Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]=[N:14][CH:15]([NH:21][C:22](=O)[CH2:23][Cl:24])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:22]([CH2:23][Cl:24])=[N:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:14]1)=[O:5]
Reactant: CCOC(=O)C(N=Nc1sc(CC)cc1C(=O)c1ccccc1Cl)NC(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)c1nc(CCl)n(-c2sc(CC)cc2C(=O)c2ccccc2Cl)n1

Procedure:
A mixture of 4.44 g. of ethyl [3-(2-chlorobenzoyl)-5-ethyl-2-thienyl]azochloroacetylaminoacetate, 1.90 g. of p-toluenesulfonic acid (monohydrate) and 80 ml. of benzene is refluxed for 40 minutes, then washed successively with an aqueous solution of sodium hydrogen carbonate and water, and dried over sodium sulfate. Thereafter, the solvent is evaporated to give ethyl 1-[3-(2-chlorobenzoyl)-5-ethyl-2-thienyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylate as crystals. Recrystallization from ethanol yields pale yellow prisms melting at 114° to 115° C.
Reaction SMILES: COC1C=CC([Bi]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)C2C=CC(OC)=CC=2)=CC=1.C(OO)(=O)C.[CH2:31]([CH:33]1[CH:59]=[C:58]([CH3:60])[CH2:57][CH:56]([CH3:61])[CH2:55][CH:54]([O:62][CH3:63])[CH:53]2[O:64][C:49]([OH:68])([CH:50]([CH3:67])[CH2:51][CH:52]2[O:65][CH3:66])[C:48](=[O:69])[C:47](=[O:70])[N:46]2[CH:41]([CH2:42][CH2:43][CH2:44][CH2:45]2)[C:40](=[O:71])[O:39][CH:38]([C:72]([CH3:82])=[CH:73][CH:74]2[CH2:79][CH2:78][CH:77]([OH:80])[CH:76]([OH:81])[CH2:75]2)[CH:37]([CH3:83])[CH:36]([OH:84])[CH2:35][C:34]1=[O:85])[CH3:32].CC(=O)C(=O)CCCCCCC(=O)CCCCCC(=O)CC=CCCCCCCCCC.C(C1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(=O)C(=O)N2C(CCCC2)C(=O)OC(C(C)=CC2CCC(O)C(OC3C=CC(OC)=CC=3)C2)C(C)C(O)CC1=O)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C1COCC1>[CH2:31]([CH:33]1[CH:59]=[C:58]([CH3:60])[CH2:57][CH:56]([CH3:61])[CH2:55][CH:54]([O:62][CH3:63])[CH:53]2[O:64][C:49]([OH:68])([CH:50]([CH3:67])[CH2:51][CH:52]2[O:65][CH3:66])[C:48](=[O:69])[C:47](=[O:70])[N:46]2[CH:41]([CH2:42][CH2:43][CH2:44][CH2:45]2)[C:40](=[O:71])[O:39][CH:38]([C:72]([CH3:82])=[CH:73][CH:74]2[CH2:79][CH2:78][CH:77]([O:80][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:76]([OH:81])[CH2:75]2)[CH:37]([CH3:83])[CH:36]([OH:84])[CH2:35][C:34]1=[O:85])[CH3:32]
Reactant: COc1ccc([Bi](c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Cu+2]
Agent: CC(=O)OO
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc(OC)cc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 168 h

Procedure:
To a stirred solution of tri(4-methoxyphenyl)bismuthine (136 mg, 0.257 mmol, 2 eq.) in methylene chloride (4 mL) was added peracetic acid (0.054 mL, 0.257 mmol, 2 eq, 32% solution in dilute acetic acid). To this stirred solution was added 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg, 0.126 mmol, 1 eq), THF (0.5 mL), and copper (II) acetate (7 mg, 0.038 mmol, 0.3 eq). The mixture was allowed to stir for 7 days. The reaction was quenched with saturated aqueous NaCl plus 2 drops 2N HCl and extracted 4× with methylene chloride. The organic extracts were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The products were separated by preparative TLC on silica gel (2:1 hexanes/acetone). Each compound was repurified 2× by preparative TLC on silica gel (3:1 hexanes/acetone then 3.5% MeOH/CH2Cl2) affording 23.4 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-methoxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-22.3.1.04,9 !octacos-18-ene-2,3,10,16-tetraone and 28.4 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-methoxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis were consistent with the desired structures).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1)=[CH2:2].B.C1C[O:18]CC1.[OH-].[Na+].OO>C1COCC1.O>[OH:18][CH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[S:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1
Reactant: C=Cc1ccc2c(c1)NC(=O)CS2
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C1CSc2ccc(CCO)cc2N1
Temperature: 50 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
To a stirred solution of 6-vinyl-4H-benzo[1,4]thiazin-3-one (5.73 g, 30.0 mmole) in dry THF (100 mL) at RT was added 2M BH3.THF (7.5 mL, 15.0 mmole). After 24 h, H2O (15 mL) was slowly added to the reaction mixture followed by 3M NaOH (5 mL) and 30% H2O2 (3.3 mL). After the reaction solution was stirred for 3 h at 50° C., the reaction was concentrated under vacuum. The residue was dissolved in EtOAc and washed with H2O (20 mL) and 1M HCl (20 mL). The organic solution was dried (Na2SO4), concentrated under vacuum, and the remaining solid purified on silica (CH2Cl2/CH3OH, 95:5) afforded the title compound (2.60 g, 41%) as light yellow solid: LC-MS (ES): m/e 210 (M+H)+.
Reaction SMILES: CN(CCC1[C:10]2[CH:11]=[C:12]([CH2:15][C@@H:16]3[NH:21][C:19](=[O:20])[O:18][CH2:17]3)[CH:13]=[CH:14][C:9]=2[NH:8]C=1)C.[NH2:22]C1C=CC(C[C@H]2COC(=O)N2)=CC=1.N([O-])=O.[Na+].Cl>>[NH:8]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]2[CH2:17][O:18][C:19](=[O:20])[NH:21]2)=[CH:11][CH:10]=1)[NH2:22]
Reactant: Nc1ccc(C[C@H]2COC(=O)N2)cc1
Reactant: CN(C)CCc1c[nH]c2ccc(C[C@H]3COC(=O)N3)cc12
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: NNc1ccc(C[C@H]2COC(=O)N2)cc1

Procedure:
Zolmitriptan was first disclosed in U.S. Pat. No. 5,466,699 and the synthetic route comprises diazotization of (S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one with sodium nitrite in presence of hydrochloric acid, followed by treatment of the diazonium salt with stannous chloride to give (S)-4-(4-hydrazinobenzyl)-1,3-oxazolidin-2-one. Further reaction of the hydrazine derivative with dimethylamino butyraldehyde diethyl acetal followed by chromatographic purification gave Zolmitriptan (I) as oil, which upon further crystallization from isopropanol gave Zolmitriptan of desired purity. (S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one, in turn, was obtained from L-4-nitrophenyl alanine by treating it with thionyl chloride and methanol to give (S)-methyl-4-nitrophenyl alanate, which on reduction with sodium borohydride gave the corresponding alcohol. Further reaction of the said alcohol with phosgene in presence of potassium hydroxide followed by hydrogenation in presence of palladium on carbon gave the desired (S)-4-(4-aminobenzyl)-1,3-oxazolidin-2-one.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([NH2:17])[C:11]=1[Cl:18])[CH3:7].O[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>O>[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([NH:17][CH2:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:11]=1[Cl:18])[CH3:7]
Reactant: O=S(=O)(CO)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc(Cl)cc(N)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cc(Cl)cc(NCS(=O)(=O)c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
1 g of concentrated sulfuric acid was added to 2.32 g (10mmoles) of 2,5-dichloro-3-aminobenzoic acid ethyl ester, 2.27 g (11mmoles) of hydroxymethyl-(4-chlorophenyl)-sulfone and 40 ml of water whilst stirring at room temperature. The mixture was stirred for a further 3 hours at room temperature, the solid was filtered off and dissolved in about 100 ml of methylene chloride, the solution was dried over magnesium sulfate and worked up in the usual manner and the product was recrystallized from ethylene chloride. 3.0 g (71% of theory) of 2,5-dichloro-3-[(4-chlorophenyl)-sulfonylmethylamino]-benzoic acid ethyl ester were obtained in the form of colorless crystals of melting point 173°-175° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:16]([CH2:19][CH3:20])([O-:18])=[O:17]>>[F:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[C:19]([N+:16]([O-:18])=[O:17])[CH3:20])=[CH:3][C:2]=1[F:1]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1ccc(F)c(F)c1)[N+](=O)[O-]
Temperature: 4 °C
Yield: 75.6 %

Procedure:
3,4-difluorobenzaldehyde (54 g, 380 mmol), ammonium acetate (19 g, 247 mmol), and 4 Å molecular sieves (54 g) were combined in nitroethane (810 mL) and heated at reflux for 24 hours. The reaction was filtered, and concentrated in vacuo. The resultant mixture was partitioned between ethyl acetate (500 mL) and water (300 mL). The organic phase was separated, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was cooled to 4° C. for 2 hours then ethanol (100 mL) was added to give yellow crystals which were collected by filtration. (57.2 g 75.6% yield). 1H NMR (400 MHz, CDCl3) δ 8.0 (s, 1H), 7.15-7.25 (m, 2H), 3.7 (t, 1H), 2.4 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.CS(C)=O.N1CCOCC1>C1COCC1.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.6 %

Procedure:
A flask containing tetrakis(triphenylphosphine)-palladium (0) (56 mg, 0.049 mmol) was flushed with nitrogen, before a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (96 mg, 0.323 mmol) in anhydrous THF (1.5 ml) was added, followed by DMSO (0.1 ml) and morpholine (0.28 ml, 0.049 mmol). The resulting mixture was stirred at room temperature under nitrogen for 72 hours. The reaction mixture was dissolved in EtOAc (25 ml) and washed with 2M HCl aq. (25 ml). The organic extract was dried (MgSO4) filtered and evaporated under reduced pressure. Purification by amino propyl SPE (2 g) loading and washing with methanol and then eluting the product with 5% acetic acid in methanol. Evaporation of fractions containing product afforded the title compound as a white solid (27 mg, 33%). NMR; δH (400 MHz, d6-DMSO) 0.85 (t, 3H, J=7 Hz), 1.20-1.34 (m, 4H), 1.57-1.67 (m, 2H), 3.84 (t, 2H, J=7 Hz), 11.19 (s, 1H), 14.38 (br. s, 1H); m/z 257.2 [MH+].
Reaction SMILES: [C:1]([CH2:3][C@@:4]1([C:30](OC)=[O:31])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]CC3C=CC=CC=3)[CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])#[N:2]>CO.[Ni]>[OH:15][C:11]1[CH:10]=[C:9]([C@H:6]2[CH2:7][CH2:8][C@:4]3([CH2:3][CH2:1][NH:2][C:30]3=[O:31])[N:5]2[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@]1(CC#N)CC[C@H](c2cccc(OCc3ccccc3)c2)N1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@@H](c2cccc(O)c2)CC[C@]12CCNC2=O
Reaction time: 4 h
Yield: 48.4 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-2-(cyanomethyl)-5-{3-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D44, 1.15 g, 2.55 mmol) in methanol (40 mL) was added Raney Nickel (slurry in water, 10 g) and the mixture was stirred under a hydrogen atmosphere (7 atm) for 4 hours. The catalyst was filtered off, the solvent removed under reduced pressure, and the solid residue was treated with toluene (3×20 mL) and dried under vacuum. The crude oil obtained was refluxed in methanol (100 mL) for 7 hours until a complete cyclization was observed. The solvent was removed under reduced pressure and the crude material purified by chromatography on silica gel using dichloromethane/methanol (100:0 to 95:5) to afford the title compound (0.41 g, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:7][CH:8]=1>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=CCCCCCOc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cccc(CCCCCCCOc2ccccc2)c1

Procedure:
1-(3-Methoxyphenyl)-7-phenoxy-heptane (8.2) was synthesized as described in 8.1 using 7.2 (0.55 g, 1.86 mmol), AcOEt (20 mL), and 10% Pd/C (0.080 g, 15% w/w). The title compound (8.2) was isolated as a colorless viscous liquid (0.53 g, 0.96% yield).
Reaction SMILES: [C:1]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[BH4-].[Na+]>C(O)C>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:15][CH:16]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC#Cc1ccc(CO)cc1
Yield: 82.6 %

Procedure:
To a solution of 4-(1-octynyl)benzaldehyde (15 g, 0.07 mole from example 4) in ethanol (200 ml) was added sodium borohydride (1.32 g, 0.035 mole) in ethanol and the mixture was stirred for 5 minutes until no further aldehyde remained. The solution was concentrated, ether was added and the solution was washed with water and dried (MgSO4). Evaporation gave an oil which was chromatographed on silica eluting with dichloromethane to give 12.5 g (82%) of the alcohol as an oil, νmax (film) 815, 840, 1020, 1040, 1510, 2220, 3300 cm-1 ; δ(CDCl3) 0.88 (3H, distorted t, terminal CH3), 1.1-1.8 (8H, m, alkylene chain), 2.2 (1H exchangeable, OH), 2.36 (2H, t, J 7 Hz, CH2 --C≡C), 4.56 (2H, s, CH2O), 7.3 (4H, ABq, aromatics). M+ 216.1524 (C15H20O requires, 216.1514).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>O1CCCC1.O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH3:13]
Reactant: COCCCN
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CNCCCOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A solution containing 52 g of 3-methoxypropylamine in 100 ml of tetrahydrofuran is immersed in iced water and a solution containing 27 g of ethyl bromoacetate in 30 ml of tetrahydrofuran is added dropwise for 1 hour. The resultant is stirred at room temperature for 2 hours and the solvent and the excess 3-methoxypropylamine are evaporated under reduced pressure. The residue is purified by silica gel column chromatography (ethanol:dichloromethane=1:20) to obtain 19 g of the captioned compound in the form of colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([C@H:22]4[CH2:26][CH2:25][O:24][CH2:23]4)[N:20]=[CH:19][C:18]=3[C:27]([O:29]CC)=O)=[C:13]([N+:32]([O-])=O)[CH:12]=2)=[C:6]([CH3:35])[CH:5]=1)[CH3:2].O>C(O)(=O)C.[Fe]>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[N:21]([C@H:22]5[CH2:26][CH2:25][O:24][CH2:23]5)[N:20]=[CH:19][C:18]=4[C:27](=[O:29])[NH:32][C:13]=3[CH:12]=2)=[C:6]([CH3:35])[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cc(OCC)nc2C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn([C@H]4CCOC4)c23)c(C)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 19.6 %

Procedure:
Ethyl 5-[4-(6-ethoxy-2,4-dimethylpyridin-3-yl)-2-nitrophenyl]-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (97 mg) was dissolved in acetic acid (1 mL). Iron powder (56 mg) was added to the solution, and the mixture was stirred at 90° C. for four hours. The reaction mixture was returned to room temperature, and water (2 mL) was added to the reaction mixture. The precipitated solid was collected by filtration and washed with water. The resulting solid was dissolved in ethanol (1 mL) at 90° C. The solution was ice-cooled, and the precipitated solid was collected by filtration. The resulting solid was washed with MTBE to give the title compound (16 mg).
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[O:5][N:4]=1.[Cl-].[Li+].CS([Cl:26])(=O)=O>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:26][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[O:5][N:4]=1
Reactant: COc1cc(-c2cc(CO)no2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(-c2cc(CCl)no2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
3-Hydroxymethyl-5-(3,4,5-trimethoxyphenyl)isoxazole (1.62 g) was dissolved in pyridine (10 mL), and lithium chloride (336 mg) was added to the solution. Methanesulfonyl chloride (908 mg) was added dropwise to the resultant mixture under ice cooling, and the mixture was stirred at room temperature for2 hours. The reaction mixture was diluted with ethyl acetate, washed with 2 M hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([OH:24])=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH2:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:36][C:22]([CH:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:24])([CH3:34])[CH3:35])=[CH:29][CH:28]=1
Reactant: COc1ccc(C(C)(C)N)cc1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: COc1ccc(C(C)(C)NC(=O)C2CC[C@H]3[C@@H]4CC=C5N(C)C(=O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 72 %

Procedure:
The title compound was prepared in a yield of 72% in a similar manner to that described in Example 37 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and 1-(4-methoxyphenyl)-1-methylethylamine.
Reaction SMILES: N1CCC[CH2:2]1.[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:15]=2)[CH:12]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[C:14]([N:16]3[CH2:17][CH2:2][CH:20]([O:19][CH3:18])[CH2:21]3)[N:15]=2)[CH:12]=1
Reactant: Brc1ccc2nc(N3CCOCC3)nn2c1
Reactant: C1CCNC1
Product: COC1CCN(c2nc3ccc(Br)cn3n2)C1

Procedure:
Using pyrrolidine, this compound was prepared following the same method as for the synthesis of 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridine Brown solid (2.5 g, 47%). MS: m/z=298 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]3)[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:7]=1.C([O-])([O-])=O.[Na+:33].[Na+]>>[Na+:33].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[N:9]=[C:10]([CH:18]3[CH2:19][CH2:20][CH:21]([C:24]([O-:26])=[O:25])[CH2:22][CH2:23]3)[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1nc(C2CCC(C(=O)O)CC2)cc2cccnc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(F)cc1-c1nc(C2CCC(C(=O)[O-])CC2)cc2cccnc12

Procedure:
This is prepared, analogously to Example 3, from the product of Example 7, using anhydrous Na2CO3. MH+ 381.1 (parent acid seen).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].Cl.[H][H].N[C@H](CC1C=CC=CC=1)CO>CO.O.[Pd]>[C:6]1([CH2:5][C@@H:2]([NH2:1])[CH2:3][NH2:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#C[C@H](N)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: N[C@@H](CO)Cc1ccccc1
Solvent: CO
Solvent: O
Product: NC[C@H](N)Cc1ccccc1
Reaction time: 19 h
Yield: 6 %

Procedure:
To a solution of 9.0 g (49 mmol) of (R)-2-amino-3-phenylpropionitrile.HCl-salt (97.5% e.e.) in 280 mL of methanol-water 1:1 was added 2.2 equiv. of conc. HCl solution and 2.0 g of 5% Pd/C. The solution was hydrogenated for 19 h at 35° C. and 0.9 MPa of hydrogen pressure. Then additional 2 g of Pd/C was added and hydrogenation was continued for 24 h at 3.0 MPa. According to chiral HPLC 91% of (R)-2-amino-3-phenyl-1-propanol was formed together with 6% of (R)-3-phenyl-1,2-diaminopropane The reaction mixture was filtered and partially evaporated. The solution was basified to pH 10 using diluted NaOH solution and extracted with CH2CL2. The organic solution was dried over Na2SO4 and evaporated.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C(OCC)(=O)C.C(OCC)C>[Br:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: FC(F)(F)c1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 100 °C
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-trifluoromethylpyrimidine (1.224 g, 6.71 mmol) and 3-bromo-5-(trifluoromethyl)aniline (1.4 g, 5.83 mmol) in dioxane (20 ml) was added p-toluene-sulfonic acid monohydrate (1.220 g, 6.42 mmol). An immediate white suspension formed. The tube was sealed and the slurry was stirred and heated at 100° C. for 24 h. The now clear solution was diluted with ethyl acetate and diethyl ether and washed with saturated NaHCO3 (aq.). The organic fraction was dried over MgSO4 and concentrated in vacuo. Product was further purified by column chromatography on silica gel, eluting with ethyl acetate/hexane with a gradient 0-30% to afford N-[3-bromo-5-(trifluoromethyl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (2.252 g, 87%) as a light beige solid. MS APCI: [M+H]+ m/z 386.0. 1H NMR (400 MHz, CDCl3): δ 8.75 (d, J=4.9 Hz, 1H); 8.09 (s, 1H); 7.94 (s, 1H); 7.52-7.43 (m, 2H); 7.17 (d, J=4.9 Hz, 1H). rhSYK activity=+.