Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[C:14]([C:16](OC)=[O:17])=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:3]1[C:15]2[C:14]([CH2:16][OH:17])=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2cccc(C(=O)OC)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2cccc(CO)c21
Reaction time: 0.5 h

Procedure:
A 50-mL round-bottom flask was placed a solution of methyl 9-ethyl-9H-carbazole-1-carboxylate (1.3 g, 5.14 mmol, 1.00 equiv) in THF (50 mL). To the mixture was added LiAlH4 (840 mg, 22.11 mmol, 4.00 equiv) in several batches at 0° C. and allowed to stir at this temperature 30 minutes. Then, the reaction was quenched with aqueous NaOH (2M, 12 mL). The mixture was then extracted with ethyl acetate (3×50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (50:1) affording (9-ethyl-9H-carbazol-1-yl)methanol as white solid (1 g, (86%). Meanwhile, a 250-mL 3-necked round-bottom was charged with a solution of (COCl)2 (840 mg, 6.67 mmol, 1.50 equiv) in DCM (40 mL). To this was added DMSO (1 g, 12.80 mmol, 3.00 equiv)-78° C. and allowed to stir for 30 min at this temperature. To this solution was added a solution of (9-ethyl-9H-carbazol-1-yl)methanol (1 g, 4.44 mmol, 1.00 equiv) in DCM (5 mL) at −78° C. The resulting solution was stirred at −78° C. for 5 hours. Then, triethylamine (TEA) (10 mL) was added and allowed to stir an additional hour at −78° C. Upon completion, the reaction was quenched with water and extracted with DCM (3×50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (50:1) affording 9-ethyl-9H-carbazole-1-carbaldehyde as light yellow solid (0.9 g, 90.8%).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][NH2:25].CCOC(C)=O>CS(C)=O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][NH:25][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COc1ccc2ncc(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cnc3ccc(OC)cc3n2)c(OC)c1
Yield: 93.2 %

Procedure:
2-Chloro-7-methoxyquinoxaline (0.51 g, 2.62 mmol), prepared according to J. Chem. Soc. Perk Trans. 1, 2001, 978-984, and (2,4-dimethoxyphenyl)methanamine (1.181 mL, 7.86 mmol) were microwaved in DMSO (2.5 mL) for 30 min at 150° C. This was diluted into 150 mL EtOAc and extracted three times with 100 mL brine. The crude product was purified by flash chromatography on a 90 g silica gel cartridge with 20 to 80% EtOAc in hexane, 50 min, at 40 mL/min to afford N-(2,4-dimethoxybenzyl)-7-methoxyquinoxalin-2-amine (795 mg, 2.443 mmol, 93% yield).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C@@H:26]([NH2:28])[CH3:27]>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C@@H:26]([NH:28][CH2:16][CH2:15][C:2]1([OH:1])[CH2:3][CH2:4][C:5]2([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]2)[CH2:13][CH2:14]1)[CH3:27]
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: Cc1ccc(C)c([C@H](C)N)c1
Product: Cc1ccc(C)c([C@H](C)NCCC2(O)CCC3(CC2)OCC(C)(C)CO3)c1
Yield: 77 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(2,5-dimethyl-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 77% of theory; LC (method 5): tR=1.12 min; Mass spectrum (ESI+): m/z=376 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:21])[CH2:4][C:5](=[O:20])[CH2:6][C:7]([O:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].COB(CC)CC.[BH4-].[Na+].OO>O1CCCC1.CO.C(OCC)(=O)C.C(O)(=O)C>[Cl:1][CH2:2][C@@H:3]([OH:21])[CH2:4][C@@H:5]([OH:20])[CH2:6][C:7]([O:9][C:10]([CH3:18])([CH3:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8]
Reactant: CC(C)(Cc1ccccc1)OC(=O)CC(=O)CC(O)CCl
Agent: CCB(CC)OC
Agent: OO
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H](O)C[C@H](O)CCl
Temperature: -75 °C
Reaction time: 0.67 h
Yield: 4.5 %

Procedure:
The crude compound 2-methyl-1-phenylpropan-2-yl 6-chloro-5-hydroxy-3-oxohexanoate (7a, 298 g) prepared in Example 1 was dissolved in a mixed solvent of tetrahydrofuran (2000 ml) and methanol (1000 ml), and the solution was cooled to −75° C. At the same temperature, methoxydiethylborane (78.8 ml) was gradually added dropwise to this solution over 20 minutes, followed by stirring for 40 minutes. Thereafter, sodium borohydride (25.0 g) was added in 5 divided portions, followed by stirring for 5 hours, and acetic acid (96 ml) was gradually added dropwise thereto. The mixture was warmed to room temperature and allowed to stand. Ethyl acetate (1800 ml) and a 3% hydrogen peroxide aqueous solution (1500 ml) were charged to the reaction section, followed by stirring for 30 minutes and extraction. The aqueous layer was reversely extracted with ethyl acetate (1000 ml), and the organic layer was combined and washed three times with a saturated sodium bicarbonate aqueous solution (1500 ml). The residue was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the crude title compound (13.6 g). A portion of the crude compound was purified by silica gel column (ethyl acetate:n-hexane=3:7(v/v)) to obtain the following NMR data.
Reaction SMILES: [OH:1][CH:2]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=N)[CH2:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1.S(=O)(=O)(O)[OH:26]>>[OH:26][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:6][CH:7]=2)[O:12][C:11](=[O:15])[CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: N=C1CC(=O)Oc2cc(OCC(O)COc3ccccc3)ccc21
Product: O=c1cc(O)c2ccc(OCC(O)COc3ccccc3)cc2o1
Reaction time: 4.5 h
Yield: 34.6 %

Procedure:
A solution of 3,4-dihydro-7-(2-hydroxy-3-phenoxypropoxy)-4-iminocoumarin (6.5 g; 0.02 mole) in 50% w/v sulphuric acid (80 g) was stirred at 100° for 3-6 hours. The initial pale red solution precipitated a yellow solid which after cooling and dilution with water was separated by decantation. After several decantations with water the oily solid was taken up in hot ethanol, charcoaled, filtered and the filtrate gradually diluted with water. The precipitated oily solid crystallised overnight to give 2.934 of buff solid of m.p. 145°-175°. Recrystallisation from aqueous methanol gave 2.275 g (34%) of material of m.p. 181°-183°, νmax (mull) 3250, 3060, 1705, 1610 cm-1 ; τ(DMSO); 5.85 (5H, m); 4.75 (1H broad exchangeable); 4.50 (1H, sharp exchangeable singlet); 3.19-2.50 (7H, complex m); 2.22 (1H, d, J 9.0 Hz); 1 low field exchangeable singlet. (Found; C, 65.48; H, 5.19; C18H16O6 requires; C, 65.85; H, 4.91%)
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].O.[N:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:2][CH2:3][CH2:4][CH2:5][N:6]=[CH:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1
Reactant: O=Cc1ccncc1
Reactant: NCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: ClCCCN=Cc1ccncc1

Procedure:
To 3-chloropropylamine HCl (15.1 g, 0.120 moles (hereinafter mol)) and H2O (100 mL) was added pyridine-4-carboxaldehyde (9.55 mL, 0.100 mol), then K2CO3 (8.28 g, 0.060 mol) then CH2Cl2 (100 mL) and the mixture was stirred for 40 min. The phases were separated and the aq phase was extracted with additional CH2Cl2 (2×50 mL), dried (Na2SO4) and concentrated to afford 17.1 g (94%) 1H NMR (CD3Cl): d 8.69 (d, J=4.5 Hz, 2H, 8.32 (s, 1H), 8.28 (s, 1H), 7.58 (d, J=4.5 Hz, 2H), 3.71 (m, 2H), 3.63 (t, J=6 Hz, 2H), 2.24 (t, J=6Hz, 2H). The presence of 9% of the aldehyde was evident by 1H NMR.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:38][CH2:39][CH2:40][C@H:41]([OH:44])[CH2:42][OH:43].OCC[C@H]1COC(C)(C)O1>>[OH:44][C@H:41]([CH2:42][OH:43])[CH2:40][CH2:39][NH:38][C:32]([N:12]1[C@@:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)([CH3:24])[C@@:14]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[N:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][C:7]=1[O:35][CH2:36][CH3:37])=[O:33]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NCC[C@H](O)CO
Agent: CC1(C)OC[C@H](CCO)O1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NCC[C@H](O)CO

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (S)-4-amino-butane-1,2-diol (prepared from (4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H41C12N4O4 [(M+H)+] 627.25, observed 627.2497.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:19]([O:26][C:27](=[O:35])[C@@H:28]([NH2:34])[CH2:29][O:30][CH:31]([F:33])[F:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CN1CCOCC1>ClCCl.C(OCC)(=O)C>[CH2:19]([O:26][C:27](=[O:35])[C@@H:28]([NH:34][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][O:14][CH:15]([F:17])[F:16])[CH2:29][O:30][CH:31]([F:33])[F:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H](COC(F)F)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)N[C@@H](COC(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of the compound of Formula IV(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxypropionic acid (1.15 g, 4.49 mmol) and the compound of Formula V(a), (S)-2-amino-3-difluoromethoxypropionic acid benzyl ester hydrochloride salt (1.15 g, 4.08 mmol), HOBt (0.689 g, 5.10 mmol) and EDCl.HCl (0.867 g, 5.10 mmol) in dichloromethane (20 mL) was added N-methylmorpholine (0.45 mL, 8.16 mmol) dropwise at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then diluted with ethyl acetate and washed successively with water, 1N HCl and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica-gel column chromatography, eluting with 10% to 12.5% ethyl acetate in hexanes, to give the compound of Formula II(a)(ii), (S)-2-((S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionylamino)-3-di-fluoromethoxy-propionic acid benzyl ester (1.29 g, 65%) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.35-7.41 (m, 5H), 7.18 (td, 1H), 6.18 (wt, 1H), 6.22 (wt, 1H), 5.25-5.20 (m, 1H), 5.19 (s, 2H), 4.82 (td, 1H), 4.42 (br s, 1H), 4.31 (td, 1H), 4.20-4.15 (m, 2H), 4.01 (dd, 1H), 1.41 (s, 9H).
Reaction SMILES: O[CH2:2][C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]4=[O:24])=[CH:14][CH:13]=3)[C:7](=[O:25])[C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:4]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C(O)(=O)C>C(Cl)Cl>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([N:5]2[C:6]3[C:7](=[O:25])[N:8]([C:12]4[CH:17]=[CH:16][C:15]([N:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]5=[O:24])=[CH:14][CH:13]=4)[CH2:9][CH2:10][C:11]=3[C:3]([CH3:2])=[N:4]2)=[CH:31][CH:30]=1
Reactant: COc1ccc(-n2nc(CO)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Agent: CC[SiH](CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2nc(C)c3c2C(=O)N(c2ccc(-n4ccccc4=O)cc2)CC3)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
To 3-hydroxymethyl-1-(4-methoxy-phenyl)-6-[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-1,4,5,6-tetrahydro-pyrazolo[3,4-c]pyridin-7-one (65 mg, 0.15 mmol) in CH2Cl2 (10 mL) was added triethylsilane (0.1 mL) and TFA (0.05 mL). After 2 h more triethylsilane (0.2 mL) and TFA (0.1 mL) were added and the reaction was stirred for 72 h. The reaction was not proceeding so the solvents were stripped and replaced with acetic acid (10 mL), triethylsilane (0.5 mL), and TFA (0.1 mL). The reaction was heated 24 h at 80° C. Mass spectra indicated only the acetyl product formed. The solvents were removed. The acetyl group was removed by stirring with LiOH (0.1 g) in THF/H2O for 3 h. The reaction was quenched with 1N HCl, extracted with EtOAc, and dried (MgSO4) to recover the alcohol. To the alcohol in CHCl3 was added PBr3 and the reaction was stirred 24 h. The reaction was quenched with ice water, extracted with CHCl3, and dried (Na2SO4). To the crude bromide were added activated Zn (80 mg) and acetic acid (10 mL) and heated to 120° C. for 24 h. The product was purified by silica gel chromatography using 0-3% MeOH in CH2Cl2 and recrystallized from CH3CN/H2O to afford 22 mg (35%); Mass Spec (M+H)+ 427.3.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][C:11]=2[F:22])[CH2:5][C@H:4]1O.C(N(C(C)C)CC)(C)C.[O:33]=[C:34]1[CH2:39][S:38][C:37]2[CH:40]=[CH:41][C:42]([C:44](O)=[O:45])=[N:43][C:36]=2[NH:35]1.O.OC1C2N=NNC=2C=CC=1.C(Cl)CCl>CN(C=O)C>[F:22][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[CH2:9][CH2:8][N:6]1[CH2:5][CH2:4][C@@H:3]([CH2:2][NH:1][C:44]([C:42]3[CH:41]=[CH:40][C:37]4[S:38][CH2:39][C:34](=[O:33])[NH:35][C:36]=4[N:43]=3)=[O:45])[CH2:7]1)=[N:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Reactant: COc1ccc2ncc(F)c(CCN3C[C@H](CN)[C@H](O)C3)c2n1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2ncc(F)c(CCN3CC[C@@H](CNC(=O)c4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 18 h
Yield: 17.8 %

Procedure:
To a stirred solution of (3S,4S)-4-(aminomethyl)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinol (105 mg, 0.34 mmole) in dry in DMF (25 mL) at RT was added diisopropylethylamine (0.18 mL, 1.02 mmole), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (0.93 mg, 0.44 mmole), hydroxybenzotriazole hydrate (51 mg, 0.38 mmole) and EDC (73 mg, 0.38 mmole). After 18 h, the reaction contents were concentrated under high vacuum. Purification on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) afforded the title compound (30 mg, 17%) as a light yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.62 (m, 1H), 8.56 (s, 1H), 8.16 (d, J=9.04 Hz, 1H), 7.99 (m, 1H), 7.83 (d, J=7.91 Hz, 1H), 7.76 (d, J=7.92 Hz, 1H), 7.05 (d, J=9.04 Hz, 1H), 4.07 (s, 3H), 3.53 (d, 2H), 2.43-3.51 (br m, 11H), 2.06 (m, 1H), 1.58 (m, 1H). LC-MS (ES) m/e 497 (M+H)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH:24]#[C:25][CH:26]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH:26]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[C:25]2[N:1]([C@H:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:24]=2)=[CH:32][CH:31]=1
Reactant: C#CC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)C[C@H](n1nncc1C(c1ccc(F)cc1)c1ccc(F)cc1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 8 from enantiomerically pure propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1,1′-prop-1-yne-3,3-diylbis(4-fluorobenzene) MS (+ESI) m/z: 499.2.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[O:31][C:32]([F:35])([F:34])[F:33]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[C:24]([O:31][C:32]([F:33])([F:34])[F:35])[CH:25]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: COc1ccc(C=O)cc1OC(F)(F)F
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1ccc(CN2C(=O)C(C)CC2c2c(OC)cccc2OC)cc1OC(F)(F)F

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-methoxy-3-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 439.85 g/mol.
Reaction SMILES: C1([C@@H](N)C)C=CC=CC=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11].C1([C@H](O)C)C=CC=CC=1>COCCOCCOC>[C:13]1([C@@H:10]([OH:12])[CH3:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)c1ccccc1
Agent: C[C@@H](O)c1ccccc1
Agent: C[C@H](N)c1ccccc1
Solvent: COCCOCCOC
Product: C[C@H](O)c1ccccc1

Procedure:
It is to be understood that for a particular chiral hydride complex, the chiral ligand thereof will produce an enantiomeric excess of a reduction product such that for that particular hydride complex, the use of the same chiral ligand but of the opposite enantiomer will give rise to the reduction product of the opposite stereochemistry. For example, whereas NaAlH2 ((+)-DDM) reduces acetophenone to (R)-1-phenylethan-1-ol in 91% enantiomeric excess (0° C.; 48 h; diglyme), reduction of acetophenone with NaAlH2 ((-)-DDM) under identical conditions will give an enantiomeric excess of (S)-1-phenylethan-1-ol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[C:11]2[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[CH3:23].[NH2:24][C:25]([NH2:27])=[O:26]>Cl.O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=3)[NH:24][C:25](=[O:26])[N:27]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: NC(N)=O
Reactant: Cc1cc(C(=O)/C=C/c2ccc(OCC(=O)O)cc2)ccc1O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(-c3ccc(OCC(=O)O)cc3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Yield: 35.5 %

Procedure:
(E)-2-(4-[3-(4-Hydroxy-3-methylphenyl)-3-oxoprop-1-enyl]phenoxy)acetic acid (10.0 g, 32.0 mmol) and urea (5.9 g, 0.10 mol) was suspended in 150 mL of 4N HCl solution in dioxane, and the reaction mixture was heated to reflux overnight, then cooled to room temperature. The resulted mixture was concentrated in vacuo to remove dioxane. The residues were suspended in 100 mL of 2-propanol and heated in a 90° C. oil bath for 10 minutes, then let it cooled down to room temperature by itself. The suspension was filtered, washed with 50 mL of 2-propanol and dried in the air. 4.0 g (35%) of yellow powder was obtained. 1H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.94 (d, 1H), 7.46 (s, 1H), 7.13 (d, 2H), 7.03 (d, 1H), 7.03 (d, 1H), 4.86 (s, 2H), 2.21 (s, 3H). MS (EI): 353 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[I:17]I>C(Cl)Cl.O.O.O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Fe+2].[N+]([O-])([O-])=O>[I:17][C:15]1[CH:14]=[CH:13][C:4]([O:5][CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[C:3]([CH2:1][CH3:2])[CH:16]=1
Reactant: CCc1ccccc1OCCN1CCCC1
Reactant: II
Agent: [Fe+2]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CCc1cc(I)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A finely triturated mixture of 0.8 g of silica gel (0.2-0.5 mm) and 0.41 g (1.00 mmol) of iron (II) nitrate nonahydrate was added to a solution of 0.44 g (2.01 mmol) of 1-[2-(2-ethylphenoxy)ethyl]pyrrolidine and 0.28 g (1.10 mmol) of iodine in 5 mL of DCM and the mixture was stirred for 12 hours at RT. The reaction mixture was filtered and the filtrate was evaporated down in vacuo. The residue was purified by column chromatography (silica gel, DCM/MeOH/sat. aqueous ammonia 9:1:0.1). Yield: 0.286 g (41% of theoretical); C14H20INO (M=345.219); calc.: molpeak (M+H)+: 346; found: molpeak (M+H)+: 346; HPLC-MS: 6.74 minutes (method A).
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14]OCC)=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:34]([NH2:36])=[O:35]>>[NH:1]([C:8]1[C:13]([CH2:14][NH:36][CH:34]=[O:35])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:30])[CH3:31])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: CCOCc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1Nc1ccccc1
Agent: Cl
Product: CN(C)CC(O)COc1ccc(Nc2ncc(CNC=O)c(Nc3ccccc3)n2)cc1
Yield: 24 %

Procedure:
4-Anilino-5-(ethoxymethyl)-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine (Example 86, 70 mg, 0.16 mmol) was dissolved in formamide (5 ml). Ethereal hydrogen chloride (1.0M; 0.19 ml, 0.19 mmol) was added, and the mixture was heated on power level 2 in a Toshiba Deltawave III domestic microwave oven (650 W) for 90 seconds. Excess formamide was removed by vacuum distillation and the residue was triturated with ethanol and diethyl ether, giving the product as a hygroscopic dihydrochloride salt (20 mg, 24%). NMR: 2.18 (s, 6H), 2.2-2.45 (m, 2H), 3.75-3.9 (m, 3H), 4.21 (d, 2H), 4.76 (br d, 1H), 6.79 (d, 2H), 7.01 (t, 1H), 7.29 (dd, 2H), 7.52 (d, 2H), 7.71 (d, 2H), 7.92 (s, 1H), 8.13 (d, 1H), 8.69 (t, 1H), 8.92 (s, 1H), 8.94 (s, 1H); MS (MH+): 437.4.