Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O[C:6](=[O:19])[NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH2:17])=[O:16])[C:9]1=[O:18])(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:44][C:45]1[CH:54]=[C:53]2[C:48]([C:49]([N:56]3[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]3)=[CH:50][C:51]([NH2:55])=[N:52]2)=[CH:47][CH:46]=1>>[NH2:55][C:51]1[CH:50]=[C:49]([N:56]2[CH2:57][CH2:58][N:59]([C:6]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH2:17])=[O:16])[C:9]3=[O:18])=[O:19])[CH2:60][CH2:61]2)[C:48]2[C:53](=[CH:54][C:45]([Cl:44])=[CH:46][CH:47]=2)[N:52]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(C(N)=O)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, [(3S)-1-(aminocarbonyl)hexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid-1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a white solid. LC-MS: 460 (M++1). 1H NMR (DMSO-d6+TFA): 1.16˜1.30 (m, 1H), 1.54˜1.88 (m, 5H), 3.26 (m, 4H), 3.60 (m, 4H), 4.56 (ddd, 1H), 4.70 (br.dd, 1H), 6.32 (s, 1H), 7.38–7.46 (m, 2H), 7.62 (d, 1H), 7.88 (d, 1H), 8.20–8.50 (m, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([CH3:17])=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:19]=[C:20]([CH:28]4[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[C:16]([CH3:17])=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:19]=[C:20]([CH:28]4[CH2:33][CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])[CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c2ccc(-c3cc(C4CCCNC4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c2ccc(-c3cc(C4CCCN(C(=O)CN(C)C)C4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.8 %

Procedure:
A mixture of 5-(2-benzyl-3-methyl-2H-indazol-6-yl)-7-piperidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.23 mmol), N,N-dimethylglycine (28 mg, 0.27 mmol), EDCl (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), and N,N-diisopropylethylamine (119 μL, 0.69 mmol) in DMF (1.5 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 19 mg (16%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (d, 1 H), 7.76 (d, 1 H), 7.53 (s, 1 H), 7.25-7.38 (m, 3 H), 7.21 (d, 2 H), 7.08 (d, 1 H), 6.63-6.68 (m, 1 H), 5.63 (s, 2 H), 3.96-4.95 (m, 2 H), 2.83-3.34 (m, 5 H), 2.57-2.77 (m, 4 H), 2.06-2.23 (m, 6 H), 1.69-1.92 (m, 2 H), 1.39-1.64 (m, 1 H); ES-MS m/z 523.41 [M+H]+, HPLC RT (min) 2.20.
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:33][C:30]2[S:31][CH:32]=[C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[N:29]=2)=[O:18])(=[O:11])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: O=C(Nc1nc(-c2ccccn2)cs1)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (100 mg, 0.33 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (49 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 75-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 3-(indolin-1-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a white solid. Yield: 17 mg (13%). 1H-NMR: 8.65-8.61 (m, 1H), 8.60-8.58 (m, 1H), 8.38 (dt, J=8.0, 1.0, 1.0 Hz, 1H), 8.05-7.99 (m, 2H), 7.95-7.88 (m, 2H), 7.74 (t, J=8.0 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.38-7.33 (m, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H) 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 4.03 (t, J=8.5 Hz, 2H), 2.93 (t, J=8.5 Hz, 2H).
Reaction SMILES: BrC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[F:33].[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([N:43]=[C:44]=[S:45])=[O:42])=[CH:39][CH:40]=1.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([NH:43][C:44]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][C:16]3[C:15]4[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=4)[N:19]=[CH:18][CH:17]=3)=[C:27]([F:33])[CH:28]=2)=[S:45])=[O:42])=[CH:37][CH:36]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc(Br)cc1
Agent: O=C(N=C=S)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Br)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
4-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (81 mg, yield 91%).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH2:11]([N:13](CC)[CH2:14]C)[CH3:12].C(OC(=O)C)(=O)C>O.CCOCC>[ClH:1].[ClH:1].[CH3:14][NH:13][C:11]1[NH:9][C:6]2[C:7]([CH:12]=1)=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2
Reactant: Cc1ccc(NN)cc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CNc1cc2cc(C)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5 g of 1-(4-methylphenyl)hydrazine hydrochloride are dissolved in water and then triethylamine is added until the salt has been neutralized. Extraction is carried out with AcOEt and then the extract is evaporated to dryness. The precipitate formed is dissolved in 30 ml of ether and then a solution of 4.6 ml of acetic anhydride dissolved in 30 ml of ether is added dropwise. The mixture is stirred at 0° C. for 15 minutes and then the precipitate formed is filtered off to produce 3 g of the expected compound.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH:10]([F:12])[F:11])=[C:6]([Cl:9])OC)C.[CH3:14][NH:15][NH2:16]>>[Cl:9][C:6]1[N:15]([CH3:14])[N:16]=[C:4]([OH:3])[C:5]=1[CH:10]([F:12])[F:11]
Reactant: CNN
Reactant: CCOC(=O)C(=C(Cl)OC)C(F)F
Product: Cn1nc(O)c(C(F)F)c1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
50.14 g (0.25 mol) of 3-chlorodifluoromethyl-3-methoxypropenoic acid ethyl ester was placed in a flask in ice water. 12.67 g (0.275 mol) of methylhydrazine was added while stirring until the reaction mixture boiled. Additional methylhydrazine was added and the mixture was left standing overnight. The solvent was evaporated off and the residue recrystallized from hot methylcyclohexane to give 17.4 g of off-white solid, m.p. 122°-123° C.
Reaction SMILES: [ClH:1].[CH2:2]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:24]3[CH:23]=[C:22]([C:25](=[O:27])[CH3:26])[S:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+].O>CO>[ClH:1].[CH2:2]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:24]3[CH:23]=[C:22]([CH:25]([OH:27])[CH3:26])[S:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1cc2c(N3CCN(CCc4ccccc4)CC3)cccc2s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1cc2c(N3CCN(CCc4ccccc4)CC3)cccc2s1
Reaction time: 0.33 h

Procedure:
To partially dissolved 1-[4-(4-phenethyl-piperazin-1-yl)benzo[b]thiophen-2-yl]-ethanone hydrochloride (0.92 g, 2.5 mmol, product from Example 42) in methanol (70 mL) is added sodium borohydride (0.19 g, 5.0 mmol). After 0.33 h, the reaction is clear and homogeneous. The reaction is worked up after 2 h by pouring into water (10 mL), extracting with dichloromethane (3×75 mL), and concentrating the sodium sulfate dried extracts in vacuo. The product (Rf of 0.3 in ethyl acetate) is dissolved in acetonitrile (50 mL), treated with 1.0M hydrochloric acid (2.5 mL), concentrated in vacuo, then reconcentrated from acetonitrile:methanol to give a white solid. After vacuum drying for 9 h at 70° C., the title compound is isolated as a white solid (0.865 g). 1H NMR (d6 -DMSO): 11.48 (1H, bs), 7.61 (1H, d, J=8.0 Hz), 7.40-7.23 (7H), 6.95 (1H, d, J=7.6 Hz), 5.76 (1H, bs), 5.07 (1H, q, J=6.2 Hz), 3.69 (2H, bd, J=10.6 Hz), 3.53 (2H, m), 3.45-3.25(6H), 3.17 (2H, m), 1.50 (3H, d, J=6.4 Hz) ppm. 13C NMR (d6 -DMSO): 152.13, 146.05, 139.74, 137.10, 133.35, 128.67, 126.79, 124.47, 117.62, 116.20, 112.54, 64.86, 56.19, 51.18, 48.45, 48.24, 29.29, 25.68 ppm. IR (KBr): 3351, 2575, 2554, 2446, 1570 cm-1. CIMS (methane): 367 (92%), 349 (100%), 275 (82% ).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[NH2:24]>>[CH3:20][O:21][C:22](=[O:27])[C:23]([NH:24][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:26])[CH3:25]
Reactant: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Reactant: COC(=O)C(C)(C)N
Product: COC(=O)C(C)(C)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14 a) and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 362.2 [M+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:13][C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:5]=2[CH:6]=1.Cl.[Cl:15]N1C(=O)CCC1=O.C([O-])([O-])=O.[K+].[K+]>O>[Cl:15][C:2]1[CH:3]=[C:4]2[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][C:12]=3[NH:13]2)=[CH:6][CH:1]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1ccc2c(c1)[nH]c1cnccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1ccc2c(c1)[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To a solution of norharmane (2.0 g, 11.9 mmol) in water (89 ml) and 1M aqueous HCl (29.8 ml, 29.8 mmol) was added N-chlorosuccinimide (3.17 g, 23.8 mmol) portionwise. The resulting solution was stirred at RT for 6 h, and then at 0° C. to 5° C. for 12 h. The reaction was diluted with water (100 ml) and basified cautiously with solid K2CO3 (4.3 g). After stirring at RT for 1 h, the product was collected and washed with water. The crude product was refluxed in chloroform for 1 h and filtered after cooling to 15° C. to provide 2.05 g of 7-chloro-β-carboline.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:3]=1.FC(F)(F)C(O)=O.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[N:21]1.C(N(CC)CC)C.O>CN(C)C=O>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([NH:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[S:6][N:5]=[C:4]([N:7]4[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]4)[N:3]=3)[CH2:34][CH2:33]2)=[O:31])=[N:21]1
Reactant: Clc1nc(N2CCCCC2)ns1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(N3CCCCC3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5-chloro-1,2,4-thiadiazol-3-yl)piperidine (114 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to give the desired product as a solid. The resulting solid was recrystallized from a mixed solvent of ethyl acetate, tetrahydrofuran and hexane to yield 44.0 mg (10.7%) of the desired product. mp 214-215° C.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]=O)[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:23][CH2:24][CH2:25][SH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH:20]2[NH:23][CH2:24][CH2:25][S:26]2)[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c(C=O)c(OC)c2cc(C)ccc21
Reactant: NCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCCCCn1c(=O)c(C2NCCS2)c(OC)c2cc(C)ccc21
Reaction time: 3 h

Procedure:
A solution of 1 -hexyl-3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone (Step (2) of Example 1, 1 g) and 2-aminoethanethiol (0.26 g) in methylene chloride (20 ml) containing p-toluenesulfonic acid (0.1 g) was stirred for 3hrs. The mixture was washed with aqueous sodium bicarbonate, dried, evaporated and then crystallized from ether-hexane to give 1-Hexyl-3-(2-thiazolidinyl)-4-methoxy-6-methyl-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: m/e 360 (M+); NMR (CDCl3): δ3.17 (m, 2H, CH2S), 3.86 (m, 2H, CH2N), 6.0 (d, 1H, S-CH-N).
Reaction SMILES: CS(C1C=CC(CCC)=C(C=1)N)(=O)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-])=O>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=1[NH2:26]
Reactant: CS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CCCc1ccc(S(C)(=O)=O)cc1N
Product: CS(=O)(=O)c1ccc(Cl)c(N)c1

Procedure:
Following the general method as outlined in Intermediate 61, starting from 2-chloro-5-methylsulphonylnitrobenzene, the title compound was obtained as a dark green sticky solid in quantitative yield.
Reaction SMILES: [F:1][CH:2]([F:43])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([NH:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:11]([N+:28]([O-])=O)=[C:10]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[N:9]=2)[C:6]2[CH:37]=[CH:38][CH:39]=[C:40]([O:41][CH3:42])[C:5]=2[N:4]=1>CO.C1COCC1.[Pd]>[NH2:28][C:11]1[C:12]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[N:13][C:8]([N:7]2[C:6]3[CH:37]=[CH:38][CH:39]=[C:40]([O:41][CH3:42])[C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:43])=[N:9][C:10]=1[N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c(N2CCOCC2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c(N2CCOCC2)n1
Reaction time: 5 h
Yield: 93.3 %

Procedure:
A mixture of the above nitro compound (700 mg, 1.16 mmol) and 10% Pd on carbon in MeOH/THF (70 mL: 15 mL) was hydrogenated for 5 hrs. The reaction mixture was filtered through celite, the celite pad was washed with MeOH and CH2Cl2, and the solvents were removed under vacuum. Recrystallization from CH2Cl2/MeOH gave tert-butyl 4-{[5-amino-2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]amino}-1-piperidinecarboxylate (622 mg, 94%): mp 223-225° C.; 1H NMR (CDCl3) δ 7.92 (dd, J=8.4, 0.6 Hz, 1H), 7.54 (t, JHF=53.7 Hz, 1H), 7.32 (t, J=8.2 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 4.68 (d, J=7.6 Hz, 1H), 4.23-4.10 (m, 3H), 4.05 (s, 3H), 3.89 (m, 4H), 3.25 (m, 4H), 3.06 (br s, 2H), 2.96 (t, J=12.0 Hz, 2H), 2.11 (m, 2H), 1.47 (s, 9H), 1.50-1.40 (m, 2H); Anal. Calcd. for C27H36F2N8O4: C, 56.4. H, 6.3; N, 19.5. Found: C, 56.3; H, 6.4; N, 19.7%.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([I:8])[N:3]=1.[CH2:9]([OH:12])[CH:10]=[CH2:11].C=O>ClCCl>[I:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:12][CH2:9][CH:10]=[CH2:11])[N:3]=1
Reactant: C=CCO
Reactant: Ic1cncc(I)n1
Agent: C=O
Solvent: ClCCl
Product: C=CCOc1cncc(I)n1

Procedure:
This was prepared from 2,6-diiodopyrazine (5.5 g, 16.6 mmol) and allyl alcohol by the procedure described for Example 31 part 1. Chromatography through silica gel using dichloromethane as eluant gave the pure product (2 g), δ (250 MHz, CDCl3) 4.83-4.86 (2H, m, CH2O); 5.29-5.35 (1H, m, cis-vinyl-H); 5.39-5.48 (1H, m, trans-vinyl-H); 5.98-6.13 (1H, m, vinyl-H); 8.16 (1H, s, pyrazine-H); 8.40 (1H, s, pyrazine-H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][N:42]3[CH:44]=[C:45]([C:47]([OH:49])=O)[N:46]=[C:41]3[CH2:40][CH2:39]2)=[CH:34][C:33]=1[CH3:50].[CH2:51]([CH:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C>[CH2:51]([CH:58]1[CH2:63][CH2:62][N:61]([C:47]([C:45]2[N:46]=[C:41]3[CH2:40][CH2:39][CH:38]([C:35]4[CH:36]=[CH:37][C:32]([F:31])=[C:33]([CH3:50])[CH:34]=4)[CH2:43][N:42]3[CH:44]=2)=[O:49])[CH2:60][CH2:59]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Cc1cc(C2CCc3nc(C(=O)O)cn3C2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(C2CCc3nc(C(=O)N4CCC(Cc5ccccc5)CC4)cn3C2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (295 mg; 0.92 mmol) and N-methylmorpholine (253 μl; 232 mg; 2.3 mmol) were added to a solution of 6-(4-fluoro-3-methylphenyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (210 mg; 0.68 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 4-benzylpiperidine (162 μl; 161 mg; 0.9 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and then poured onto water. The precipitated solid was filtered out and washed with petroleum ether. Yield: 205 mg (72%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][C@@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][C@@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1Cc1ccc(F)c(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](Cc3ccc(F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
(2S,4R)-Methyl 2-(3,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (596 mg, 1.69 mmol) (from example 120, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 15 mL, 85.65 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx I, 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-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (136 mg, 27%). 1H NMR (600 MHz, cd3od) δ 1.42 (q, 1H), 1.68 (dq, 1H), 2.04 (t, 2H), 2.78-2.95 (m, 4H), 3.19-3.25 (m, 1H), 3.29-3.35 (m, 1H), 5.49 (s, 1H), 7.00-7.05 (m, 1H), 7.14-7.22 (m, 2H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1264
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][CH:18]([F:37])[N:19]1[C:23]([CH2:24]O)=[CH:22][C:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[N:20]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][C:23]3[N:19]([CH:18]([F:37])[F:17])[N:20]=[C:21]([C:26]4[CH:27]=[CH:28][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[CH:30][CH:31]=4)[CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1C(F)F
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C(F)F)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [2-difluoromethyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[2-difluoromethyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[S-:9][C:10]#[N:11].[Na+].BrBr.[Br-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Br:1][C:2]1[CH:8]=[C:7]([S:9][C:10]#[N:11])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccccc1Br
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CO
Solvent: O
Product: N#CSc1ccc(N)c(Br)c1
Reaction time: 1 h

Procedure:
To a cold (0°-5° C.), stirred solution of o-bromo-aniline (20.6 g., 0.12 mole) and sodium thiocyanate (29.2 g., 0.36 mole) in methanol (300 ml.) is added dropwise a solution of bromine (19.5 g., 0.122 mole) in methanol (75 ml.) saturated with sodium bromide. The solution is stirred for 1 hour following the addition of the bromine and then poured into water (2 liters) and neutralized with sodium carbonate. The resulting solid is collected, washed with water and dried, m.p. 74°-79° C.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[N:15]1[N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]2[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=2)[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=12
Reactant: Cc1ccc(N)c(Br)n1
Reactant: C#CCCn1nc2ccccc2n1
Product: Cc1ccc(N)c(C#CCCn2nc3ccccc3n2)n1
Yield: 44.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-methyl-pyridin-3-ylamine (80 mg, 0.43 mmol) and 2-but-3-ynyl-2H-benzo[d][1,2,3]triazole (73 mg, 0.43 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/AcOEt 1:1) to yield 53 mg (0.19 mmol, 45%) of 2-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)-6-methylpyridin-3-amine as a brown solid.