of 1-methoxy-2-methylnaphthalene and the amount of 35% hydrogen peroxide was increased to 36.0 g. The yield was 9.3 g (58.1%).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]([O:25]CC)=O)=[O:20])[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH3:28]>CO>[C:1]1([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]([NH2:28])=[O:25])=[O:20])[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: CCOC(=O)COC(=O)N1CCC(COc2cccc3ccccc23)CC1
Solvent: CO
Product: NC(=O)COC(=O)N1CCC(COc2cccc3ccccc23)CC1
Yield: 83.6 %

Procedure:
1.0 g (2.69 mmol) of 2-(ethyloxy)-2-oxoethyl 4-[(1-naphthalenyloxy)methyl]-1-piperidinecarboxylate, prepared in Step 7.3, is dissolved in 12 ml of a 7N solution of ammonia (84 mmol) in methanol. The solution is left to react at ambient temperature for 3 days. It is evaporated to dryness and the residue is purified by chromatography on silica gel, eluting with a 90/10 then 80/20, 70/30 and 50/50 mixture of dichloromethane and ethyl acetate and then with a 95/5 mixture of ethyl acetate and methanol. The eluate is subsequently recrystallized from ethyl acetate, to give 0.77 g of product.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:2]2[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: OB(O)c1ccccc1
Product: CC(C)c1ccc(N)c(-c2ccccc2)c1

Procedure:
2-bromo-4-isopropylaniline and benzene boronic acid were combined to form 2-phenyl-4-isopropylaniline,
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[C:32]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:41]4[CH2:42][CH2:43][CH:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:39][CH2:40]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCC(c3ccccc3)CC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 38.7 mg (0.24 mmol) 4-phenylpiperidine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 14 mg (19.7%) product as an orange powder. MS (ESI) m/z 592.25 (M+1).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH2:14][C:15]1[S:19][CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)[CH:16]=1)[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O1CCCC1.CO.O>C(O)(=O)C>[CH3:3][N:4]([CH2:14][C:15]1[S:19][CH:18]=[C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:25]=2)[CH:16]=1)[C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC(=O)N(C)Cc1cc(-c2ccc(CCC(=O)OCC)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCCC(=O)N(C)Cc1cc(-c2ccc(CCC(=O)O)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
100 mg (2.5 mmol, 4 eq) of sodium hydroxide are added to a solution of 245 mg (0.57 mmol, 1 eq) of ethyl 3-(4-{5-[(methyloctanoylamino)methyl]thiophen-3-yl}phenyl)propanoate in 4 mL of 9/1 tetrahydrofuran/methanol. The reaction mixture is stirred for two hours at room temperature. The reaction is stopped by adding 20 mL of water and 3 mL of acetic acid and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (90/10 dichloromethane/methanol). The oil obtained is crystallized from pentane. 85 mg of 3-(4-{5-[(methyloctanoylamino)methyl]thiophen-3-yl}phenyl)propanoic acid are obtained. Yield=37%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:12]([N:18]1[CH2:22][CH2:21][O:20][C:19]1=[O:23])(=[O:17])[CH:13]=[CH:14][CH2:15][CH3:16].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH:14]([CH2:15][CH3:16])[CH2:13][C:12]([N:18]2[CH2:22][CH2:21][O:20][C:19]2=[O:23])=[O:17])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCC=CC(=O)N1CCOC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCC(CC(=O)N1CCOC1=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of 4-trifluoromethylaniline (193 mg, 1.2 mmol) and 3-(2-pentenoyl)-1,3-oxazolidin-2-one (189 mg, 1.0 mmol) in toluene (3 ml) in a stream of nitrogen was added Pd((R)-binap)(H2O)2(OTf)2 (26.6 mg, 0.025 mmol), and the resulting mixture was stirred at room temperature for 16 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (10 ml). The organic layer was dried over anhydrous magnesium sulfate. The solvent was then evaporated off and the crude product obtained was purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective compound 3-[3-(4-trifluoromethylanilino)pentanoyl]-1,3-oxazolidin-2-one (165 mg, 50% yield). Enantiomeric excess ratio of this product was determined by a liquid chromatography using a column for separation of optical isomers (column: OA-2000) to be 70% e.e.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:10]([F:46])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([O:26][C@@H:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[C@@H:29]([C:40]([NH:42][CH3:43])=[O:41])[CH2:28]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:46])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([O:26][C@@H:27]4[CH2:32][CH2:31][NH:30][C@@H:29]([C:40]([NH:42][CH3:43])=[O:41])[CH2:28]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
TFA (25 ml) was added over a period of 5 minutes to a stirred solution of tert-butyl (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-2-[(methylamino)carbonyl]piperidine-1-carboxylate (5.94 g, 10.63 mmol) in DCM (25 ml) at 0° C., was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour after which time, the reaction was complete. The reaction mixture was concentrated to dryness, azeotroped twice with toluene and the residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 5%) to give (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-methylpiperidine-2-carboxamide (3.6 g, 74%) as a white solid: 1H NMR Spectrum: (DMSO d6) 1.60-2.03 (m, 4H), 2.50-2.58 (m, 1H), 2.59 (d, 3H), 2.78 (m, 1H), 3.53 (m, 1H), 3.84 (s, 1H), 3.96 (s, 3H), 4.84 (m, 1H), 7.27 (s, 1H), 7.35 (t, 1H), 7.47-7.60 (m, 2H), 7.85 (m, 2H), 8.38 (s, 1H), 9.56 (s, 1H); Mass Spectrum: (M+H)+ 460.1.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[C:18]([F:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=3[Cl:24])=[CH:11][C:5]=2[N+:4]=1[O-])#[N:2].P(Cl)(Cl)Cl.O.N>C(Cl)(Cl)Cl>[C:1]([C:3]1[NH:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[C:18]([F:19])=[CH:17][C:16]([C:20]([F:22])([F:23])[F:21])=[CH:15][C:14]=3[Cl:24])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: N#Cc1[nH]c2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc2[n+]1[O-]
Agent: N
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Solvent: O
Product: N#Cc1nc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc2[nH]1
Temperature: 5 °C

Procedure:
2-cyano-5-(2-chloro-4-trifluoromethyl-6-fluorophenoxy)-1H-benzimidazole-3-oxide (0.8 g) was suspended in chloroform (5cm3) stirred and cooled to 5° C. in an ice bath. Phosphorus trichloride (0.25cm ) was added dropwise and when addition was complete the mixture was heated under reflux for 5 minutes. The resulting solution was cooled, water (10cm3) added slowly and the mixture made basic with aqueous ammonia. The organic layer was separated and the aqueous layer extracted twice with chloroform. The combined organic phase was washed with water, dried (MgSO4), filtered and the filtrate evaporated under vacuum. A portion of the residue was purified by preparative plate chromatogrpahy (SiO2 ; ether) to give 2-cyano-5-(2-chloro-4-trifluormethyl-6-fluorophenoxy)benzimidazole as a pale yellow solid, recrystallised from ether/hexane. MS (positive FAB) MH+ =356.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.Br.Br[CH2:13][C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]([C:13]2[O:10][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=3[CH:7]=2)=[O:15])[CH:17]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1cccnc1)c1cc2cc(Br)ccc2o1
Reaction time: 5 h
Yield: 72.2 %

Procedure:
A mixture of 5-bromosalicylaldehyde (17.7 g), 3-bromoacetylpyridine hydrobromide (25.3 g) and anhydrous potassium carbonate (60.8 g), in 2-butanone (200 ml) was heated under reflux with stirring for 5 hours. The mixture was filtered and the solid was washed with 2-butanone. The combined filtrate and washings were evaporated and the residue was crystallised from methanol to give 5-bromobenzofuran-2-yl pyrid-3-yl ketone (19.2 g), m.p.144°-145°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH2:18]Br)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH2:20]([O:22][P:23]([O:27]CC)[O:24][CH2:25][CH3:26])[CH3:21]>>[CH2:20]([O:22][P:23]([CH2:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[O:10][C:11]=2[CH:17]=1)([O:24][CH2:25][CH3:26])=[O:27])[CH3:21]
Reactant: COc1ccc(-c2nc3ccc(CBr)cc3o2)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc2nc(-c3ccc(OC)cc3)oc2c1)OCC
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
A round bottom flask is charged with 38 g (0.12 mole) of 2-(p-methoxyphenyl)-6-bromomethyl-benzoxazole (compound of the formula (221)) in 38 ml of triethylphosphite and the reaction mixture is heated to 150° C., kept for 30 minutes at this temperature and then excess triethylphosphite is distilled off in vacuo (10 mm). The residue, a brown oil, congeals after 10 hours. The crude product (44.5 g =98.9% of theory) is stirred with hexane in a mixer. The fine crystalline suspension is filtered by suction and the filter cake is washed with hexane, affording 40 g (88.9% of theory) of 6-(diethylphosphonomethyl)-2-(p-methoxyphenyl)-benzoxazole of the formula ##STR63## in the form of light beige-coloured crystals with a melting point of 86°-88° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[CH2:14]([O:16][C:17]([NH:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:18])[CH3:15].C(=O)([O-])O.[Na+]>C(O)C>[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:22][CH2:21][N:20]([NH:19][C:17]([O:16][CH2:14][CH3:15])=[O:18])[CH2:25][CH2:24]1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)NN1CCNCC1
Reactant: O=C(CCCCBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)NN1CCN(CCCCC(=O)c2ccccc2)CC1
Yield: 89.7 %

Procedure:
29.2 g of 5-bromovalerophenone and 23 g of 1-(ethoxycarbonylamino)piperazine were dissolved in 250 ml of ethanol. 30.5 g of sodium hydrogen carbonate was added, and the mixture was heated under reflux for 6 hours. Ethanol was evaporated from the reaction mixture. After addition of water, the residue was extracted with benzene. The extract was recrystallized from benzene-hexane to give 36.2 g of the title compound having a melting point of 105° to 106° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1.[CH3:25][OH:26].[C-]#N.[Na+]>C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[O:16][C:15]([C:17]([O:26][CH3:25])=[O:18])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CO
Reactant: O=Cc1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 100 mL flask, 5-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)furan-2-carbaldehyde (0.38 g, 0.0011 mol) and methanol (30 mL) were added and the solution cooled to 0° C. To the reaction mixture, manganese (IV) oxide (0.191 g, 0.0022 mol) and sodium cyanide (0.109 g, 0.0022 mol) were added at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and was evaporated under reduced pressure to provide methyl 5-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)furan-2-carboxylate as a solid (0.35 g). 1H NMR (300 MHz, DMSO-d6): δ 9.19 (d, J=2.1 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 7.62 (d, J=3.6 Hz, 1H), 7.54 (d, J=3.6 Hz, 1H), 4.84-4.10 (br s, 4H), 3.87 (s, 3H), 3.81 (t, J=4.8 Hz, 4H): LC-MS (ESI): Calculated mass: 374.0; Observed mass [M+H]+: 375.0 (RT=1.51 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH3:12][S-:13](C)[C:14](=[N:16][C:17]#[N:18])[S-]>>[C:17]([NH:16][C:14](=[N:6][C:5]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[S:13][CH3:12])#[N:18]
Reactant: COc1ccc(N)cc1OC
Reactant: C[S-](C)C([S-])=NC#N
Product: COc1ccc(N=C(NC#N)SC)cc1OC

Procedure:
South African OPI specification No. 79/1059 describes a process for the production of 4-amino-6,7-dimethoxy-2-[4-(furo-2-yl)-piperazin-1-yl]-quinazoline (prazosin), in which 3,4-dimethoxyaniline is reacted with S,S-dimethyl-N-cyanodithioimidocarbonate to form N-cyano-N'-(3,4-dimethoxyphenyl)-S-methylisothiourea which is then condensed with 1-(furo-2-yl)-piperazine to form 4-(furo-2-yl)-piperazine-1-[N-cyano-N'-(3,4-dimethoxyphenyl)]-carboximide amide which, in turn, is closed at 180° C. to form the 4-amino-6,7-dimethoxy-2-[4-(furo-2-yl)-piperazin-1-yl]-quinazoline ring.
Reaction SMILES: [OH-].[Na+].C1(C[O:10][C:11]([C:13]2([NH:19][C:20]([C:22]3[S:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[CH:26]=3)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])C=CC=CC=1.CCOCC>O1CCCC1>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[CH:26]=[C:22]1[C:20]([NH:19][C:13]1([C:11]([OH:12])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:21]
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1cc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CCCCC1)c1cc2ccccc2s1
Yield: 83.8 %

Procedure:
42 ml of 2N aqueous sodium hydroxide solution was added to a solution of 10 g (24 mmol) of 1-[(2-benzothienylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethyl ester in 20 ml of tetrahydrofuran, and the mixture was heated under reflux for 3 days. After ether was added to the reaction solution to wash it, the aqueous layer was neutralized by concentrated hydrochloric acid and the precipitated crystal was collected by filtration. The obtained crystal was dried under reduced pressure to obtain 6.1 g (80%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.[BrH:11]>>[BrH:11].[Br:11][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: OCCCc1ccncc1
Agent: Br
Product: BrCCCc1ccncc1
Temperature: 135 °C

Procedure:
A solution of 3-pyridin-4-yl-propan-1-ol (2.88 mL) in hydrobromic acid (16 mL, 141.43 mmol) was heated at reflux at 135° C. for 18 h. The cooled solution was concentrated under vacuum and the residue was re-dissolved in isopropanol and re-concentrated (this process was repeated three more times). The residue was dissolved in isopropanol, decolouriseed by boiling with activated charcoal, filtered, and the clear solution left to crystallise in a freezer over 48 h. The resulting crystals were removed by filtration, washed with isopropanol/diethyl ether (1:1) followed by diethyl ether and then dried under vacuum at 40° C. and at room temperature to afford the sub-titled compound as a pale brown solid (3.55 g).
Reaction SMILES: [NH2:1][C:2]1([C:5]2[N:10]=[C:9]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:8]3=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=[CH:21][N:7]3[N:6]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[C:22]1([C:19]2[CH:20]=[CH:21][N:7]3[C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][C:5]([C:2]2([NH:1][C:35](=[O:36])[O:37][CH3:38])[CH2:3][CH2:4]2)=[N:6]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)Cl
Reactant: NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.2 %

Procedure:
To a stirred solution of 2-(1-aminocyclopropyl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (60.0 mg, 0.168 mmol) in DCM (10 mL) was added pyridine (0.0270 mL, 0.337 mmol) followed by methyl chloroformate (0.0140 mL, 0.185 mmol) and the reaction mixture stirred at RT for 2 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed water (2×30 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-93 as described in general methods) to give methyl (1-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (21.0 mg, 30.1%) as white solid. LCMS Condition B-34: retention time 2.29 min, [M+1]=415.0. HPLC Condition B-31: retention time 7.09 min, Purity 99.15%. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.06 (m, 2H), 1.34-1.41 (m, 2H), 3.54 (s, 3H), 4.67 (d, J=4.8 Hz, 2H), 6.68 (d, J=2.7 Hz, 1H), 7.00 (s, 1H), 7.27 (ddd, J=7.5 Hz, J=4.9 Hz, J=1.1 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.39-7.45 (m, 1H), 7.48-7.57 (m, 4H), 7.70 (d, J=2.7 Hz, 1H), 7.73-7.80 (m, 2H), 8.36-8.41 (m, 1H).