Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.O>CN(C=O)C>[C:7]1(=[O:11])[C:8]2[C:4](=[CH:3][C:2]([O:1][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)[CH2:5][NH:6]1
Reactant: O=C1NCc2cc(O)ccc21
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
To a slurry of Nail (0.39 g, 16.1 mmol) in DMF at 0° C. was added 5-hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp. and was stirred for 45 min., then 4-fluoro-1-nitrobenzene was added and then mixture was heated at 70° C. for 3 h. The mixture was cooled to 0° C. and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene as a dark yellow solid (3.23 g, 89%): TLC (100% EtOAc) Rf 0.35.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C@@H:6]([C:8]([OH:10])=O)[C@H:5]([C:11]([OH:13])=O)[CH2:4][C:3]=1[CH3:14].S(Cl)(Cl)=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C(OCC)C>[CH2:19]([N:21]([CH2:22][CH3:23])[C:8]([C@H:6]1[C@H:5]([C:11]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:13])[CH2:4][C:3]([CH3:14])=[C:2]([CH3:1])[CH2:7]1)=[O:10])[CH3:20]
Reactant: CC1=C(C)C[C@@H](C(=O)O)[C@H](C(=O)O)C1
Reactant: CCNCC
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)[C@@H]1CC(C)=C(C)C[C@H]1C(=O)N(CC)CC
Reaction time: 2 h

Procedure:
To trans-1,2-dimethylcyclohexene-4,5-dicarboxylic acid (1.98 g 0.01 mol) heated to 80° C., was added thionyl chloride (2.38 g, 0.02 mol) over 1 hr. The mixture was kept at this temperature for a further two hours, then cooled and added dropwise to a diethyl ether solution (45 ml) of excess diethylamine (14.6 g, 0.2 mol) cooled to ice bath temperature. The solvent was removed to give the crude product as an oil which was not purified for use in the next stage.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=3)[S:13][C:6]=12.S(Cl)([Cl:31])=O>>[Cl:31][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:2]=3[F:1])[CH:11]=2)=[N:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CO)cn4)sc23)c(F)c1
Reactant: O=S(Cl)Cl
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cn4)sc23)c(F)c1
Temperature: 0 °C
Yield: 88 %

Procedure:
A solution of 101 (2.23 g, 5.61 mmol) in thionyl chloride (8.14 mL) under nitrogen was stirred at RT overnight. The reaction mixture was cooled down to 0° C., and ice was added. The resultant suspension was stirred for 1 h, the solid was collected by filtration, rinsed with water and dried under high vacuum to afford the title compound 102 (2.06 g, 4.96 mmol, 88% yield) as a yellow fluffy solid which was used in the next step without any further purification. MS (m/z): 416.4 and 418.4 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[N:18]([CH3:33])[N:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:33][N:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:34])=[O:3])=[CH:10][CH:11]=2)=[CH:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=2)=[N:19]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described for example 1 f], {6-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain {6-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid as off-white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[CH3:13][CH2:14][CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[CH3:13][CH2:14][CH:15]([NH:19][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH3:12])[CH:5]=1)[CH2:16][CH2:17][CH3:18]
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: CCCC(N)CC
Product: CCCC(CC)NC(=O)c1ccc(OC)c(C)c1

Procedure:
Prepared in a similar manner to example 4 using 4-methoxy-3-methylbenzoic acid and hexan-3-amine (example 28a). 1H NMR (500 MHz, CDCl3): δ 0.94 (m, 6H); 1.41 (m, 4H); 1.46 (m, 1H); 1.64 (m, 1H); 2.24 (s, 3H); 3.87 (s, 3H); 4.08 (m, 1H); 5.69 (d, 1H); 6.83 (d, 1H); 7.54 (s, 1H); 7.62 (d, 1H). MS (M+H, 250).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O>C(O)C>[CH2:15]([O:14][C:7](=[O:13])[C:8]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:8](=[O:10])[C:7]([OH:14])=[O:13])=[O:10])[CH3:16]
Reactant: NCCCCN
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=O)NCCCCNC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1,4-diaminobutane (88.2 grams) in 100 mL ethanol was added to ice cooled diethyl oxalate (1461 grams) in ethanol (1400 mL) over 40 minutes, maintaining the internal temperature below 8° C. The reaction was allowed to gradually warm to ambient temperature, and after 48 hours, the crude solids (168 grams) were collected by filtration. The product (22 grams) was purified by flash column chromatography (EtOAc as the eluent) and then boiled in MTBE (200 mL) to obtain butylene-bis-oxamic acid ethyl ester as a white solid having a melting point in the range of 114.4 to 116.4° C. 1H NMR (CDCl3, 300 MHz) δ 7.23 (brs, 2H), 4.33 (q, J=7.1 Hz, 4H), 3.36 (q, J=6.5 Hz, 4H), 1.64-1.59 (m, 4H), 1.36 (t, J=7.2 Hz, 6H).
Reaction SMILES: [Cl:1]CCl.[OH-].[Na+].Cl.C[O:8][C:9]1[CH:10]=[C:11](/[C:15](=[CH:22]/[CH2:23][CH3:24])/[CH:16]([CH3:21])[CH2:17][N:18]([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1>>[ClH:1].[CH3:20][N:18]([CH3:19])[CH2:17][CH:16](/[C:15](/[C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1)=[CH:22]\[CH2:23][CH3:24])[CH3:21]
Reactant: CC/C=C(/c1cccc(OC)c1)C(C)CN(C)C
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC/C=C(/c1cccc(O)c1)C(C)CN(C)C
Yield: 86 %

Procedure:
The base was released with dichloromethane/sodium hydroxide solution from (14), which was prepared as in Example 13, and after drying the solution the dichloromethane was removed by distillation. Hydrochloride (17) was obtained, under the conditions given in Example 2, from the base thus obtained, in a yield of 86% theoretical and with a melting point of 214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]2[CH2:33][O:32]2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]([OH:32])[CH2:33][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=4[S:18][CH2:17]3)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=5)[CH2:12][CH2:13]2)=[CH:27][CH:26]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Reactant: Clc1ccc(OC[C@@H]2CO2)cc1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C[C@H](O)COc3ccc(Cl)cc3)CC2)CS1

Procedure:
Compound 205 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=189-191° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (dd, J=1.5, 6.8 Hz, 3H), 6.98 (d, J=3.5 Hz, 1H), 4.90 (d, J=4.7 Hz, 1H), 4.05-3.92 (m, 2H), 3.87 (s, 3H), 3.05 (s, 2H), 2.86-2.74 (m, 2H), 2.55-2.38 (m, 4H), 2.01-1.93 (m, 2H), 1.86-1.73 (m, 2H). LCMS: 516 [M+H].
Reaction SMILES: O1C2C(=CC=CC=2)C=[CH:2]1.[CH2:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.O1C2C(=CC=CC=2)C=C1.C1C2C(=CC=CC=2)C=C1>>[CH3:2][C:12]1([CH3:11])[CH:13]2[CH2:14][CH:15]1[CH2:16][CH2:17][C:18]2=[CH2:10]
Reactant: C1=Cc2ccccc2C1
Reactant: c1ccc2occc2c1
Product: C=C1CCC2CC1C2(C)C

Procedure:
As petroleum resins, known products are obtained by heat-polymerizing a petroleum type unsaturated hydrocarbon such as cyclopentadiene or a higher olefinic hydrocarbon having 5 to 11 carbon atoms in the presence of a catalyst. In the present invention, any of these known petroleum resins may be used for formation of the coating layer 3. As the coumarone-indene resin, there are known resins having a relatively low degree of polymerization, which are obtained by polymerizing a tar fraction composed mainly of coumarone and indene (ordinarlly boiling at 160° to 180° C.) in the presence of a catalyst or under application of heat. Any of these known resins can be used in the present invention. As the terpene resin, there can be used synthetic and natural polymers of terpene type hydrocarbons, particularly resins obtained by polymerizing a terpene oil or nopinene fraction in the presence of a catalyst. As the rosin, there can be used so-called raw rosins such as gum rosin and wood rosin, rosin esters obtained by esterifying abietic acid in the rosin, such as rosin glycerin ester (ester gum), diethylene glycol diabietate, diethylene glycol 2-hydroxyabietate, rosin monoethylene glycol ester and rosin pentaerythritol ester. These rosins may be modified with known thermosetting resins or the like.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]([NH2:9])=[O:8])[NH:4][N:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])(=O)=O>ClCCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:6]=[C:5]([C:7]([NH:9][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:8])[NH:4][N:3]=1
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: NC(=O)c1nc(N)n[nH]1
Solvent: ClCCCl
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)NC(=O)c1nc(N)n[nH]1
Temperature: 50 °C
Yield: 26.5 %

Procedure:
A stirred mixture of 3-amino-1H-1,2,4-triazole-5-carboxamide (103 mg, 0.810 mol) in 1,2-dichloroethane (1.62 mL) treated at room temperature with 2,6-lutidine (283 μL, 2.43 mmol) and triethylsilyl trifluoromethanesulfonate (458 μL, 2.03 mmol). After 22 hours the reaction was heated at 50° C. and after 1.5 hours of heating the reaction was allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (25 mL), dried over magnesium sulfate, filtered, and evaporated to an oil which was flash chromatographed (silica gel, 0-10% ethyl acetate:hexane) to give the title compound as a white solid (130 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:22][CH:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[N:14]([CH2:22][CH:23]([CH3:25])[CH3:24])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(Cl)c2)n[nH]c1=O
Reactant: CC(C)CBr
Product: COC(=O)c1cc(-c2ccc(OC)c(Cl)c2)nn(CC(C)C)c1=O
Yield: 79.5 %

Procedure:
Using 6-(3-chloro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 1-bromo-2-methylpropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 79.5%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[N:5]2[CH:20]=[CH:21][N:22]=[C:4]2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[N:5]4[CH:20]=[CH:21][N:22]=[C:4]4[CH:3]=[C:2]([C:33]4[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:19][CH2:18]1
Reactant: N#CCC(C1CC1)n1cc(-c2nc(Cl)cc3nccn23)cn1
Reactant: Cc1ccc(B(O)O)cn1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 80 °C
Yield: 33.8 %

Procedure:
To 3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-cyclopropyl-propanenitrile (Preparation M; 50 mg, 0.16 mmol) in dioxane (5 mL) was added K2CO3 (66 mg, 0.48 mmol), diacetoxypalladium (1.8 mg, 0.0080 mmol), 6-methylpyridin-3-ylboronic acid (44 mg, 0.32 mmol) and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (8.2 mg, 0.016 mmol). The reaction mixture was degassed with argon, sealed and heated to 80° C. for 5 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH 10:1) to give the final product (20 mg, 34% yield). MS (apci) m/z=370.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([CH3:22])[C:9]([NH:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([C:9]1[S:33][C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:12][N:11]=1)[CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A solution of (S)-tert-butyl(1-(2-(4-chlorobenzoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (1.0 g, 2.93 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (1.18 g, 2.93 mmol, 1.0 equiv) in THF (29 mL) was heated at reflux for 2 hours. The reaction wash then cooled to room temperature and filtered through a pad of celite, using THF to wash through. The filtrate was concentrated in vacuo. Silica gel column chromatography (EtOAc/Heptane, 0 to 30%) provided (S)-tert-butyl(1-(5-(4-chlorophenyl)-1,3,4-thiadiazol-2-yl)ethyl)carbamate (0.600 g, light green solid) in 60% yield. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 5.23 (m, 1H), 1.72 (d, J=6.5 Hz, 3H), 1.48 (s, 9H). MS m/z 340.1 (M+H)+; Rt-0.99 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(=O)(O)[O-].[Na+]>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH:2]=[O:1]
Reactant: OCCc1ccc2ccccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=CCc1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2-(2-hydroxyethyl)naphthalene (50 mmol, 8.60 g) in dichloromethane (400 ml) at 0° C. was added Dess-Martin periodinate (50 mmol, 21.2 g) [J. Org. Chem. 48 4155 (1983)] in one portion. The solution was stirred at 0° C. for 10 mintes and at room temperature for 45 minutes. The reaction mixture was diluted with dichloromethane (400 ml) and sodium bicarbonate (1.0 L) containing sodium thiosulfate (55 g). The mixture was shaken for five minutes and the layers separated. The aqueous phase was extracted with dichloromethane (800 ml) and the combined organic solutions were washed with saturated sodium bicarbonate (800 ml), dried over sodium sulfate and concentrated in vacuo to provide naphthalen-2-ylacetaldehyde.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7]P(=O)(OCC)OCC.[CH:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[NH4+].[Cl-]>C1COCC1>[I:3][C:4]1[CH:18]=[CH:17][CH:16]=[C:6](/[CH:7]=[CH:19]/[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:5]=1
Reactant: CCOP(=O)(Cc1cccc(I)c1)OCC
Reactant: COc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(/C=C/c2cccc(I)c2)cc1
Reaction time: 72 h
Yield: 93.7 %

Procedure:
To a mixture of NaH (2 mmol, 80% suspension in oil), and 3-iodobenzylphosphonate 13 (450 mg, 1.27 mmol) in 7 mL of THF at 80° C. under nitrogen atmosphere, was added dropwise p-anisaldehyde (172 mg, 1.27 mmol). After 3 days at room temperature, NH4Cl solution (saturated, 5 mL) was added and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic extract was dried over Na2SO4, evaporated and purified by flash chromatography (EtOAc: Hex, 1:9) to give (E)-1-iodo-3-[2-(4-methoxyphenyl)ethenyl] benzene 8 (400 mg, 90%). 1H NMR (200 MHz, CDCl3): δ 3.84 (s, 3H), 6.84 (d, J=16.29 Hz, 1H), 6.90 (m, 2H), 7.05 (d, J=16.30 Hz, 1H), 7.07 (t, J=7.8 Hz, 1H), 7.42-7.56 (m, 4H), 7.85 (s, 1H); 13C NMR (50 MHz, CDCl3): δ 55.32, 94.76, 114.20, 124.85, 125.48, 127.88, 129.58, 129.62, 130.25, 135.00, 135.91, 139.97, 159.62; HRMS: m/z Calcd for C15H13IO: 336.0011; Found: 336.0006.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[N:12]=[C:13]([CH3:15])[CH:14]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:42]([O:46][C:47]([N:49]1[CH2:54][CH2:53][CH:52]([O:22][C:19]2[CH:20]=[CH:21][C:16]([N:11]3[C:10]([C:8](=[O:9])[NH:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:14][C:13]([CH3:15])=[N:12]3)=[CH:17][CH:18]=2)[CH2:51][CH2:50]1)=[O:48])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(O)cc2)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-hydroxyphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid cyclohexylamide (300 mg, 1.00 mmol) and triphenylphosphine (291 mg, 1.11 mmol) in tetrahydrofuran (5 mL) was added 1-tert-butoxycarbonyl-4-hydroxypiperidine (221 mg, 1.10 mmol) followed by dropwise addition of diisopropylazodicarboxylate (216 μL, 1.10 mmol). The solution was stirred at room temperature overnight, concentrated and dissolved in ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4) and concentrated to give the crude product in quantitative yield. LC-MS (C27H38N4O4 calculated 482) m/z 483 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]2[N:8]=[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]#[N:18])[CH2:13][CH2:12]3)[S:10][C:6]=2[CH:5]=1)([O-])=O>O1CCOCC1.[Pd]>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]2[N:8]=[C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]#[N:18])[CH2:13][CH2:12]3)[S:10][C:6]=2[CH:5]=1
Reactant: N#CC1CCN(c2nc3ccc([N+](=O)[O-])cc3s2)CC1
Agent: [Pd]
Solvent: C1COCCO1
Product: N#CC1CCN(c2nc3ccc(N)cc3s2)CC1
Yield: 94.9 %

Procedure:
60 g of the N-(6-nitrobenzothiazol-2-yl)-4-cyanopiperidine obtained in the Preparation Example 13 was dissolved in 2,000 ml of dioxane and hydrogenated in the presence of 3 g of a 10% palladium/carbon catalyst at room temperature under atmospheric pressure for 2 h. Then the catalyst was removed by filtration and the solution was concentrated under reduced pressure to give 51 g of the titled compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]=1[O:32][CH3:33])[CH:8]1[CH2:34][C:35]3[C:40]([CH:7]21)=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[NH:3])[NH2:2].[CH:41]1([NH2:44])[CH2:43][CH2:42]1>>[CH:41]1([NH:44][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:15]3[CH:16]=[C:17]([OH:22])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[CH:9]3[CH:8]4[CH2:34][C:35]5[C:40]([CH:7]4[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([C:1](=[NH:2])[NH2:3])[CH:5]=4)[NH:10]3)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:24]([O:32][CH3:33])[CH:25]=2)=[O:30])[CH2:43][CH2:42]1
Reactant: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)O)cc2OC)cc1O
Reactant: NC1CC1
Product: COc1cc(C2Nc3ccc(C(=N)N)cc3C3c4ccccc4CC23)c(-c2ccc(C(=O)NC3CC3)cc2OC)cc1O

Procedure:
Example 239 was prepared according to the protocol described for example 235 from 2′-(2-Carbamimidoyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-5′-hydroxy-2,4′-dimethoxy-biphenyl-4-carboxylic acid (example 235 step a) and cyclopropylamine. Mass Spectrum: 575 (M+1).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][F:19])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=1)C1C=CC=CC=1>CO.[C].[Pd]>[F:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([NH2:10])=[CH:12][C:13]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=C(Nc1ccc(CCF)c(C(F)(F)F)c1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCF)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
[4-(2-Fluoroethyl)-3-(trifluoromethyl)phenyl]carbamic acid benzyl ester (194 mg, 0.8 mmol) was dissolved in methanol (4 mL), and palladium carbon (10%, 45 mg) was added thereto. The resulting mixture was stirred under hydrogen atmosphere at room temperature for 3 hours. The catalyst was removed by filtration to give 4-(2-fluoroethyl)-3-(trifluoromethyl)aniline (49 mg, 29%) as a light-yellow oil.
Reaction SMILES: [N:1]1([C@H:7]2[CH2:11][C@@H:10]([OH:12])[CH:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pt](=O)=O>[N:1]1([C@@H:7]2[CH2:8][CH2:9][C@H:10]([OH:12])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O[C@H]1C=C[C@@H](N2CCCCC2)C1
Agent: O=[Pt]=O
Solvent: CO
Product: O[C@H]1CC[C@@H](N2CCCCC2)C1
Reaction time: 4 h
Yield: 63.3 %

Procedure:
To a solution of (1R,4S)-4-piperidin-1-ylcyclopent-2-en-1-ol (50 mg, 0.30 mmol) in methanol (1 mL), was added a catalytic amount of platinum (IV) oxide (PtO2). The mixture was stirred under a hydrogen atmosphere (1 atm.) for 4 h. The mixture was filtered and solvent evaporated in vacuo to afford (1S,3R)-3-piperidin-1-ylcyclopentanol (32 mg, 0.19 mmol, 63%). This was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].Br[C:37]([CH3:46])([CH3:45])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].O>CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:27][CH2:28][CH3:29])=[C:16]([CH:23]4[CH2:24][N:25]([C:37]([CH3:46])([CH3:45])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26]4)[C:17]([C:18]#[N:19])=[C:20]([Cl:22])[CH:21]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)(C)C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Yield: 84.4 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (0.38 g, 0.92 mmol, chiral intermediate from Example 212) in N,N-dimethylformamide (4.6 mL) was treated with potassium carbonate (0.51 g, 3.7 mmol) followed by tert-butyl 2-bromo-2-methylpropanoate (0.86 mL, 4.6 mmol) and heated at 60° C. for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated to a crude oil. The crude material was purified by flash column chromatography using methanol in dichloromethane (0%-10%) to give the desired product (0.43 g, 83%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.44 (s, 1H), 6.22 (q, J=6.8 Hz, 1H), 4.12-3.97 (m, 1H), 3.88-3.70 (m, 4H), 3.62-3.48 (m, 2H), 2.54 (s, 3H), 1.70 (d, J=7.0 Hz, 3H), 1.33 (t, J=6.9 Hz, 3H), 1.17 (s, 9H), 1.05 (s, 6H). LCMS for C28H37ClN7O3 (M+H)+: m/z=554.3; Found: 554.3.