Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C@H:7]([CH3:18])[CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.[Rh]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@H:7]([CH3:18])[C@@H:8]([OH:17])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:19][CH:20]=1
Reactant: C[C@@H](Oc1ccc(Br)cc1)C(O)C#Cc1cccnc1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: C[C@@H](Oc1ccc(Br)cc1)[C@@H](O)CCc1cccnc1

Procedure:
Prepared according to the method described in Example 1d) from (3RS,4R)-4-(4-bromophenoxy)-1-pyridin-3-yl-pent-1-yn-3-ol (5.93 g, Example 4c)) and 5% rhodium on charcoal (2.0 g) in ethyl acetate (100 ml) to give the sub-title compound as an oil and as a 4:1 mixture of diastereomers (5.6 g). The diastereomers were separated using normal-phase HPLC eluting with 3% isopropyl alcohol in dichloromethane to give (2S, 3R)-2-(4-bromophenoxy)-5-pyridin-3-yl-pentan-3-ol as the majordiastereomer (3.21 g) and (2S, 3S)-2-(4-bromophenoxy)-5-pyridin-3-yl-pentan-3-ol as the second eluting and minor diastereomer (0.71 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1.[NH:10]1[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>C1COCC1>[I:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:10]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[CH:4][CH:5]=1
Reactant: O=S1(=O)CCNCC1
Reactant: BrCc1ccc(I)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S1(=O)CCN(Cc2ccc(I)cc2)CC1

Procedure:
1-(bromomethyl)-4-iodobenzene (1 g, 3.37 mmol), thiomorpholine 1,1-dioxide (0.546 g, 4.04 mmol) and DIPEA (0.882 mL, 5.05 mmol) were stirred in THF (15 mL) at room temperature overnight. The solvent was removed in vacuo while loading onto silica. Purification of the residue by MPLC (12-100% EtOAc-hexanes) gave 4-(4-iodobenzyl)thiomorpholine 1,1-dioxide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[CH:31]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:32]4[CH:33]=[CH:34][S:30][CH:31]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1ccsc1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccsc2)c1

Procedure:
Prepared as described in Example 105 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 39 mg, 100 μmol) and 3-thiophenecarboxylic acid (38 mg, 300 μmol). Yield 47 mg (94%).
Reaction SMILES: O.[N+:2]([CH:5]([CH:8]=O)[CH:6]=O)([O-:4])=[O:3].[Na].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)=O>CN(C=O)C.O>[CH2:11](/[N:18]=[CH:6]/[CH:5]([N+:2]([O-:4])=[O:3])/[CH:8]=[N:18]/[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=CO
Product: O=[N+]([O-])C(/C=N/Cc1ccccc1)/C=N/Cc1ccccc1
Reaction time: 24 h
Yield: 10.2 %

Procedure:
A turbid, yellow-orange solution of sodium nitromalonaldehyde monohydrate (15.7 mg, 0.10 mmol) in DMF (275 uL) and water (25 uL) was added dropwise over a 2 min period to a solution of benzylamine (27.4 uL, 0.25 mmol) in DMF (165 uL), water (15 uL) and 96% formic acid (0.94 uL, 0.025 mmol) and was stirred at room-temperature for 24 h. A few drops of the reaction mixture were added to ˜1 mL water giving a white, opaque emulsion that was extracted with EtOAc twice. The combined organics were dried over Na2SO4, evaporated under N2 and dried in vacuo at room-temperature to give 3.0 mg of the crude title compound (I1) as a pale-pink residue (3.0 mg, 10% crude yield); HRMS calcd for C17H18N3O2 (M+H+) 296.13990, obsd 296.13733 (100%); 1H NMR (300 MHz, DMSO-d6) δ 4.719 (s, 4H), 7.274-7.304 (m, 10H), 8.898 (s, 2H), ˜11.7 (br s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([NH:15][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:17])[CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:16]([NH:15][C:4]2[CH:3]=[C:2]([N:25]3[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]3)[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]=3)[N:5]=2)[CH3:17])=[CH:19][CH:20]=1
Reactant: C[C@H](Nc1cc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Reactant: CC(=O)N[C@H]1CCNC1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N[C@H]1CCN(c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)c2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
100 mg of (S)-4-chloro-N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,6-diamine (Reference Example 2), 112 mg of (S)—N-(pyrrolidin-3-yl)acetamide, 69 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 92 mg of sodium t-butoxide and 30 mg of tris (dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 115 mg of N-{(S)-1-[2-{[(S)-1-(4-fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyridin-4-yl]pyrrolidin-3-yl}acetamide as pale brown powder. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 67 mg of the objective compound as brown powder.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: CN1CCNCC1
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCN1CCN(C)CC1

Procedure:
Using 3.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) and 24 ml of 1-methylpiperazine, a reaction similar to that conducted in Example 142 was carried out. As a result, 2.24 g of N-(trans-4-methylcyclohexyl)-4-[2-(4-methylpiperazinyl)ethoxy]-3-methoxycinnamamide (a compound of the present invention) was obtained as light-brownish white crystal, which had the following physioche mical properties:
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([CH:20]=O)=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[CH:20]=[CH2:2])=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: O=Cc1ccc(Cl)cc1-c1ccc(Br)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(Cl)cc1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
BuLi (2.5M in hexanes, 11.3 mL, 28.2 mmol) was added to a solution of methyltriphenylphosphonium bromide (10.1 g, 28.2 mmol) in THF (65 mL). The mixture was stirred at 0° C. for 1 hr. A solution of 4′-bromo-5-chlorobiphenyl-2-carbaldehyde (4.2 g, 14.11 mmol) in THF (65 mL) was added dropwise at 0° C. The mixture was stirred overnight from 0° C. to r.t. The reaction was filtered and evaporated. The residue was diluted with diethyl ether and washed with water and brine. The ether layer was collected, dried (MgSO4), filtered and evaporated to give the crude material. The crude material was purified on the Biotage (5-15% EtOAc:Hex) to give 4′-bromo-5-chloro-2-vinylbiphenyl (3.43 g, 11.68 mmol, 83% yield) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:10]/[S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])[CH:5]=[CH:4][N:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH:10][S:11]([C:13]([CH3:14])([CH3:16])[CH3:15])=[O:12])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: C/C(=N\S(=O)C(C)(C)C)c1ccnc(Br)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](NS(=O)C(C)(C)C)c1ccnc(Br)c1
Reaction time: 2.5 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [1-(2-bromo-pyridin-4-yl)-eth-(E)-ylidene]-amide (9.3 g, 31 mmol) in THF (280 mL) was added a 1 M solution of L-Selectride in THF (61.3 ml, 61.3 mmol) dropwise. After 2.5 hours, the chilled mixture was quenched with saturated aqueous NH4Cl (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×400 mL). The combined organic layers were washed with brine, and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 50-90% EtOAc in hexanes to afford 2-methyl-propane-2-sulfinic acid [(S)-1-(2-bromo-pyridin-4-yl)-ethyl]amide as a light yellow oil which contained 5% of the opposite diastereomer.
Reaction SMILES: [FH:1].[CH3:2][C:3]1([CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH3:11])[CH2:5]1)N.N([O-])=O.[Na+]>CS(C)=O>[F:1][C:9]1[C:3]([CH3:2])=[CH:5][C:6]([CH3:11])=[C:7]([F:10])[CH:8]=1
Reactant: CC1=C(F)C=CC(C)(N)C1
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(F)cc1F
Temperature: 25 °C

Procedure:
1.8 l of anhydrous hydrogen fluoride are initially introduced into a stirred vessel made of stainless steel and 625 g of 1,3-dimethyl-4-fluoro-aniline (see Am. Soc. 54, 2981) are introduced, whilst cooling. Subsequently, a diazotisation reaction is carried out, at 0° C, by adding 374 g of sodium nitrite in portions. The mixture is then slowly heated to room temperature. Since the splitting of the diazonium fluoride proceeds only slowly at this temperature, the temperature is raised up to the reflux temperature for hydrogen fluoride. Towards the end of the reaction 800 ml of dimethylsulphoxide are added and the temperature is further raised to 80° C and this temperature is maintained for 30 minutes. Subsequently, the reaction mixture is poured onto ice and extracted with methylene chloride and the organic phase is separated off, dried over sodium sulphate and then distilled. 428 g of 1,3-difluoro-4,6-dimethylbenzene with a boiling point of 143° C and a melting point of 30° to 31° C are obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:26]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCCN3CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCCN3CC(C)C)cc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 97.2 %

Procedure:
To methyl 9-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.65 g) were added tetrahydrofuran (35 ml) and methanol (35 ml), followed by adding aqueous 1N sodium hydroxide solution (11.4 ml), and the mixture was stirred at 90° C. for 7 hours. After cooling to 0° C., water was added and the mixture was neutralized with 1N hydrochloric acid. After extracting with ethyl acetate, the organic layer was washed with saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give 9-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylic acid (2.5 g) as a yellow oily material.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([N:27]([CH3:35])C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:61]>O1CCOCC1.C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[ClH:37].[ClH:61].[ClH:37].[Cl:37][C:38]1[CH:43]=[C:42]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:13]3[NH:14][C:15]2[CH:20]=[N:19][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][CH3:35])[CH2:22]3)=[CH:17][CH:16]=2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: CNC1CCCN(c2ccc(Nc3c(C(C)=O)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Temperature: 80 °C
Yield: 107.6 %

Procedure:
To a suspension of tert-butyl (1-(5-((3-acetyl-6-bromoquinolin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)(methyl)carbamate (80 mg, 0.144 mmol), 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (68 mg, 0.28 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80° C. for 2 h. The solution was allowed to cool to room temperature, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded a brown solid. This solid was dissolved in THF (3 mL), water (3 mL) and HCl (6 M in water, 2 mL, 12 mmol). The reaction mixture was heated at 65° C. for 4 h, cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The residue was dissolved in methanol (8 mL) and HCl (6 M in water, 1.0 mL, 6 mmol) was added. The resultant solution was concentrated to give the desired product (63.2 mg, 70%) as an orange solid. 1H NMR (500 MHz, MeOD) δ 9.28 (s, 1H), 8.29-8.19 (m, 2H), 8.04-7.96 (m, 2H), 7.78 (d, J=9.5 Hz, 1H), 7.24 (d, J=9.3 Hz, 1H), 7.13-7.06 (m, 2H), 4.46 (br s, 1H), 3.96 (d, J=13.1 Hz, 1H), 3.61 (br s, 1H), 3.48-3.37 (m, 1H), 2.82 (s, 3H), 2.80 (s, 3H), 2.28-2.24 (m, 1H), 2.02-1.94 (m, 1H), 1.88-1.70 (m, 2H). ESI MS m/z 520 [C32H32Cl2N4O2+H]+; HPLC 98.8% (AUC), tR=9.82 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[NH2:17][OH:18]>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([NH:17][OH:18])[N:3]=1)[CH2:14][CH3:15]
Reactant: NO
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Product: CCCNc1nc(NO)nc(NCCC)n1

Procedure:
N-(4,6-Bis-n-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLV) was prepared from 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and hydroxylamine hydrochloride as described in Example 13 (99% yield). 400 MHz 1H NMR (DMSO-d6, ppm) 9.0-8.6 (1H, br s), 8.39-8.14 (1H, s), 6.89-6.55 (2H, m), 3.23-3.06 (4H, m), 1.54-1.40 (4H, m), 0.84 (6H, t, J=7.4 Hz). ESI-MS (m/z): 227 [M+H]+. MP: 138-141° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(Cl)(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2](/[CH:14]=[CH:13]/[C:12]([O:16][CH3:17])=[O:15])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1cnc2ccccc2c1
Reaction time: 0.5 h

Procedure:
In an amount of 10.2 g of 3-bromoquinoline was stirred together with 7 ml of methyl acrylate, 110 mg of palladium(II) acetate, 599 mg of tri-o-tolylphosphine, and 29 ml of triethylamine at 100° C. for 17 hours in a sealed tube. The reaction mixture was diluted with 300 ml of chloroform, and successively washed with 250 ml of saturated brine, and 250 ml of saturated aqueous ammonium chloride. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 80 ml of chloroform, added with 200 ml of hexane under ice cooling, and stirred for 30 minutes. The precipitates were taken by filtration, washed with hexane, and then dried under reduced pressure to obtain 8.0 g of methyl (E)-3-(quinolin-3-yl)acrylate. Physicochemical Properties of this Compound
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1>[CH3:8][C:3]1([NH:2][S:10]([CH3:9])(=[O:12])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(N)CCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC1(NS(C)(=O)=O)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a stirred solution of 1-amino-1-methylcyclopentane hydrochloride (0.165 g, 1.2 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.169 mL, 2.2 mmol). The reaction mixture was stirred at room temperature for 16 hrs and then concentrated. The mixture was diluted with ethyl acetate and washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown oil (0.100 g, 46%). 1H NMR (300 MHz, CDCl3) δ 4.27 (br s, 1H), 3.04 (s, 3H), 2.00-1.60 (m, 8H), 1.50 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@H:12]([CH:17]([CH3:19])C)[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.Br[C:21]1C=CC(C(OC)=O)=C(CBr)[CH:22]=1.Cl.NC1(C(OC)=O)CCCC1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1([C:13]([O:15][CH3:16])=[O:14])[CH2:17][CH2:19][CH2:22][CH2:21]1)[CH2:5]2
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: COC(=O)C1(N)CCCC1
Agent: Cl
Product: COC(=O)C1(N2Cc3cc(Br)ccc3C2=O)CCCC1

Procedure:
The compound of example 368 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and methyl 1-aminocyclopentanecarboxylate hydrochloride.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.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>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:22])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccccc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Yield: 92 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see example 4) (78.6 mg, 0.213 mmol), phenyl boronic acid (31.1 mg, 0.255 mmol), potassium carbonate (73.5 mg, 0.532 mmol) and tetrakis(triphenylphosphine)palladium(0) (12.30 mg, 10.64 μmol) in ethanol (2.5 mL) and toluene (2.5 mL) was degassed under house vacuum and quenched several times with nitrogen, and then was heated at 100° C. for 30 min before being cooled to room temperature. The mixture was filtered through celite and the insoluble washed with EtOH. Most of the solvent was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 25 to 55% AcOEt in hexanes) gave 1-methylethyl [(2S,4R)-1-acetyl-2-methyl-6-phenyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (71.6 mg, 0.195 mmol, 92%) as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[CH:7]=[C:6]2[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.[F:26][B-](F)(F)F.F[N+]1C(C)=CC(C)=CC=1C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[C:7]([F:26])=[C:6]2[C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Reactant: F[B-](F)(F)F
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: ClCCl
Product: CCOc1ccc2c(F)c(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.4 %

Procedure:
To 1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (600 mg, 1.79 mmol) in CH2Cl2 (4 mL) was added 1-fluoro-2,4,6-trimethyl pyridinium tetrafluoroborate (418 mg, 1.85 mmol). The reaction mixture was stirred at room temperature for 3 days and then diluted in CH2Cl2 and washed with aq. NaHCO3. The organic layer was dried, concentrated and purified by silica gel chromatography (1:1 CH2Cl2/hexane) to provide 1-cyclopropylmethyl-6-ethoxy-3-fluoro-2-(4-nitro-phenyl)-1H-indole (161 mg, 25%) as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]/[C:5](=[CH:13]\[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([N:22]2[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]2)=[CH:16][C:15]=1[F:28])/[C:6]([O:8]C(C)(C)C)=[O:7].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Cl:1][CH2:2][CH2:3][CH2:4]/[C:5](=[CH:13]\[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([N:22]2[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]2)=[CH:16][C:15]=1[F:28])/[C:6]([OH:8])=[O:7]
Reactant: COc1cc(/C=C(\CCCCl)C(=O)OC(C)(C)C)c(F)cc1-n1cnc(C)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C(\CCCCl)C(=O)O)c(F)cc1-n1cnc(C)c1
Reaction time: 2 h

Procedure:
Sodium hydride (containing mineral oil at 40%, 0.68 g) was added to a solution of tert-butyl 5-chloro-2-(diethoxyphosphoryl)valerate (5.59 g) in THF (50 mL) in a nitrogen atmosphere at room temperature, and the reaction solution was stirred at room temperature for 30 minutes. A solution of 2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (3.19 g) in THF (10 mL) was added to the reaction mixture, and the reaction solution was stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain tert-butyl (E)-5-chloro-2-(2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerate (5.93 g). A solution of tert-butyl (E)-5-chloro-2-(2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valerate in trifluoroacetic acid (30 mL) was stirred while cooling with ice. After 2 hours, the reaction solution was concentrated under reduced pressure. Tert-butyl methyl ether was added to the resulting residue, and the resulting deposited solid was filtered to obtain 3 g of the title compound. Properties data of the compound are as follows.