Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1[CH2:20]Br)=[O:5])[CH3:2].[CH2:22]([O:24][C:25](=[O:35])[CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([Br:12])[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1[CH2:20][N:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][C:25]([O:24][CH2:22][CH3:23])=[O:35])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(Br)c(Br)n(Cc2ccccc2)c1CBr
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(Br)n1Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 1-benzyl-4,5-dibromo-2-bromomethyl-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 623 (M+Na+).
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][Zn+])([CH3:5])([CH3:4])[CH3:3].[CH2:11]([O:18][C:19]1[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]=1[CH:26]=[CH:27][CH3:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:2]([O:6][C:7](=[O:10])[CH2:8][C:23]1[CH:22]=[CH:21][C:20]([CH:26]=[CH:27][CH3:28])=[C:19]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:24]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC=Cc1ccc(Br)cc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC=Cc1ccc(CC(=O)OC(C)(C)C)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-tert-butoxy-2-oxoethylzinc chloride (12.2 mL, 6.13 mmol, 1.8 eq.) was added to a solution of 2-benzyloxy-4-bromo-1-(propenyl)-benzene (mixture of E- and Z-isomers ca. 9:1) (1.17 g, 3.40 mmol, 1.00 eq.) and bis(tri-tert-butylphosphine)palladium(0) (266 mg, 0.51 mmol, 0.15 eq.) in dioxane (27 mL). The resulting mixture was stirred at r.t. for 18 hours. The mixture was filtered through Celite and the filter cake was rinsed with dioxane. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane 100% to Heptane+12% AcOEt) to yield [3-benzyloxy-4-(propenyl)-phenyl]-acetic acid tert-butyl ester as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=O)[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]([O-:28])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:25](=[O:28])[N:15]([CH:14]4[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1n(C2CCCCC2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Yield: 107.6 %

Procedure:
The title compound was prepared using 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (40 mg, 0.11 mmol), prepared as described in Example 1, Cs2CO3 (44 mg, 0.135 mmol), bromoclohexane (100 mg, 0.61 mmol) in DMF (1 mL) and by following the procedure described in Example 9. The title compound, 7,8-bis(4-chlorophenyl)-2-cyclohexyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (26 mg, 54%) was obtained as yellow lyophilate. MS M+H=439; 1H NMR (CDCl3) δ 8.17 (1H, s), 7.30-7.38 (6H, m), 7.11 (2H, d, J=5.0 Hz), 4.38-4.41 (1H, m), 1.75-2.0 (6H, m), 1.65-1.75 (1H, m), 1.35-1.50 (2H, m), 1.1-1.30 (1H, m).
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[CH:25](=[O:28])[CH2:26][CH3:27].CC([O:32]C([C@H](O)[C@@H](O)C(OC(C)C)=O)=O)C>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:15]([CH:16]1[O:32][CH:17]1[CH:25]([OH:28])[CH2:26][CH3:27])([CH3:19])([CH3:18])[CH3:14]
Reactant: C#CC(C)(C)C
Reactant: CCC=O
Reactant: CC(C)OC(=O)[C@H](O)[C@@H](O)C(=O)OC(C)C
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CCC(O)C1OC1C(C)(C)C
Yield: 69 %

Procedure:
The product was prepared by General procedure T using 196 mg (1.1 mmol) Cy2BH, 137 μL (1.1 mmol) 3,3-dimethyl-1-butyne, 1.1 mL (2.1 mmol, 2.0 M in hexanes) Et2Zn, 9.6 mg (0.04 mmol) (−)-MIB, 72 μL (1.0 mmol) propanal, 200 μL (0.20 mmol, 1.0 M in hexanes) Ti(OiPr)4, and 42 μL (0.20 mmol) (+)-DIPT. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound in 69% yield (109 mg, 0.69 mmol). threo-diastereomer: Colorless oil. [α]D20=+80.3 (c=0.79, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.90 (s, 9H), 0.96 (t, 3H, J=7.5 Hz), 1.56-1.62 (m, 2H), 1.84 (br d, 1H, J=4.6 Hz), 2.67 (d, 1H, J=2.2 Hz), 2.80 (dd, 1H, J=5.1, 1.8 Hz), and 3.32 (m, 1H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 22.6, 25.8, 27.4, 31.6, 58.5, 64.7, and 73.2 ppm; IR (neat): 3401, 2955, 2851, 1728, 1602, 1578, 1462, 1370, 1367, and 1273 cm−1; LRMS-CI m/z 141.08 [(M−OH)+; calcd for C9H17O: 141.13]. erythro-diastereomer: Colorless oil. [α]D20=28.0 (c=0.79, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 0.90 (s, 9H), 0.99 (t, 3H, J=7.5 Hz), 1.47-1.60 (m, 2H), 1.79 (br s, 1H), 2.78 (d, 1H, J=2.2 Hz), 2.85 (t, 1H, J=2.7 Hz), and 3.72 (m, 1H) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 22.6, 25.8, 26.6, 31.6, 57.5, 62.4, and 69.6 ppm; IR (neat): 3366, 2955, 2922, 2849, 2367, 2332, 1725, 1596, 1455, and 1373 cm−1; LRMS-CI m/z 141.08 [(M−OH)+; calcd for C9H17O: 141.13].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@H:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[Cl:28])[CH:20]=4)[OH:15])=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@@H](O)c1cn(Cc2ccccc2Cl)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@@H](O)c4cn(Cc5ccccc5Cl)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (R)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]([Cl:6])=[CH:3][CH2:4]Cl.[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:12]=[CH:11]2>>[CH3:22][CH:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:4][CH:3]=[C:2]([Cl:6])[Cl:1])[CH:9]=2)[CH:14]=1)[C:19]([OH:21])=[O:20]
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reactant: ClCC=C(Cl)Cl
Product: CC(C(=O)O)c1ccc2cc(OCC=C(Cl)Cl)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 3,3-dichloroallyl chloride and racemic 6-hydroxy-α-methyl-2-naphthaleneacetic acid. White crystals are obtained having a melting point of 107°-109° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]([C:26]2[CH:35]=[C:34]([O:36][CH3:37])[C:29]3[O:30][CH2:31][CH2:32][O:33][C:28]=3[C:27]=2[F:38])[C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:22]=[CH:21][S:20][C:19]=3[C:23]([OH:25])=[O:24])[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[F:39]C1C=C(N)C=CC=1C#N.NC1C=CC(C#N)=CC=1>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C@@H:11]([C:26]2[CH:35]=[C:34]([O:36][CH3:37])[C:29]3[O:30][CH2:31][CH2:32][O:33][C:28]=3[C:27]=2[F:38])[C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:22]=[CH:21][S:20][C:19]=3[C:23]([OH:25])=[O:24])[N:13]=2)=[CH:8][C:9]=1[F:39])(=[NH:2])[NH2:3]
Reactant: COc1cc([C@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCO2
Reactant: N#Cc1ccc(N)cc1F
Agent: N#Cc1ccc(N)cc1
Product: COc1cc([C@H](Nc2ccc(C(=N)N)c(F)c2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)c(F)c2c1OCCO2

Procedure:
The same procedure was carried out as in Examples (168a) to (168d), except that 2-fluoro-4-aminobenzonitrile [CAS No. 53312-80-4] was used instead of 4-aminobenzonitrile in Example (168a), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=O)[O:10][C:9]=2[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:10])[N:25]([CH:22]([CH3:24])[CH3:23])[C:9]=2[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=C(O)c1oc(=O)c2ccccc2c1-c1ccc(F)cc1
Solvent: CCO
Product: CC(C)n1c(C(=O)O)c(-c2ccc(F)cc2)c2ccccc2c1=O
Temperature: 100 °C

Procedure:
A mixture of 4-(4-fluorophenyl)isocoumarin-3-carboxylic acid (59.8 g) and isopropylamine (210 ml) in ethanol (610 ml) was heated in a sealed pressure vessel at 100° C. for 16 hours. The mixture was then evaporated to dryness and the resulting residue was suspended in water (500 ml) and extracted with diethyl ether (100 ml). The layers were separated, and the aqueous layer was acidified to pH1 by treatment with concentrated hydrochloric acid. The precipitate was filtered off, washed with water, and crystallised from aqueous ethanol, to give 4-(4-fluorophenyl)-2-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (51.3 g) in the form of white microcrystals, m.p.128°-130° C. [Elemental analysis: C,65.0; H,5.16; N,3.98; F,5.6; H2O, 6.1%; calculated for C19H16FNO3 :1.3H2O: C,65.4; H,5.38; N,4.02; F,5.45; H2O, 6.7%].
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16]C=2)[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=C[CH:22]=1>Cl.O>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:22])[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccncc1
Reactant: COc1cccc(CCCCCc2ccccc2)c1
Agent: Cl
Solvent: O
Product: CC(CCCc1ccccc1)c1cccc(O)c1
Temperature: 190 °C

Procedure:
A mixture of 2-(3-methoxyphenyl-5-phenylpentane (20 g.) and pyridine hydrochloride (94 g.) under nitrogen is heated to 190° C. for 2 hours with vigorous stirring. The reaction mixture is cooled, dissolved in 6 N hydrochloric acid (200 ml.) and diluted with water to 600 ml. The aqueous solution is extracted with ethyl acetate (4×100 ml.), the ethyl acetate extracts dried over sodium sulfate and concentrated under vacuum to yield the crude product which is purified by silica gel chromatography to yield 2-(3-hydroxyphenyl)-5-phenylpentane as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C.[NH4+].[Cl-].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (645 mg, 3.33 mmol) was dissolved in DCM (20 ml) and then DMAP (40.7 mg, 0.333 mmol), triethylamine (1.858 ml, 13.33 mmol), and methane sulfonylchloride (0.286 ml, 3.67 mmol) were added. The reaction was stirred 1 h at rt, then diluted with DCM and saturated NH4Cl/water (1:1). The aqueous phase was extracted with DCM (×2) and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 50 g column by eluting with 10% to 100% EtOAc:Hexane to provide the desired product. LC-MS: calculated for C12H14ClNO2S 271.04 observed m/e: 271.91 (M+H)+ (Rt 1.15/2 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:39]#[C:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:39]#[C:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=1)[C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: COc1ccc(C#CBr)cc1F
Reactant: CN1CCc2c([nH]c3ccc(Cl)cc23)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: COc1ccc(C#Cn2c3c(c4cc(Cl)ccc42)CCN(C)C3)cc1F
Temperature: 80 °C
Yield: 18.1 %

Procedure:
6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (100 mg, 0.45 mmol) was mixed with CuSO4.5H2O (23 mg, 0.090 mmol), 1,10-phenanthroline (33 mg, 0.18 mmol), K3PO4 (192 mg, 0.90 mmol) and 4-(bromoethynyl)-2-fluoro-1-methoxybenzene (113 mg, 0.49 mmol) in toluene (5 ml). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 h. Product was detected by LCMS. The reaction mixture was filtered through Celite and Celite bed was rinsed with dichloromethane. Combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain 6-chloro-9-((3-fluoro-4-methoxyphenyl)ethynyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (30 mg). 1H NMR (CDCl3) FREE BASE 7.42 (d, 2H), 7.25 (m, 3H), 6.95 (t, 1H), 3.90 (s, 3H), 3.70 (s, 2H), 2.80 (m, 4H), 2.56 (s, 3H).
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[CH2:43][CH3:44])[C:37]([OH:39])=O)=[O:33].[CH2:45]([C:47]1[CH:62]=[C:61]([C:63](=[NH:66])[NH:64]O)[CH:60]=[C:59]([CH3:67])[C:48]=1[O:49][CH2:50][C@@H:51]([OH:58])[CH2:52][NH:53][C:54](=[O:57])[CH2:55][OH:56])[CH3:46]>>[CH2:45]([C:47]1[CH:62]=[C:61]([C:63]2[N:66]=[C:37]([C:36]3[CH:40]=[CH:41][C:42]([CH2:43][CH3:44])=[C:34]([CH:32]=[O:33])[CH:35]=3)[O:39][N:64]=2)[CH:60]=[C:59]([CH3:67])[C:48]=1[O:49][CH2:50][C@@H:51]([OH:58])[CH2:52][NH:53][C:54](=[O:57])[CH2:55][OH:56])[CH3:46]
Reactant: CCc1ccc(C(=O)O)cc1C=O
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCc1ccc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)cc1C=O
Yield: 24.7 %

Procedure:
The title compound (233 mg) is prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 3-formyl-4-ethyl-benzoic acid (360 mg, 2.02 mmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (657 mg, 2.02 mmol). LC-MS**: tR=0.72 min; [M+1]+=468.21; 1H NMR (D6-DMSO): δ 1.23 (t, J=7.5 Hz, 3H), 1.26 (t, J=7.5 Hz, 3H), 2.35 (s, 3H), 2.74 (q, J=7.5 Hz, 2H), 3.17 (q, J=7.3 Hz, 2H), 3.21-3.29 (m, 1H), 3.40-3.48 (m, 1H), 3.70-3.80 (m, 2H), 3.84 (d, J=5.8 Hz, 2H), 3.93-4.01 (m, 1H), 5.32 (d, J=5.0 Hz, 1H), 5.56 (t, J=5.8 Hz, 1H), 7.68-7.73 (m, 2H), 7.81 (s, 2H), 8.37 (dd, J=8.0, 1.8 Hz, 1H), 8.61 (d, J=1.8 Hz, 1H), 10.38 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6](C(=O)C(F)(F)F)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[CH:3]=1>CO.[OH-].[Na+].O>[Br:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[CH:3]=1
Reactant: O=C(N1c2ccccc2C=C(Br)c2ccccc21)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: BrC1=Cc2ccccc2Nc2ccccc21

Procedure:
A solution of 85.9 g of 10-bromo-5-(trifluoroacetyl)-5H-dibenz[b,f]azepine in 500 ml of methanol and 233 ml of normal sodium hydroxide solution is refluxed for 2 hours. The methanol is evaporated off, the concentrated reaction mixture diluted with water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is purified by chromatography over 380 g of silica gel with benzene/petroleum ether (1:1) as eluant. The fraction containing pure 10-bromo-5H-dibenz[b,f]azepine are combined and concentrated by evaporation. The residue is crystallised from cyclohexane to yield 10-bromo-5H-dibenz[b,f]azepine which melts at 65°-69° C.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH2:9][CH:10]([CH2:14][CH:15]=O)[CH2:11][CH2:12][CH:13]=1)(C)(C)C.S([CH2:29][N+:30]#[C-:31])(C1C=CC(C)=CC=1)(=O)=O.[C-]#N.[Na+].CCCC[N+:39](CCCC)(CCCC)CCCC.[F-]>CCO.C1COCC1>[NH:30]1[CH:31]=[C:15]([CH2:14][CH:10]2[CH2:9][C:8]([CH2:7][OH:6])=[CH:13][CH2:12][CH2:11]2)[N:39]=[CH:29]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1=CCCC(CC=O)C1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Agent: [F-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCC1=CCCC(Cc2c[nH]cn2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The following preparation followed the procedure by Horne et al., Heterocycles 39:139 (1994). A solution of the aldehyde (Intermediate R5; 0.34 g, 1.3 mmol) in EtOH (5 mL) was treated with tosylmethyl isocyanide (TosMIC; Aldrich; 0.25 g; 1.3 mmol) and NaCN (˜15 mg, cat) and allowed to stir at room temperature for 20 minutes. The solvent was removed in vacuo; the residue was dissolved in ˜7M NH3 in MeOH and transferred to a resealable tube before heating at 100° C. for 15 hours. The mixture was concentrated and purified by chromatography on SiO2 with 5% MeOH (sat. w/NH3):CH2Cl2. A solution of the product in THF with TBAF (1.5 eq.) was stirred at room temperature after aqueous workup. The crude product was chromatographed (5-7% NH3/MeOH in CH2Cl2) and designated Compound 2.
Reaction SMILES: CC(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)C.[CH3:18]OC(OC)(C)C.Cl.CCOCC>CO>[CH3:18][O:17][C:15]([CH:12]1[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]1)=[O:16]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1CCC(N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
(1r,4r)-4-(tert-Butoxycarbonylamino)cyclohexanecarboxylic acid (25 g, 103 mmol) was dissolved in MeOH (250 ml), to which 2,2-dimethoxypropane (10.70 g, 12.63 ml, 103 mmol) and then 2M HCl in ether (51 ml, 103 mmol) were added. The reaction mixture was stirred at room temperature overnight, then concentrated and the residue was treated with ether (100 ml). The resulting white suspension was filtered then dried to afford a white powder (16.8 g, 84% yield).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:5])[O-:4].C[NH3+].Cl[CH:9]([C:13](=[O:15])[CH3:14])[C:10](=O)[CH3:11].CCOCC>CO>[C:13]([C:9]1[S:5][C:3](=[O:4])[N:2]([CH3:1])[C:10]=1[CH3:11])(=[O:15])[CH3:14]
Reactant: CNC([O-])=S
Reactant: CC(=O)C(Cl)C(C)=O
Agent: C[NH3+]
Solvent: CCOCC
Solvent: CO
Product: CC(=O)c1sc(=O)n(C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylammonium N-methylthio-carbamate (13.1 g, 0.105 mol; prepared from methylamine and carbonyl sulfide as described, Y. Gelernt et al. 1974, J. Chem. Soc. Perkin Trans. 1, 2610) was partially dissolved in MeOH (150 mL). 3-Chloro-pentane-2,4-dione (14.9 mL, 0.125 mol) was added drop-wise at room temperature, producing a gradual exotherm to 40° C. After stirring at room temperature for 1 h, the solvent was removed in vacuo. The residue was treated with H2O (50 mL) and was extracted with CH2Cl2 (3×50 mL). The combined organic fractions were washed (brine), dried (Na2SO4), filtered, and evaporated in vacuo to an amber-coloured oil. This was purified by chromatography (300 g SiO2, eluting with 1:1 heptane/Et2O to obtain non-cyclized adduct, then Et2O to obtain 5-acetyl-3,4-dimethyl-3H-thiazol-2-one, which was recrystallized from EtOH as colourless needles (14.2 g). 1H-NMR (CDCl3): δ 2.34 (s, 3H), 2.59 (s, 3H), 3.33 (s, 3H). IR (ATR): 1655 and 1621 cm−1 (CO str).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([NH:34][C@@H:35]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][CH:41]=3)[C:36](O)=[O:37])=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>>[CH2:1]([N:8]([CH2:9][CH:10]([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])[C:36](=[O:37])[C@@H:35]([NH:34][C:32](=[O:33])[O:31][CH2:30][CH:28]1[C:29]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CNCc1ccccc1)OCC
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(CN(Cc1ccccc1)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Yield: 43.5 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, N-benzyl-2,2-diethoxyethanamine (Compound IX-13) (43.3 g, 190 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (128.6 g, 280 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=4:1) to obtain the title compound (55.0 g, 43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cccc(F)c4)ncnc32)CC1

Procedure:
4-[4-(3-Fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 3-fluorophenol (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.93-2.08 (m, 4H), 2.97-3.07 (m, 2H), 4.05-4.15 (m, 2H), 4.98-5.03 (m, 1H), 7.20-7.24 (m, 2H), 7.33-7.38 (m, 1H), 7.52-7.56 (m, 1H), 8.28 (s, 1H), 8.58 (s, 1H). Mass spectrum MH+=414.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH2:23]2)=[CH:18][C:17]=1[OH:26]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][C:16]([O:15][CH3:14])=[C:17]([OH:26])[CH:18]=4)[CH2:23]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1cc2c(cc1O)CCNC2
Product: COc1cc2c(cc1O)CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-methoxy-1,2,3,4-tetrahydro-isoquinolin-6-ol to provide the title compound as a solid.