Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@H:9]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:25][C:19]1[CH:18]=[C:17]([C@@H:9]2[CH2:8][C@H:7]([C:5]3[O:4][NH:3][C:2](=[O:1])[CH:6]=3)[CH2:12][CH2:11][NH:10]2)[CH:22]=[C:21]([F:23])[C:20]=1[F:24]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1c1cc(F)c(F)c(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](c3cc(F)c(F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
(2S,4R)-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorophenyl)piperidine-1-carboxylate (160 mg, 0.45 mmol) (from example 60, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 3.54 mL, 20.21 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(3,4,5-trifluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (85 mg, 63%) 1H NMR (600 MHz, dmso) δ 1.29 (q, 1H), 1.43 (qd, 1H), 1.83-1.88 (m, 1H), 1.97-2.02 (m, 1H), 2.70 (td, 1H), 2.80-2.87 (m, 1H), 3.06-3.12 (m, 1H), 3.64 (dd, 1H), 5.73 (s, 1H), 7.27-7.34 (m, 2H). HRMS Calculated for [C14H13F3N2O2+H]+: 299.1007. Found: 299.1037
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=O>O>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][CH:2]([CH3:1])[C:3]2=[O:5])=[CH:8][CH:9]=1
Reactant: COc1ccc(CC(C)C(=O)O)cc1
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(C)C2
Temperature: 86.5 °C

Procedure:
α-Methyl-β-(p-methoxyphenyl)propionic acid (15 g) is added to polyphosphoric acid (170 g) at 50° C. and the mixture is heated at 83-90° C. for two hours. The syrup is poured into iced water, stirred for one-half hour, and then extracted with ether three times. The ether solution is washed with water twice, and with 5% NaHCO3 five times until all the acidic material has been removed. The remaining neutral solution is washed with water and dried over sodium sulfate. Evaporation of the solution gives the indanone as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[F:20][CH:21]([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH:21]([F:20])[F:30])=[CH:24][CH:25]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc(OC(F)F)cc2)=C(c2ccccc2)S1(=O)=O
Reaction time: 1 h
Yield: 77.6 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.63 g, 2.1 mmol) and 4-(difluoromethoxy)-aniline (0.67 g, 4.2 mmol) were mixed in MeCN (4 mL, dry). The mixture was put in the microwave reactor at 160° C. for 1 h, then additional 1 h and then 1 h more. It was evaporated to dryness. The residue was purified by column chromatography (ISOLUTE SI, 50 g/150 mL), eluting with DCM/heptane (50:50, then 75:25), to give the title compound (0.688 g, 78%) as a yellow solid; 1H-NMR (400 MHz; CDCl3): δ 0.99 (t, 3H), 1.42-1.52 (m, 2H), 1.82-1.90 (m, 2H), 3.77 (t, 2H), 6.34 (t, 1H), 6.67 (d, 2H), 6.76 (d, 2H), 7.11-7.17 (m, 4H), 7.22-7.26 (m, 1H); Mass Spectrum: M−H+ 421.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#CCCCC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 5-hexynoate (109 mg, 0.87 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (179 mg, 0.62 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and CuI (15 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 70° C. for 15 h to yield (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynoic acid methyl ester. (Yield 78 mg, 35%).
Reaction SMILES: C([O:8][C:9](=[O:45])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42](=[O:44])[NH2:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])C1C=CC=CC=1.C([C@H](NC(=O)[C@H](N1C=CC(C2C=CC(C3C=CC(C(=O)N)=CC=3)=CC=2)=C1)CC(O)=O)CO)C1C=CC=CC=1.[K+].[Br-]>C(Cl)(Cl)Cl>[CH2:18]([CH:15]([NH:14][C:12](=[O:13])[C@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][C:39]([C:42](=[O:44])[NH2:43])=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[CH2:10][C:9]([OH:45])=[O:8])[CH2:16][OH:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)OCc4ccccc4)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Agent: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)O)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)O)C(=O)NC(CO)Cc4ccccc4)c3)cc2)cc1
Yield: 95 %

Procedure:
According to the procedure described in Example 1(a), N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4'-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester was hydrogenolyzed to N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4'-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid in 95% yield, mp 218-20° C. 1H NMR (DMSO-d6): ∂ 8.12 (d, 1H, J=8.5 Hz), 7.97 (s, 1H), 7.88 (d, 2H, J=8.5 Hz), 7.72 (d, 2H, J=8.5 Hz), 7.57 (d, 2H, J=8.1 Hz), 7.33 (bs, 1H), 7.24 (s, 1H), 7.22-7.11 (m, 6H), 6.80 (bs, 1H), 6.42 (bs, 1H), 4.98-4.90 (bm, 1H), 4.80-4.72 (m, 1H), 3.82-3.76 (m, 1H), 2.82-2.70 (m, 2H), 2.62-2.50 (m, 1H). IR (KBr): 3402, 2925, 1658, 1601, 1400, 1202, 825, 782, 702, 633 cm-1. HRFABMS: Calculated for C30H29N3O5Cs (M+Cs+): 644.1162. Found: 644.1147. Anal. Calculated for C30H29N3O5.0.3 CHCl3 : C, 66.49; H, 5.40; N, 7.68. Found: C, 66.30; H, 5.50; N, 7.50.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Br:37])[CH:32]=2)([C:17]2[CH:22]=[CH:21][C:20]([O:23][Si](C(C)(C)C)(C)C)=[CH:19][CH:18]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Br:37])[CH:32]=2)([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=NC(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)(c2cccc(Br)c2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=NC(c2ccc(O)cc2)(c2cccc(Br)c2)c2ccccc21
Yield: 105 %

Procedure:
To {3-(3-bromo-phenyl)-3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-3H-isoindol-1-yl}-carbamic acid tert-butyl ester (Scheme #6, R) (1.07 g, 1.80 mmol) in tetrahydrofuran (20 mL) was added 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (1.98 mL, 1.98 mmol). After 10 minutes the reaction was quenched with water (50 mL) and extracted twice with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride, dried over magnesium sulfate and the solvent removed under reduced pressure to give a yellow oil. This was chromatographed on 20 g silica gel eluting with 40% ethyl acetate/hexanes and the combined purified fractions removed of solvent under reduced pressure to give the title compound as a yellow solid (906 mg, quantitative yield). 1H NMR (300 MHz, DMSO-d6/TFA-d) δ 8.64 (d, J=7.7 Hz, 1 H), 7.89 (t, J=7.7 Hz, 1 H), 7.74 (t, J=7.5 Hz, 2 H), 7.61-7.57 (m, 2 H), 7.33 (dd, J=4.7, 1.2 Hz, 2 H), 7.14 (dd, J=6.8, 1.9 Hz, 2 H), 6.78 (d, J=8.9 Hz, 2 H), 1.62 (s, 9 H); MS (APCI+) m/z 479 [M+1]+; tR=2.23 min.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:11])[O:7][CH2:8][C:9]#[CH:10])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[I-:14].[Na+].ClCl>O.CO>[CH2:1]([NH:5][C:6](=[O:11])[O:7][CH2:8][C:9]#[C:10][I:14])[CH2:2][CH2:3][CH3:4]
Reactant: C#CCOC(=O)NCCCC
Reactant: [I-]
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCNC(=O)OCC#CI
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
At 5° C., 19.0 g of propargyl butylcarbamate (0.122 mol), 12.2 g of sodium hydroxide (0.305 mol) and 18.5 g of sodium iodide (0.123 mol) are introduced as initial charge in 50 g of water and 48 g of methanol. Chlorine (11.7 g, 0.165 mmol) is then slowly introduced so that the temperature remains below 5° C. When the metered addition is complete, the mixture is stirred at this temperature for 1 h, then slowly heated to room temperature and stirred for 1 hour. After adding 100 g of water, the precipitated solid is isolated by filtration, washed with water and dried in vacuo. This gives 29.1 g of 3-iodo-2-propynyl N-butylcarbamate (purity: 94.7% (HPLC), polyiodized compounds: <0.1% (HPLC), yield: 80%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:25][CH2:26][CH3:27])[C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34]>>[O:34]=[C:29]1[NH:30][C:31](=[O:33])[C:32](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:25][CH2:26][CH3:27])[C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)=[CH:7][CH:8]=2)[S:28]1
Reactant: O=C1CSC(=O)N1
Reactant: CCCN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Product: CCCN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)c1ccccc1
Yield: 72.6 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 580 mg (1.6 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)-N-propylbenzamide with 190 mg (1.6 mmol) of 2,4-thiazolidine dione, 530 mg (72%) of the expected product, with a melting point of 250-251° C., are obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](=[O:16])(Cl)[S:11][CH:12]([CH3:14])[CH3:13].[Br:17][C:18]1[N:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:25]=[CH:26][C:21]2=[N:20][CH:19]=1>C(OCC)(=O)C>[Br:17][C:18]1[N:22]2[N:23]=[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:10](=[O:16])[S:11][CH:12]([CH3:14])[CH3:13])[CH2:31][CH2:32]3)[CH:25]=[CH:26][C:21]2=[N:20][CH:19]=1
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)SC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)SC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Hunig's base [7087-68-5] (0.4 mL, 2.4 mmol), then S-isopropyl carbonochloridothioate [13889-93-5] (0.2 mL, 1.6 mmol) were added to a stirred, ambient temperature solution of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine (450.0 mg, 1.6 mmol) in ethyl acetate (30 mL). Then rapidly formed suspension was stirred overnight, under N2 blanket, then washed with brine, dried (MgSO4), evaporated, and crystallized from ethyl acetate/heptane to afford 482.9 mg of white powder, mp. 186-187° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.82 Hz, 6H) 2.51 (dt, J=3.60, 1.86 Hz, 1H) 3.49-3.59 (m, 1H) 3.59-3.71 (m, 7H) 7.58 (d, J=9.85 Hz, 1H) 8.09-8.13 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 23.22, 35.48, 44.71, 101.63, 110.84, 113.71, 114.69, 116.58, 119.46, 123.56, 126.04, 134.22, 155.61, 157.77, 158.15, 158.53, 158.90, 166.18. LRMS (ESI) m/z 384.0/386.0 [(M+H)]+, calc'd for C14H15BrN6OS: 384.30.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.C(Cl)Cl.C(N(C(C)C)C(C)C)C.[CH2:37]([O:39][CH2:40]Cl)[CH3:38]>CCOCC>[CH2:37]([O:39][CH2:40][O:1][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1)[CH3:38]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CO)c3c2)c1=O
Reactant: CCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCOCOCc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12

Procedure:
To a mixture of 3-[3-(hydroxymethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.800 g, 0.00224 mol) and methylene chloride is added ethyldiisopropylamine (0.780 ml, 0.00448 mol) followed by chloromethyl ethyl ether (0.310 ml, 0.00336 mol). The resultant mixture is stirred 42.5 hours at room temperature, diluted with ether, washed sequentially with 1 M aqueous hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to a yellow syrup. The syrup is chromatographed on silica gel with hexanes:ethyl acetate to give the product as a white solid which is identified by NMR spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:26])[CH:17]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9].[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>N1C=CC=CC=1>[CH3:10][N:8]([CH3:9])[C:7]1[CH:6]=[CH:5][C:4]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([F:26])[CH:17]=3)[N:12]=2)=[CH:3][C:2]=1[NH:1][S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(N(C)C)c(N)c3)n2)cc1F
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N(C)C)c(NS(C)(=O)=O)c3)n2)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
Methyl 4-{5-[3-amino-4-(dimethylamino)phenyl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzoate was taken up in Pyridine (750 μL) and mesylchloride (40 μL; 0.46 mmol) was added and stirred at RT for 72 h. After the time, the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (DCM:MeOH from 100:0 to 90:10) to give the title compound as a yellow powder (150 mg; 88%, 2 steps). 1H NMR (DMSO-d6, 300 MHz) δ 9.07 (bs, 1H), 8.13-8.08 (m, 1H), 8.04-7.91 (m, 4H), 7.23 (d, J=8.7 Hz, 1H), 3.90 (s, 3H), 3.14 (s, 3H), 2.88 (s, 6H). LC/MS (Method B): 435.3 (M+H)+. HPLC (Method A) Rt. 4.33 min (purity: 94.4%).
Reaction SMILES: [C@@H:1]1(C(O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C(Cl)(Cl)Cl.[N-:17]=[N+]=[N-].[Na+].CCOCC>S(=O)(=O)(O)O>[NH2:17][C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)[C@@H]1CCCC[C@H]1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: N[C@@H]1CCCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Trans-cyclohexane-1,2-dicarboxylic acid (8.105 g; racemic modification) is dissolved in conc. sulfuric acid (25 ml) and chloroform (50 ml) and kept at a temperature of 45° C., to which is added sodium azide (3.6 g) in one hour. After this, the solution is stirred for 90 minutes, added with ice water (25 ml) and is added with ether to remove chloroform. Barium carbonate (90 g) is added to the water layer of the solution to effect the neutralization. Barium sulfate is removed from the solution by filtration and the filtrate is concentrated to dryness to result in needle crystals of rac-trans-2-aminocyclohexanecarboxylic acid (referred to as A) having the following characteristics. When a corresponding rac-cis-compound is used as starting material, there is obtained the corresponding cis-compound i.e. rac-cis-aminocyclohexanecarboxylic acid, referred to as B).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[CH3:24][N:25]1[CH2:39][CH2:38][N:28]2[C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[NH:31][CH2:32][CH2:33][CH:27]2[CH2:26]1.C(O)(=O)C>O1CCCC1.Cl>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:31]2[C:30]3[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=3[N:28]3[CH2:38][CH2:39][N:25]([CH3:24])[CH2:26][CH:27]3[CH2:33][CH2:32]2)=[CH:18][CH:17]=1
Reactant: CN1CCN2c3ccccc3NCCC2C1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCN2c3ccccc3N(Cc3ccc(Br)cc3)CCC2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium triacetoxyborohydride (200 mg, 0.944 mmol) was added to an ice-cooled solution of 4-bromobenzaldehyde (122 mg, 0.659 mmol) and the product of Example 22F (63 mg, 0.290 mmol) in tetrahydrofuran (5 mL). A few drops of 10% HCl (aq) were added, and the mixture was allowed to warm to room temperature. After 5 hours, acetic acid (2 mL) and additional sodium triacetoxyborohydride (200 mg, 0.944 mmol) were added, and the mixture was stirred an additional 15 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by flash chromatography (SiO2, eluted with CH2Cl2, then CH2Cl2-methanol-15 M NH4OH, 95:5:0.5-90:10:1) to provide the title compound: 1H NMR (300 MHz, CD3OD) δ ppm 1.62 (tt, J=15.3, 5.3, 2.6 Hz, 1H), 1.84-2.00 (m, 1H), 2.33 (t, J=10.9 Hz, 1H), 2.42-2.51 (m, 1H), 2.43 (s, 3H), 2.77 (dt, J=10.7, 2.0 Hz, 1H), 2.85 (ddd, J=11.1, 5.2, 3.6 Hz, 1H), 2.89-3.04 (m, 2H), 3.13 (dt, J=11.9, 2.8 Hz, 1H), 3.30 (s, 1H), 3.45 (td, J=11.3, 2.8 Hz, 1H), 4.22 (d, J=15.1 Hz, 1H), 4.46 (d, J=15.1 Hz, 1H), 6.77-6.96 (m, 4H), 7.27 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H); MS (DCI) m/z 386/388 (M+H)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.Br[C:10]([C:12]([F:15])([F:14])[F:13])=[CH2:11].CN(CCN(C)C)C.I[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)[N:29]=[CH:28]2>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH:34]1[N:30]1[C:31]2[C:27](=[CH:26][C:25]([C:11]#[C:10][C:12]([F:15])([F:14])[F:13])=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: Ic1ccc2c(cnn2C2CCCCO2)c1
Reactant: C=C(Br)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: FC(F)(F)C#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
To a solution of LDA (2 M in THF, 3.2 mL, 6.4 mmol) in anhydrous THF (10 mL) was added dropwise 2-bromo-3,3,3-trifluoroprop-1-ene (0.55 g, 3.1 mmol) at −78° C. The resulting mixture was stirred at that temperature for 15 minutes, followed by the addition of ZnCl2 (1 M in ethyl ether, 6.5 mL, 6.5 mmol) and TMEDA (1 mL, 6.5 mmol). The mixture was stirred at −78° C. for further 30 minutes and then 30 minutes at room temperature. 5-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.99 g, 3.0 mmol) and Pd(PPh3)4 (0.21 g, 0.18 mmol) were added. The reaction mixture was heated at 80° C. for 6 hours under N2 atmosphere. Upon completion, the reaction mixture was quenched with water (100 mL) and then diluted with ethyl acetate (300 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜20% EtOAc in petroleum ether) affording the title compound (299 mg). 1H NMR (300 MHz, DMSO-d6): δ 8.28 (s, 1H), 8.24 (s, 1H), 7.87 (d, 1H), 7.68 (dd, 1H), 5.91 (dd, 1H), 3.90-3.86 (m, 1H), 3.79-3.72 (m, 1H), 2.41-2.36 (m, 1H), 2.05-1.96 (m, 2H), 1.76-1.72 (m, 1H), 1.60-1.56 (m, 2H); LCMS: 295 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:45]=[CH:44][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:45]=[CH:44][C:36]([CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:31])([F:29])[F:30])[C:9]=5[CH:17]=4)[CH:19]=3)=[O:22])[CH2:40][CH2:39]2)=[CH:35][CH:34]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-chlorobenzyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=639.99 (M+H+); retention time=0.7 minutes.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)C=CC=CC=1.CO.Cl.[H][H]>[Pd].O>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCC(Nc3cccnc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: c1cncc(NC2CCNCC2)c1

Procedure:
A mixture of 20 parts of N-[1-(phenylmethyl)-4-piperidinyl]-3-pyridinamine, 160 parts of methanol, 30 parts of water and 12 parts of a concentrated hydrochloric acid solution is hydrogenated at normal pressure and at a temperature between 22°-39° C., in the presence of 7 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in water. This solution is rendered alkaline with ammonium hydroxide, saturated with solid potassium carbonate and then extracted with methylbenzene. The extract is dried over potassium carbonate and evaporated. The solid residue is recrystallized from a mixture of 40 parts of benzene and 32 parts of 1,1'-oxybisethane, yielding 3 parts of N-(4-piperidinyl)-3-pyridinamine; mp. 127°-129° C.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].C([N:15]1[CH2:20][CH:19]=[C:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[NH:28][C:29](=[O:37])[C:30]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:36])[CH:31]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:7][CH:5]([O:4][C:2]([N:15]1[CH2:16][CH:17]=[C:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[NH:28][C:29]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:36])[CH:31]=2)=[O:37])[CH2:19][CH2:20]1)=[O:3])[CH3:6]
Reactant: O=C(Nc1ccc(Cl)cc1C1=CCN(Cc2ccccc2)CC1)c1ccnc(Cl)c1
Reactant: CC(Cl)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(Cl)OC(=O)N1CC=C(c2cc(Cl)ccc2NC(=O)c2ccnc(Cl)c2)CC1

Procedure:
1-Chloroethyl chloroformate (2.64 ml) was added to a suspension of N-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-chloro-phenyl]-2-chloro-isonicotinamide (530 mg) in toluene (30 ml). After 15 min. the solution was heated to reflux for 16 hours, then poured into saturated aqueous NaHCO3 solution and the mixture extracted three times with CH2Cl2. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford the crude title product (550 mg).