Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22].[F:28][C:29]1[CH:30]=[C:31]([CH2:36][C:37](O)=[O:38])[CH:32]=[C:33]([F:35])[CH:34]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[F:28][C:29]1[CH:30]=[C:31]([CH2:36][C:37]([NH:22][C@H:21]([C:20]([NH:19][C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C@@H:4]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:27])[CH2:23][CH:24]([CH3:25])[CH3:26])=[O:38])[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N1-[(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-L-leucinamide (64 g) (65 mg, 0.177 mmol) in dichloromethane (2 mL) was added 3,5-difluorophenylacetic acid (35 mg, 0.230 mmol), HOBt (31 mg, 0.230 mmol), NMM (25 mg, 0.248 mmol) and EDAC-HCl (44 mg, 0.230 mmol). The mixture was stirred at ambient temperature under nitrogen overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic extracts were washed in succession with saturated aqueous sodium bicarbonate and 1N aqueous HCl. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 6:1 (v/v) dichloromethane:ethyl acetate to afford the title compound in a 1:1 mixture with the 2S,3R diastereomer (65 mg, 70%) as a white solid. TLC Rf=0.31 (6:1 dichloromethane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ0.82 (m, 6H), 1.21-1.55 (m, 3H), 3.48 (s, 2H), 4.28 (m, 1H), 5.15 (t, 1H, J=7.2 Hz), 5.76 (m, 2H), 6.27 (d, 1H, J=7.0 Hz), 6.78 (m, 3H), 7.06 (m, 1H), 7.15-7.42 (m, 8H), 7.55 (br s, 1H). MS APCI, m/z=510 (M+1). LC/MS: 2.40 min.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:12]([NH2:15])(=[O:14])[CH3:13].C(=O)([O-])O.[Na+]>>[CH3:13][C:12]1[O:14][C:2]([CH3:11])=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:15]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc(-c2ccccc2)c(C)o1

Procedure:
A mixture of α-bromopropiophenone (9.5 g) and acetamide (26.4 g) was heated on an oil bath at 130°-140° C. for 40 minutes. After cooling, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl ether. The ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was further distilled under reduced pressure to give 2,5-dimethyl-4-phenyloxazole as an oil, yield 6.4 g (82.9%), b.p. 148°-152° C./23 mmHg.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[C:7]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[CH:6]=[CH:5][C:4]=1[C:15]1[S:19][C:18]([N:20]2[CH2:23][C:22]3([CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH2:21]2)=[N:17][N:16]=1.C(Cl)[Cl:37].O>O1CCOCC1.CO.CS(C)=O>[ClH:37].[F:2][C:3]1[C:8]([F:9])=[C:7]([C:10]2[CH:14]=[N:13][NH:12][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:15]1[S:19][C:18]([N:20]2[CH2:23][C:22]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH2:21]2)=[N:17][N:16]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(-c4cn[nH]c4)c(F)c3F)s1)C2
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: Fc1c(-c2cn[nH]c2)ccc(-c2nnc(N3CC4(CCNCC4)C3)s2)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
HCl (4M solution in dioxane, 113 μL, 0.45 mmol) was added to a stirred suspension of tert-butyl 2-(5-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (11 mg, 0.023 mmol) in dioxane (1 mL). The reaction mixture was stirred at room temperature for 18 hours then diluted with a roughly 1:1 mixture of MeOH:DCM (10 mL) and a drop of water was added. The resulting suspension was solubilized by addition of DMSO (5 mL) and the solution was loaded onto a 0.5 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) then flushed with 10% DCM in [7M NH3 in MeOH] (10 mL). The DCM/MeOH/NH3 was removed in vacuo to afford the title compound as an off-white solid (7.4 mg, 85% yield). LC-MS: Rt 0.66 min; MS m/z 389.2 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 13.30 (s, 1H), 8.18 (s, 2H), 7.84 (ddd, J=8.6, 6.8, 1.7 Hz, 1H), 7.70 (ddd, J=8.6, 7.1, 1.7 Hz, 1H), 3.87 (s, 4H), 2.65 (t, J=5.0 Hz, 4H), 1.70 (t, J=5.4 Hz, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[N:8].S(Cl)([Cl:12])(=O)=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:12][C:3]1[C:2]([C:7]#[N:8])=[N:1][CH:6]=[CH:5][N:4]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: N#Cc1cnccn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1nccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
Pyrazine-2-carbonitrile (26.36 g) is dissolved in toluene (187 ml)/N,N-dimethylformamide (19 ml), and thereto is added dropwise sulfuryl chloride (135 g) under ice-cooling. After completion of addition, the reaction solution is warmed to room temperature gradually and stirred overnight. The toluene layer is separated and the residual red oil is extracted with diethyl ether. The organic layers are combined, cooled with ice, and after pouring thereto ice-water, neutralized by adding saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated, and aqueous layer is extracted with diethyl ether. The organic layers are combined, washed with water, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (16.58 g).
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[CH:16]1[CH2:18][CH2:17]1)\[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[CH:16]1(/[C:7](/[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:19])=[O:2])[CH2:18][CH2:17]1
Reactant: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C\C=C\C(=O)O)C2CC2)cc1
Reaction time: 3 h
Yield: 68.2 %

Procedure:
As described in Example 99, (2E,4Z)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid methyl ester (3.1 g) was saponified in a refluxing mixture of methanol (15 mL) and 2N NaOH (15 mL). After 3 hours the reaction was worked up in the usual way, and the crude was crystallized from 2-propanolhexane to give 2 g of (2E,4Z)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid, mp 154°-155.5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:14]([CH3:15])[CH2:13][CH2:12][O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([N:8]1[CH:14]([CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CCOCC(=O)N1Cc1ccccc1
Solvent: C1CCOC1
Product: CC1CCOCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 4-benzyl-5-methyl-[1,4]oxazepan-3-one (0.32 g, 1.4 mmol) in tetrahydrofuran (5 mL) was added 1M solution of boran-tetrahydrofran complex in tetrahydrofuran (5 mL, 5.0 mmol) dropwise at 0° C. under nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 3 hours. Then the reaction was quenched by the addition of methanol and the solution was concentrated. The residual oil was dissolved in methanol (10 mL) and 1M sodium hydroxide aqueous solution was added at room temperature. The mixture was refluxed for 3 hours and diluted with water. Extraction with ethyl acetate was performed and the organic extracts were dried over anhydrous sodium sulfate. After evaporation of solvents, the residue was purified by flash column chromatography on silica gel to yield 4-benzyl-5-methyl-[1,4]oxazepane (0.30 g, 1.4 mmol, 100%) as colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.B(O)(O)[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[Cl:8][C:7]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1cccnc1Cl
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ncccc2Cl)cc1
Yield: 84 %

Procedure:
{circle around (1)} 100 g (0.676 mol) of 2,3-dichloropyridine, 91.87 g (0.676 mol) of p-tolylboronic acid, and 86 g (0.811 mol) of sodium carbonate were dissolved in 500 mL of 1,2-dimethoxyethane and 500 mL of distilled water, after which 78 g (0.0676 mol) of Pd(PPh3)4 was added. The mixture was heated to reflux for 18 hours so that it was allowed to react. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove 1,2-dimethoxyethane, and then extracted with ethyl acetate. The extract was treated with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 3-chloro-2-para-tolylpyridine as represented below in a 84% yield.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C[O-].[Na+].Br[CH:11]([CH2:16][CH3:17])[C:12]([O:14][CH3:15])=[O:13]>CO>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][CH2:17][CH2:16][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: CCC(Br)C(=O)OC
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCSCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
Methyl thioglycolate (5.0 mL, 55.0 mmol) was added dropwise to an ice cold solution of sodium methoxide (55.0 mmol) in methanol (18 mL) over 15 minutes. Methyl bromobutyrate (9.9 g, 55.0 mmol) was added slowly. The reaction was allowed to warm to room temperature and stirred overnight. The resulting mixture was filtered, concentrated, and taken up in methylene chloride and filtered again. The filtrate was concentrated and the product was distilled to give methyl 4-[(2-methoxy-2-oxoethyl)sulfanyl]butanoate (6.34 g, 55%) as a clear oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1)=[O:18].C(Cl)Cl>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]([CH:19]2[CH2:20][CH2:21][N:22]([C:25]3[N:26]=[CH:27][CH:28]=[CH:29][N:30]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:3][CH:4]=1
Reactant: CON(C)C(=O)C1CCN(c2ncccn2)CC1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)C1CCN(c2ncccn2)CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 83.1 %

Procedure:
A solution of 1,4-dibromobenzene (2.29 g, 9.72 mmol, 1.9 eq) in THF (20 ml) under N2 was cooled to −78° C., and n-butyllithium (1.6 M in hexanes, 4.8 ml, 7.67 mmol, 1.5 eq) was added dropwise. The reaction mixture was stirred at −78° C. for 40 minutes, and a solution of N-methoxy-N-methyl-1-(pyrimidin-2-yl)piperadine-4-carboxamide (1.28 g, 5.11 mmol, 1 eq) in THF (5 ml) was added dropwise via a cannula. After 3 hours at −78° C., the reaction mixture was warmed to 0° C., stirred for 1 hour, and then quenched with 1 N aq. HCl (10 ml). The mixture was diluted with 150 ml of ethyl acetate, washed sequentially with saturated aq. NaHCO3 and brine (75 ml each), and the organic phase was dried over Na2SO4 and concentrated. Column chromatography (silica gel, CH2Cl2 3.5% ethyl acetate/CH2Cl2) afforded 1.47 g (83% yield) of the product as a pale yellow solid: HPLC: 99% pure at 3.748 min (YMC-Pack ODS-A 4.6×33 mm column, 0% 100% solvent B over 4 min, 3 ml/min, 220 nm); LCMS (M+H)+=345.90; 400 MHz 1H NMR (CDCl3) 8.31 (d, J=4.7 Hz, 2H), 7.83 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 6.48 (t, J=4.7 Hz, 1H), 4.81 (m, 2H), 3.49 (m, 1H), 3.08 (m, 2H), 1.72-1.95 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[CH:3]=1>CO.[Pt]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CO
Product: COc1cc(Cl)ccc1N
Reaction time: 4 h
Yield: 97.9 %

Procedure:
4-Chloro-2-methoxynitrobenzene (2.8 g, 14.9 mmol) was dissolved in MeOH (110 mL), then 5% platinum on carbon (0.61 g) was added and the reaction stirred under a H2 balloon for 4 hours. The reaction was then filtered through diatomaceous earth (Celite®) and concentrated under vacuum, giving the product (2.3 g, 100%) as syrup that slowly solidified. MS (DCI) m/e 158 & 160 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 6.83 (d, J=2.4 Hz, 1H), 6.71 (dd, J=8.5, 2.4 Hz, 1H), 6.63 (d, J=8.5 Hz, 1H), 5.27 (v br s, 2H), 3.77 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].C([O:15][C:16]1[CH:17]=[CH:18][C:19]([C@@H:27]([OH:63])[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:43]([NH:45][C:46]([O:48][CH:49]3[CH2:54][CH2:53][N+:52]([CH3:56])([CH3:55])[CH2:51][CH2:50]3)=[O:47])[CH:44]=2)=[C:20]2[C:25]=1[NH:24][C:23](=[O:26])[CH:22]=[CH:21]2)C1C=CC=CC=1>CO.[C].[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[OH:63][C@H:27]([C:19]1[CH:18]=[CH:17][C:16]([OH:15])=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23](=[O:26])[NH:24]2)[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[CH:41][C:42]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)=[C:43]([NH:45][C:46]([O:48][CH:49]2[CH2:50][CH2:51][N+:52]([CH3:56])([CH3:55])[CH2:53][CH2:54]2)=[O:47])[CH:44]=1
Reactant: C[N+]1(C)CCC(OC(=O)Nc2cc(CCCCCCCCCNC[C@H](O)c3ccc(OCc4ccccc4)c4[nH]c(=O)ccc34)ccc2-c2ccccc2)CC1
Agent: [Pd]
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: C[N+]1(C)CCC(OC(=O)Nc2cc(CCCCCCCCCNC[C@H](O)c3ccc(O)c4[nH]c(=O)ccc34)ccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The obtained 4-({[5-(9-[{(2R)-[8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl]-2-hydroxyethyl}amino]nonyl)-2-phenylphenyl]carbamoyl}oxy)-1,1-dimethylpiperidin-1-ium trifluoroacetate was dissolved in methanol (5 mL), 10% palladium-carbon (50 mg) was added thereto, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC fractionation to obtain 4-({[5-(9-{[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}nonyl)-2-phenylphenyl]carbamoyl}oxy)-1,1-dimethylpiperidin-1-ium trifluoroacetate (12.79 mg).
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([NH:10][C:11]3[C:12]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:22][N:17]([C:12]1[C:11]([NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:37][C:34]4[CH:33]=[CH:32][C:31]([N:28]5[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]5)=[CH:36][CH:35]=4)[N:23]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:16][CH:15]=[CH:14][N:13]=1)[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CN(c1ncccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(Nc5cccnc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-pyridin-2-yl)-methanesulfonamide was prepared from N-[3-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-pyridin-2-yl]-N-methyl-methanesulfonamide (75.0 mg, 0.212 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (50.0 mg, 0.261 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.035 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.09 (dd, J=4.5, 1.3 Hz, 1H), 8.06 (d, J=6.6 Hz, 1H), 7.78 (dd, J=8.3, 1.3 Hz, 1H), 7.53 (s, 1H), 7.50 (d, J=8.9 Hz, 2H), 7.28-7.23 (m, 1H), 7.12 (d, J=7.7 Hz, 1H), 6.97 (d, J=9.0 Hz, 2H), 6.74 (t, J=7.3 Hz, 1H), 6.68 (s, 1H), 3.33 (s, 3H), 3.19-3.14 (m, 4H), 3.10 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=508 (MH)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:57])[CH2:39][N:40]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53](O)=[O:54])[CH:49]=[N:50][C:44]=3[NH:43][C:42](=[O:56])[CH2:41]2)[CH2:34][CH2:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13])[C:53](=[O:54])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[CH2:41][N:40]([CH2:39][C:38]([N:35]3[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]3)=[O:57])[CH2:46][C:45]=2[CH:47]=1
Reactant: CNCc1sc2ccccc2c1C
Reactant: CN1CCN(C(=O)CN2CC(=O)Nc3ncc(/C=C/C(=O)O)cc3C2)CC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CC(=O)N2CCN(C)CC2)CC(=O)N3)sc2ccccc12
Yield: 53 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-{4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl}acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.18 g, 53%) was prepared as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 10.91 (br s, 1H), 10.55 (br s, 1H), 8.61 (s, 1H), 8.18 (s, 1H), 7.88-7.86 (m, 1H), 7.75-7.72 (m, 1H), 7.61-7.52 (m, 1H), 7.42-7.28 (m, 3H), 5.14-4.89 (m, 2H), 4.42-4.38 (m, 1H), 4.01 (br s, 3H), 3.65 (s, 4H), 3.39 (br s, 4H), 3.16 (s, 2H), 3.04-2.94 (m, 3H), 2.74 (br s, 3H), 2.42 (s, 3H); MS (ESI) m/e 547 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.CC(C)([O-])C.[K+].Br[CH2:33][CH2:34][CH2:35][CH3:36]>CS(C)=O>[CH2:33]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:9][N:10]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])=[N:11]2)[CH:4]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCBr
Reactant: O=C(Nc1ccn(Cc2cc(O)ccc2Cl)n1)c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCOc1ccc(Cl)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Reaction time: 0.08 h
Yield: 27.8 %

Procedure:
To a solution of N-{1-[(2-chloro-5-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide(for as preparation see Intermediate 13) (35 mg, 0.096 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (10.80 mg, 0.096 mmol). The reaction was stirred for 5 min before adding 1-bromobutane (0.012 ml, 0.115 mmol, Acros). The reaction mixture was stirred under nitrogen for 72 h at ambient temperature. The reaction mixture was filtered through a hydrophobic frit and the filtrate diluted with methanol (0.5 ml) and the sample purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a brown gum (11.2 mg); LCMS: (System 4) MH+=420, tRET=3.41 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1(C)C=CC=CC=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[K+].[NH:64]1[CH2:69][CH2:68][S:67][CH2:66][CH2:65]1>CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:14]([C:4]1[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([N:64]2[CH2:69][CH2:68][S:67][CH2:66][CH2:65]2)[CH:3]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cc(Cl)cnc1N1CCOCC1
Reactant: C1CSCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc(N2CCSCC2)cnc1N1CCOCC1
Temperature: 115 °C

Procedure:
A stirred solution of 4-(5-chloro-3-nitropyridin-2-yl)morpholine (400 mg, 1.64 mmol) in toluene (15.7 mL, 147.7 mmol) was treated with Pd2dba3 (75 mg, 0.082 mmol), X-Phos (78 mg, 0.16 mmol), potassium tert butoxide (368 mg, 3.28 mmol) and thiomorpholine (203 mg, 1.97 mmol). The reaction was heated at 115° C. overnight. After this time the reaction was cooled to rt and diluted with EtOAc (100 mL) and water (50 mL). The separated organic layer was washed with NaHCO3 (satd aq. solution, 40 mL), brine (40 mL) and then dried over magnesium sulfate, filtered and evaporated in vacuo. Column chromatography (hexanes:EtOAc, 1:0 to 1:2) gave 4-(3-nitro-5-thiomorpholinopyridin-2-yl)morpholine as a red oil. Mass Spectrum (ESI) m/e=311.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH:4]([Br:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of 4-chlorophenylacetic acid methyl ester (14.6 g, 79.1 mmol), N-bromosuccinimide (14.4 g, 80.7 mmol), and benzoyl peroxide (1.91 g, 7.89 mmol) in carbon tetrachloride (100 mL) was heated at reflux for 3 h. After the mixture was cooled at room temperature, hexanes (500 mL) was added. The reaction mixture was filtered and the solvent was evaporated in vacuo. The crude material was purified by column chromatography on silica (EtOAc/Hexanes, 15:85) to give the title compound as colorless oil (16.9 g, 63%): 1H NMR (400 MHz, CDCl3) δ 3.81 (s, 3H, CH3), 5.34 (s, 1H, CH), 7.44 (dd, J=60.4 Hz, J=8.4 Hz, 4H, ArH).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([OH:30])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[C:7]([OH:13])=[C:8]([CH:11]=[O:12])[C:9]=1[CH3:10].Cl.[Na+].[Cl-]>CC(C)=O.CCOC(C)=O.O>[Cl:3][C:4]1[C:5]([OH:30])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:7]([OH:13])=[C:8]([CH:11]=[O:12])[C:9]=1[CH3:10]
Reactant: CCOC(=O)CCCCCCCCCCCc1c(O)c(Cl)c(C)c(C=O)c1O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)c(O)c(CCCCCCCCCCCC(=O)O)c(O)c1C=O
Reaction time: 12 h

Procedure:
NaOH (21 mg, 0.48 mmol) was added to a mixed solution of 215-15-COOEt (101 mg, 0.246 mmol) in acetone (1.3 ml)/H2O (0.7 ml) at room temperature followed by stirring for 12 hours. After dilution of the reaction solution with EtOAc, the diluted solution was acidified with a 1 M aqueous HCl solution. After addition of a saturated aqueous NaCl solution, the organic layer was separated. The aqueous layer was then extracted with EtOAc twice, and the combined organic layer was dried over Na2SO4. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (Hexane:EtOAc=2:1) to yield the target product.