Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH:15]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)O)=[CH:11][C:10]=2[S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:6][CH:7]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1.Cl>C1(C)C=CC=CC=1>[ClH:1].[CH3:2][C:3]1[N:4]=[C:5]([NH:8][C:9]2[C:10]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:11][C:12]([CH:15]=[C:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][N:14]=2)[S:6][CH:7]=1
Reactant: Cc1csc(Nc2ncc(C(O)C3CCOCC3)cc2Sc2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1csc(Nc2ncc(C=C3CCOCC3)cc2Sc2ccccc2)n1
Temperature: 25 °C
Yield: 35 %

Procedure:
A 10 mL round-bottomed flask was charged with (6-(4-methylthiazol-2-ylamino)-5-(phenylthio)pyridin-3-yl)(tetrahydro-2H-pyran-4-yl)methanol hydrochloride (125 mg, 0.278 mmol), 4-methylbenzenesulfonic acid hydrate (5.28 mg, 0.0278 mmol), Toluene (5 mL) and heated to reflux in dean stark trap for 24 7 hours. The reaction was cooled to ambient temperature and partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (25% EtOAc in hexanes) to afford the title compound (42 mg, 35.0% yield) as after HCl salt formation. 1H NMR (CDCl3) δ 12.24 (bs, 1H), 8.18 (m, 1H), 7.71 (m, 1H), 7.54 (m, 2H), 7.30 (m, 3H), 6.40 (s, 1H), 6.20 (s, 1H), 3.78 (t, 2H), 3.65 (t, 2H), 2.45 (s, 3H), 2.42 (m, 4H). Mass spectrum (apci) m/z=396.2 (M+H—HCl).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C@@H:8]([N:15]1[CH2:21][C:20](=[O:22])[C:17]2([CH2:19][CH2:18]2)[C:16]1=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C.O>C1COCC1>[CH3:7][C@@H:8]([N:15]1[CH2:21][CH:20]([OH:22])[C:17]2([CH2:18][CH2:19]2)[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[C@H](c1ccccc1)N1CC(=O)C2(CC2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](c1ccccc1)N1CC(O)C2(CC2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a suspension of LiAlH4 (0.995 g, 26.2 mmol) in THF (40 mL) was added a solution of 5-((R)-α-methylbenzyl)-4,7-dioxo-5-azaspiro[2.4]heptane (3.0 g, 13.1 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs, then warmed up to 50° C. and continued to stir for 6 hrs. The reaction mixture was then cooled to 0° C. and ethyl acetate (10 mL) and water (10 mL) were added. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:3 (v/v) 2-butanol/n-hexane) to afford the title compound as colorless oil (2.4 g, 85%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:18]2[C:22]([CH2:23][N:24]3[C:28](=O)[C:27]4=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]4C3=O)=[N:21][N:20]=[C:19]2[CH2:35][N:36]2C(=O)C3=CC=CC=C3C2=O)=[C:8]([CH:17]=1)C(C1C=CC=CC=1)=O)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:18]3[C:19]([CH2:35][NH2:36])=[N:20][N:21]=[C:22]3[CH2:23][N:24]=[C:28]([C:27]3[CH:26]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:8]=2[CH:17]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 22, 5-nitro-2-[3,5-bis-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-nitro-1-(aminomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Si]([O:31][C:32]([O:34][CH3:35])=[CH2:33])(C(C)(C)C)(C)C>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([CH2:33][C:32]([O:34][CH3:35])=[O:31])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: COC(=O)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the procedures of Example 300, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and 1-(tert-butyldimethylsilyloxy)-1-methoxyethene were reacted to give methyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate. M/z 368.2, calc. 367.16
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([S:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>O1CCCC1>[C:7]1([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:22][CH:23]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(CSc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(CSc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
To a suspension of lithium aluminum hydride (1.95 g, 51.3 mmol) in tetrahydrofuran (50 mL) was added dropwise a tetrahydrofuran solution of 4-phenylsulfanylmethyl-benzoic acid (5 g, 20.5 mmol) described in Manufacturing Example 206-1-1, which was stirred for 30 minutes at room temperature. This mixture was cooled with ice water, and water was carefully added. The mixture was filtered through a Celite bed, and the filtrate was combined. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (2.01 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:12][C@@H:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)CO)[CH2:9][CH:10]=[CH2:11].CN.I(O)(=O)(=O)=O>CO>[CH:13](=[N:12]/[C@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH2:9][CH:10]=[CH2:11])\[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C=CC[C@H](N[C@H](CO)c1ccccc1)c1ccccc1Br
Agent: CN
Agent: [O-][I+3]([O-])([O-])O
Solvent: CO
Product: C=CC[C@H](/N=C/c1ccccc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
A stirred solution of (S)-2-((S)-1-(2-bromophenyl)but-3-enylamino)-2-phenyl-ethanol (compound 2; 124 mmol, 42.8 g) in methanol (500 mL) and methylamine (680 mmol, 71.1 mL, 33% solution in ethanol) was treated dropwise with a solution of periodic acid (340 mmol, 77 g) in methanol (50 mL) with ice/water cooling to maintain an internal temp less than 25° C. The mixture was stirred at room temperature for 3 hours then left to stand overnight. The mixture was quenched with 2M aqueous sodium hydroxide (300 mL) to give a thick precipitate that was stirred for 1 hr then the methanol was removed under vacuum. The mixture was filtered through dicalite and the gelatinous cake washed water (200 mL), then methylene chloride (250 mL) was added. Layers were separated and the aqueous layer extracted with methylene chloride (200 mL). Combined extracts dried over sodium sulfate and evaporated to give crude (S,E)-N-benzylidene-1-(2-bromo phenyl)but-3-en-1-amine (31.65 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[F:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26](OC)=[O:27])[CH2:15]1>C1COCC1>[F:13][C@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@H:16]([C:26](=[O:27])[NH:1][C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:15]1
Reactant: COC(=O)[C@@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Reactant: Nc1cnccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
To a solution of aminopyrazine (3.85 g, 40.5 mmol) in THF (120 mL) was added isopropylmagnesium chloride (2.0 M THF solution, 19 mL, 38 mmol) dropwise at 0° C. The resulting slurry was stirred at room temperature for 30 min. A solution of commercially available (2S,4R)-1-tert-butyl 2-methyl 4-fluoropyrrolidine-1,2-dicarboxylate (3.2 g, 12.9 mmol) in THF (10 mL) was added to the slurry. The reaction mixture was stirred at room temperature for 4 h and quenched with methanol (3 mL). After concentration in vacuo, ethyl acetate (120 mL) and 1N HCl (60 mL) were added to the residue. The organic layers were washed with 1N HCl, water, brine, and dried over Na2SO4, and filtered. Concentration gave (2S,4R)-tert-butyl 4-fluoro-2-(pyrazin-2-ylcarbamoyl)pyrrolidine-1-carboxylate 65A (4.1 g, 100%) as a colorless foam. LC/MS [M+H]+: 311; Ret time (Method F): 1.46 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][N:23]=1)([CH3:16])([CH3:15])[CH3:14].[I:24]I.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[C:13]([O:17][C:18]1[C:19]([I:24])=[N:20][CH:21]=[CH:22][N:23]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: II
Reactant: CC(C)(C)Oc1cnccn1
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1nccnc1I
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a solution of 5.64 g of diisopropylamine in 100 ml of THF there was added 21.1 ml of n-butyllithium (2.55M, n-hexane solution) at −75° C. under a nitrogen atmosphere, and after stirring the mixture for 30 minutes, a solution of 6.78 g of 3-t-butoxypyrazine [CAS No. 70090-30-1] in 30 ml of THF was added dropwise. After stirring at the same temperature for 4 hours, a solution of 17.9 g of iodine in 100 ml of THF was added dropwise and the mixture was stirred overnight at room temperature. Next, 800 ml of saturated aqueous sodium sulfite and 800 ml of ethyl acetate were added, and the organic layer was washed with 300 ml of saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate) to give 2-t-butoxy-3-iodopyrazine (0.77 g) as a yellow oil.
Reaction SMILES: N1C([NH:6][C:7](=[O:29])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:11]=2)=NN=N1.C1(N=C=NC2CCCCC2)CCCCC1.N>O1CCCC1>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([S:19]([NH:18][CH2:17][CH2:16][C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=2)[O:9][CH2:8][C:7]([NH2:6])=[O:29])(=[O:20])=[O:21])=[CH:27][CH:26]=1
Reactant: O=C(COc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1)Nc1nnn[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: C1CCOC1
Product: NC(=O)COc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1
Reaction time: 0.17 h

Procedure:
To a solution of 29.7 g. (72 mMol) 3-[2-(4-chlorobenzenesulphonamido)-ethyl]-phenoxymalonic acid (preparation see Example 10 e)) in 150 ml. anhydrous tetrahydrofuran are added 14.8 g. (72 mMol) dicyclohexylcarbodiimide. The reaction mixture is stirred for 10 minutes and then a weak current of ammonia is passed in for about 1 hour. It is then left to stand for 2 hours and filtered. The mother liquor is evaporated and the residue recrystallised from isohexane. There are obtained 18.0 g. (68% of theory) of colourless crystals; m.p. 113° C.
Reaction SMILES: C(OC(NC1C=C([C:15]2[C:24]3[NH:23][C:22](=[O:25])[C:21](=[O:26])[NH:20][C:19]=3[C:18]3[CH2:27][CH2:28][CH2:29][CH2:30][C:17]=3[CH:16]=2)C=CC=1)=O)(C)(C)C.F[C:32](F)(F)[C:33](O)=O>ClCCl>[NH2:20][C:19]1[CH:18]=[C:17]([N:23]2[C:24]3[CH:15]=[CH:16][C:17]4[CH2:30][CH2:29][CH2:28][CH2:27][C:18]=4[C:19]=3[NH:20][C:21](=[O:26])[C:22]2=[O:25])[CH:16]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2cc3c(c4[nH]c(=O)c(=O)[nH]c24)CCCC3)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(-n2c(=O)c(=O)[nH]c3c4c(ccc32)CCCC4)c1
Reaction time: 1 h

Procedure:
To a dichloromethane (15 mL) solution of 5-(3-tert-butoxycarbonylaminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (180 mg, 0.440 mmol) was added dropwise a dichloromethane (3 mL) solution of trifluoroacetic acid (2 mL) under cooling in an ice-bath. The mixture was stirred for one hour under cooling in ice-bath. The solvent was removed by evaporation under reduced pressure. The obtained solid was washed with ethyl acetate and water, and dried to obtain 4-(3-aminophenyl)-1,4,7,8,9,10-hexahydrobenzo[f]quinoxaline-2,3-dione (93 mg). The obtained compound was dissolved in dichloromethane (5 mL) and methanol (2 mL). To the solution, a 2M hydrogen chloride/methanol solution (0.15 mL) was added. The solvent was removed by evaporation under reduced pressure. To the obtained residue was added ethyl acetate, and the mixture was stirred at room temperature for 18 hours, filtered, and dried to obtain the titled compound as a white crystal (80 mg, yield 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH:7]=1.Br[CH:23]=[C:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH:7]=1)[CH:23]=[C:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Reactant: Cc1cc(Oc2ccc(C(F)(F)F)cn2)cc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: Cc1cc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 50 °C
Yield: 18.6 %

Procedure:
To a solution of 3-methyl-5-(5-(trifluoromethyl)pyridin-2-yloxy)phenylboronic acid (2.16 g, 0.007 mol) and tert-butyl 4-(bromomethylene)piperidine-1-carboxylate (1.67 g, 0.006 mol) in THF (20 mL) was added K3PO4 (4.48 g, 0.02 mol). The flask was put under vacuum and flushed with N2 three times. Water (0.36 mL) was added and the system was flushed with N2 again. PdCl2(dppf) (571 mg, 0.0007 mol) was added and the system was flushed with N2 two to three times again. The reaction mixture was refluxed at 50° C. for 1 h. The reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4 and concentrated under reduced pressure, The residue was purified by column chromatography (2.5% EtOAc-97.5% Hexane) to give the pure title compound (0.50 g). 1H NMR (500 MHz, CDCl3): δ 8.45 (s, 1H), 7.90 (dd, J=2.07 Hz, J=0.025 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.90 (s, 1H), 6.81 (d, J=18.5 Hz, 2H), 6.31 (s, 1H), 3.50 (t, J=5.25 Hz, 2H), 3.40 (t, J=5.3 Hz, 2H), 2.47 (t, J=5 Hz, 2H), 2.36 (s, 3H), 2.31 (s, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]=[C:5]([C:10]([CH3:12])=O)[C:6]([O:8][CH3:9])=[O:7].[NH2:17][C:18]([CH3:31])=[CH:19][C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21]>>[CH3:31][C:18]1[NH:17][C:10]([CH3:12])=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]([C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[CH3:1])[C:19]=1[C:20]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21]
Reactant: COC(=O)C(=Cc1ccccc1C)C(C)=O
Reactant: CC(N)=CC(=O)NCC(=O)OC(C)(C)C
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)NCC(=O)OC(C)(C)C)C1c1ccccc1C
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 49.5 %

Procedure:
A mixture of 327 mg (1.5 mmol) of methyl 2-(2-methylbenzylidene)acetoacetate and 318 g (1.5 mmol) of t-butyl 2-[N-(3-amino-2-butenoyl)amino]acetate was stirred in a light-shielding condition at 120° C. for 10 minutes. After cooling to room temperature, the reaction mixture was chromatographed on a silica gel column for purification, whereby 308 mg (49.5%) of the captioned compound was obtained as an oily material.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:11]=1)[CH3:9])(C)(C)C.Cl>O1CCOCC1>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:12]1[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2ccccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1cccc(Oc2ccccn2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
A mixture of (S)-{1-[3-(pyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (5 g, 16 mmol), dioxane (80 mL) and HCl (64 mL, 4N) was stirred at 50° C. for 4 h and concentrated in vacuo then CH2Cl2 (100 mL) was added and the reaction mixture was basified with NaOH (5N) followed by extraction with CH2Cl2 (2×100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated to give the title compound (3.39 g, 99% yield).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][CH2:15][CH:16]=O)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([CH2:16][CH2:15][CH2:14][C:12]2[O:11][N:10]=[C:9]([CH:8]=[CH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:13]=2)[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=CCCc1cc(C=Cc2ccccc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C(=Cc1cc(CCCN2CCN(Cc3ccccc3)CC2)on1)c1ccccc1
Yield: 68.4 %

Procedure:
About 2 min after dissolving 3-[3-(2-phenylvinyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-benylpiperazine (7.6, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (28 mg, 0.13 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 16.4 hr and followed the same processes as in Example 1 to obtain 10.6 mg (62.2%) of the target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10](=[O:13])[CH2:11][CH3:12])[CH:7]=[CH:6][C:5]=1[NH:14][C:15](=[O:17])[CH3:16])([O-:3])=[O:2].[Br:18]Br.O>C(O)(=O)C>[Br:18][CH:11]([CH3:12])[C:10]([C:8]1[CH:7]=[CH:6][C:5]([NH:14][C:15](=[O:17])[CH3:16])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)=[O:13]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)C(C)Br)cc1[N+](=O)[O-]
Temperature: 35 °C

Procedure:
To 1600 ml of acetic acid are added 46.7 g (198 mM) of N-(2-nitro-4-propanoylphenyl)acetamide. To the solution obtained, heated to 35° C., is added over 2 hours a solution of 10.13 ml (198 mM) of bromine in 200 ml of acetic acid. The reaction medium is then added gently to 5000 ml of water, and a solid crystallises out. After filtering off the solid and washing with water, 56.8 g of N-[4-(2-bromopropanoyl)-2-nitrophenyl]acetamide are obtained in the form of a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6](/[CH:8]=[C:9](\[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])/[C:10]([O:12][CH3:13])=[O:11])[CH:7]=1.[H][H]>C(O)C.O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:5]([F:22])=[CH:4][CH:3]=1)[CH2:8][C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: [H][H]
Reactant: COC(=O)/C(=C/c1cc(Br)ccc1F)NC(=O)OC(C)(C)C
Solvent: CCO
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1cc(Br)ccc1F)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
20 g (53.45 mmol) of methyl (2Z)-3-(5-bromo-2-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]acrylate (Example 4O) are dissolved in 300 ml of ethanol/dioxane (3:1). Under an argon atmosphere, 200 mg of (+)-1,2-bis((2S,5S)-2,5-diethylphospolano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate are added, and argon is passed through the solution for 30 min. The mixture is then hydrogenated under a pressure of 3.5 bar of hydrogen for 3 days. The solvent is removed on a rotary evaporator, and the crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane:ethyl acetate 2:2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:15])[C:12]=1[CH:13]=[O:14].[BH4-].[Na+].[Cl-].[NH4+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:15])[C:12]=1[CH2:13][OH:14]
Reactant: Cn1nnc(-c2ccccc2F)c1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cn1nnc(-c2ccccc2F)c1CO
Temperature: 25 °C
Yield: 86.9 %

Procedure:
To a solution of 4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazole-5-carbaldehyde (411 mg, 2.0 mmol) in MeOH (42 mL) was added sodiumborohydride (38 mg, 1.00 mmol) under Argon at room temperature and the reaction mixture was allowed to warm up to room temperature over 0.5 h. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (360 mg, 87%) as a white solid. MS: m/e=208.1 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Yield: 65.1 %

Procedure:
Methyl 4-butyrylbenzoate (256.1 mg, 1.242 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3.0 mL). 1N aqueous sodium hydroxide (3.73 mL) was added and the reaction mixture was heated to 50° C. for 3 h. The reaction mixture was then cooled to room temperature and concentrated. The crude residue was taken up in water and acidified to pH 5 by addition of 1N aqueous HCl. A colorless precipitate formed. The solids were filtered off and dried under vacuum to give 4-butyrylbenzoic acid (155.4 mg, 65%) as a colorless solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:17])=[O:5])C.Cl.[C:19](N)(=[NH:21])[CH3:20]>C(O)C>[CH3:20][C:19]1[NH:21][C:4](=[O:5])[C:6]2[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][S:8][C:7]=2[N:17]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Agent: Cl
Solvent: CCO
Product: Cc1nc2scc(-c3ccccc3)c2c(=O)[nH]1
Temperature: 25 °C

Procedure:
A stirred mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (350.43 g, 1.54 mol), acetamidine hydrochloride (725.13 g, 7.676 mol) and ethanol (1500 ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol, then crystallised from ethanol to give 2-Methyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid which was used without further purification.