Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>O1CCOCC1.CO.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[CH:6]=[N:5]2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1cnc2cc(Br)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: C=C(OCC)c1cnc2cc(Br)ccc2n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
Dichlorobis(triphenylphosphine)-palladium(II) (17.30 mg, 0.025 mmol) was added to a solution of 6-bromo-2-chloroquinoxaline (60 mg, 0.246 mmol) and tributyl(1-ethoxyvinyl)stannane (107 mg, 0.296 mmol) in dioxane (1.5 mL) and the mixture was stirred at 110° C. for 2 h. The reaction was diluted with MeOH, and purified by prep HPLC (H2O-MeOH with 10 mM NH4OAc buffer) to yield 6-bromo-2-(1-ethoxyvinyl)quinoxaline (36 mg, 0.129 mmol, 52.3% yield) as white solid. LC-MS retention time 2.76 min; m/z 279 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10% methanol:0.1% TFA. Solvent B=10% water:90% methanol:0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:26]1[O:27][C:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:29]([C:31](O)=[O:32])[N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:29]3[N:30]=[C:26]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:27][C:28]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1nc(Cc2ccccc2)oc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(Cc4ccccc4)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-benzyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.09 min; [M+H]+=467.25.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[K+].Br[C:54]1[CH:59]=[C:58]([CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH:57]=[CH:56][N:55]=1.[C:68](=[NH:81])([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:64]([O:63][C:61](=[O:62])[CH2:60][C:58]1[CH:57]=[CH:56][N:55]=[C:54]([N:81]=[C:68]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[CH:59]=1)([CH3:67])([CH3:66])[CH3:65]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)Cc1ccnc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cc1ccnc(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 100 °C

Procedure:
To a solution of Pd2(dba)3 (1.9 mg, 0.0001 mmol), BINAP (5 mg, 0.008 mmol), and potassium tert-butoxide (62 mg, 0.55 mmol) in toluene (3 mL) was added tert-butyl (2-bromopyridin-4-yl)acetate (150 mg, 0.55 mmol) and benzophenone imine (140 μL, 0.83 mmol). The reaction was degassed for 15 minutes and then heated at 100° C. for 15 hours in a sealed tube. The reaction was then cooled to ambient temperature and concentrated in vacuo. The crude residue was dissolved ethyl acetate (200 mL), filtered over celite, and washed with water. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified via MPLC (0-100% EtOAc/Hex gradient) to afford title compound. LC-MS: (M+H)+373.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:27]=[CH:26][C:15]([CH2:16][S:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:14][CH:13]=1)[N:6]=[C:5]2[SH:28].[CH2:29](N(CC)CC)C.CI.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:27]=[CH:26][C:15]([CH2:16][S:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:14][CH:13]=1)[N:6]=[C:5]2[S:28][CH3:29]
Reactant: CCN(CC)CC
Reactant: CCOP(=O)(OCC)SCc1ccc(-c2nc(S)c3cc(Br)ccc3n2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CCOP(=O)(OCC)SCc1ccc(-c2nc(SC)c3cc(Br)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 0.60 g quantity of the compound obtained in Example 52 was dissolved in 10 ml of THF, and 0.2 ml of triethylamine and 0.1 ml of methyl iodide were serially added thereto with stirring at room temperature. The stirring was continued at room temperature for 30 minutes. After adding 30 ml of water, the reaction mixture was extracted with chloroform. The chloroform layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform: n-hexane=2:1) and recrystallized from diethyl ether-n-hexane to provide 0.43 g of the objective compound as yellow crystals (melting point: 126°-127° C.).
Reaction SMILES: [C:1]([CH:3]1[N:8]([CH3:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1)#[N:2].C(N(CC)CC)C>CO.[Ni]>[NH2:2][CH2:1][CH:3]1[N:8]([CH3:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1C#N
Agent: [Ni]
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)OC(C)(C)C)CC1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-cyano-4-methylpiperazine-1-carboxylate, prepared as described in Step A, (10.5 g, 47 mmol) in methanol (200 mL) was added metallic nickel (10 g) and triethylamine (5 mL). The mixture was stirred at ambient temperature overnight under atmosphere of hydrogen gas (50 psi). Upon consumption of tert-butyl 3-cyano-4-methylpiperazine-1-carboxylate, the mixture was filtered, and the filtrate was concentrated under vacuum to provide crude tert-butyl 3-(aminomethyl)-4-methylpiperazine-1-carboxylate used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[C:17](Cl)(=[NH:19])[NH2:18].CS(C)(=O)=O>O>[NH2:18][C:17]1[NH:19][C:4](=[O:5])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1
Reactant: N=C(N)Cl
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: CS(C)(=O)=O
Agent: Cl
Solvent: O
Product: COC(=O)c1ccc2c(=O)[nH]c(N)nc2c1
Temperature: 150 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Into a round bottom flask was added dimethyl 2-aminoterephthalate (1.0 g, 4.8 mmol) mixed with carbamimidic chloride-HCl (1.10 g, 9.6 mmol) and dimethyl sulfone (4.5 g, 47.8 mmol). The reaction mixture was heated to 150° C. and stirred overnight. The mixture was cooled to rt, water added and the solid was filtered. The solid was then washed with acetic acid to afford methyl 2-amino-4-oxo-3,4-dihydroquinazoline-7-carboxylate (1.0 g, 95%). LC-MS: (FA) ES+ 220.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.Cl.[NH2:20][C:21]([NH2:23])=[NH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[C:4]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[CH:3][N:20]=[C:21]([NH2:23])[N:22]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C(C(=O)c1ccco1)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccncc2)c(-c2ccco2)n1
Temperature: 70 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
A suspension of 3-(dimethylamino)-1-(2-furyl)-2-(4-pyridyl)-2-propene-1-one (2.2 g, 9.08 mmol), guanidine hydrochloride (2.6 g, 27.2 mmol) and potassium carbonate (7.5 g, 54.3 mmol) in N,N-dimethylformamide (20 mL) was stirred at 70° C. for 12 hours. After cooling as it was, the reaction mixture was diluted with water. The resulting crystals were collected by filtration and washed with water, to give the title compound (1.73 g, 80%) as a pale yellow solid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].B1C2CCCC1CCC2.C1COCC1.[OH-].[Na+].Br[C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[CH2:30][CH2:29]2>>[CH2:1]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[CH2:30][CH2:29]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCCCCCC
Reactant: O=C1CCc2cc(Br)ccc21
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2c(c1)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A Boron complex was first created by adding 1-octene (0.744 g, 6.633 mmol) to a stirring solution of 0.5M 9-BBN in THF (13.27 mL, 6.633 mmol). The reaction was left to stir at room temperature overnight. 3M NaOH (2.34 mL) was then added to the stirring solution followed by the addition of 5-Bromo-indan-1-one (1 g, 4.7 mmol) and Pd(Ph3)4 (0.145 g, 0.126 mmol). The reaction was refluxed for twelve hours. The resulting solution was concentrated and purified using silica gel chromatography eluding with hexanes-EtOAc (9:1). The reaction provided 2 (1.094 g, 4.48 mmol, 95%) as a clear liquid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2].[C:22]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[CH2:32][NH:31][CH2:30]2)(=[O:24])[CH3:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([N:31]3[CH2:30][C:29]4[C:33](=[CH:34][CH:35]=[C:27]([CH2:26][NH:25][C:22](=[O:24])[CH3:23])[CH:28]=4)[CH2:32]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3Cc4ccc(CNC(C)=O)cc4C3)c(F)cc2c1=O
Yield: 56.1 %

Procedure:
A mixture of 310 mg of 1-cyclopropyl-6-fluoro-7- chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 745 mg of 5-acetamidomethylisoindoline, 0.56 ml of triethylamine, and 5 ml of anhydrous chloroform was heated at 60°-70° C. for 0.5 hours while stirring. The resulting reaction mixture was diluted with 25 ml of chloroform. The mixture was washed with 5% acetic acid and brine in this order, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of ethylether. The crystals were collected by filtration and recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 260 mg of 7-(5- acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: C(OC(C1CCCN1C(=O)C(NC(=O)C1C=CC(N)=C(Cl)C=1)C)=O)(C)(C)C.[O:28]=[C:29]1[O:33][CH:32]([O:34][CH2:35][CH2:36][C:37]2C=CC=C[CH:38]=2)[CH:31]([NH:43][C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=2)[CH3:53])=[O:45])[CH2:30]1>>[CH2:35]([O:34][CH:32]1[CH:31]([NH:43][C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=2)[CH3:53])=[O:45])[CH2:30][C:29](=[O:28])[O:33]1)[CH2:36][CH2:37][CH3:38]
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Product: CCCCOC1OC(=O)CC1NC(=O)C1CCCN1C(=O)C(C)NC(=O)c1ccc(N)c(Cl)c1
Yield: 48 %

Procedure:
Prepared from 97a and syn-(2-butoxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 118 mg (48% yield) of the title compound as a syn diastereomer. 1H-NMR (500 MHz, CDCl3): δ 0.80-1.02 (m, 2H), 1.35-1.51 (m, 5H), 1.51-1.70 (m, 2H), 1.90-2.27 (m, 3H), 2.30-2.46 (m, H), 2.80-2.90 (m, H), 3.55-3.94 (m, 4H), 4.30-4.75 (m, 4H), 4.90-5.00 (m, H), 5.44-5.46 (m, H), 6.73-6.80 (m, H), 6.80-6.93 (m, H), 7.16-7.25 (m, H), 7.49-7.60 (m, H), 7.70-7.84 (m, H); retention time on analytical HPLC: 9.71 min; LC-MS: m/z=495 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].C(N(CC)C(C)C)(C)C.[NH2:26][C@@H:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:26][C@H:27]([CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (216 mg, 0.78 mmol)[prepared according to Example 96], N,N-diisopropylethylamine (0.68 ml, 3.90 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (252 mg, 0.78 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (401 mg, 0.86 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 40% EtOAc in hexanes) yielding 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (303 mg, 0.55 mmol, 71% yield) as a clear oil: LCMS (ES) m/e 545, 547 (M, M+2)+.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N(CC)CC)C.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(ON1C2C=CC=CC=2N=N1)(=O)=O>C(OCC)(=O)C>[C:1]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:4])[CH3:2]
Reactant: CC(=O)O
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
Acetic acid (0.3 g), triethylamine (0.7 ml) and aniline (0.5 g) are dissolved in ethyl acetate (10 ml), and thereto is added 1-methanesulfonyloxy-1,2,3-benzotriazole (1.05 g), and the mixture is stirred at room temperature for 1 hour. After allowing to stand overnight, the reaction mixture is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give acetanilide (0.7 g). The product recrystallized from water has a melting point of 110°-112° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6](O)[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10]1)=[CH2:8])[CH3:2].S(Br)([Br:25])=O.O>ClCCCl>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:19][CH:20]=[O:21])[CH:6]=[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][CH2:10]1)[CH2:8][Br:25])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(C1CCN(C(C)=O)CC1)C(O)C(NC=O)C(=O)OCC
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)C(C=C(CBr)C1CCN(C(C)=O)CC1)NC=O
Reaction time: 0.25 h

Procedure:
3.3 g (10.5 mmol) of 4-(1-acetylpiperidin-4-yl)-2-formylamino-3-hydroxy-pent-4-enoic acid ethyl ester are dissolved in 25 ml of 1,2-dichloroethane, and 0.98 ml (12.6 mmol) of thionyl bromide are added dropwise at room temperature. After 11/2 hours, 20 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with water, N-potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation. 4-(1-acetylpiperidin-4-yl)-5-bromo-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a reddish-brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:29])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:20][CH:19]=2)[CH2:13][CH2:12]1.[CH3:30][O:31][CH:32]([O:35][CH3:36])[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C(OCC)(=O)C>[CH3:30][O:31][CH:32]([O:35][CH3:36])[CH2:33][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:29])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:20][CH:19]=2)[CH2:13][CH2:12]1
Reactant: Nc1ccccc1C(=O)CCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Reactant: COC(C=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCCl
Product: COC(CNc1ccccc1C(=O)CCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound prepared in Example 309 (0.613 g) was suspended in 1,2-dichloroethane (30 mL). 2,2-Dimethoxyacetaldehyde solution in water (60% by weight) (2.28 mL) and beaded molecular sieves were added and the reaction mixture stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (2.62 g) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 2% (9:1 methanol/concentrated ammonium hydroxide)/dichloromethane) to furnish the title compound (0.555 g) with the following physical properties.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.P([O-])([O-])([O-])=[O:12]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:12])=[CH:3][CH:4]=1)#[N:7]
Reactant: O=P([O-])([O-])[O-]
Reactant: N#Cc1ccc(C#N)cc1
Product: N#Cc1ccc(C(N)=O)cc1

Procedure:
The nitrile hydratase activity was measured as follows. The cells (about 1 g by wet mass) were added to a reaction solution obtained by suspending from 1 to 10 mass % of terephthalonitrile (TPN) as a substrate in 10 ml of 20 mM phosphate buffer solution (pH: 7.0) and reacted at 30° C. while shaking, and the p-cyanobenzoic acid amide produced in the reaction solution was quantitated by HPLC at fixed intervals. The solid matter was removed from the reaction solution by centrifugation, and the supernatant 100-fold diluted with the eluant was used as the HPLC sample. The amidase activity was measured by using p-cyanobenzamide or benzamide serving as a substrate, performing the reaction under the same conditions as above, and determining the generated p-cyanobenzoic acid or benzoic acid by HPLC.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7](I)=[CH:6]2)[CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)C4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[CH:1]1([CH2:4][N:5]2[C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[CH:6]2)[CH2:3][CH2:2]1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2CC1CC1
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: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2CC1CC1

Procedure:
Following the general procedure for the Suzuki coupling, 7-cyclopropylmethyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (94.0 mg, 0.299 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (104 mg, 0.314 mmol), Na2CO3 (79.0 mg, 0.745 mmol) and Pd(PPh3)4 (21 mg, 0.018 mmol) in DMF (7.5 mL)/water (1.5 mL). The crude material was purified by an SCX column (2 g/6 mL barrel) followed by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-14)→1% MeOH in CH2Cl2 (15-34)→2% MeOH in CH2Cl2 (35-56)], yielding the title compound as an off-white yellow solid. 1H NMR (CDCl3, 400 MHz): δ=0.44-0.50 (m, 2H), 0.63-0.71 (m, 2H), 1.29-1.39 (m, 1H), 4.15 (d, J=7.2 Hz, 2H), 5.20 (brs, 2H), 7.29 (s, 1H), 7.46-7.52 (m, 11H), 7.52-7.58 (m, 2H), 7.71 (dd, J=1.8, 8.2 Hz, 11H), 7.91 (d, J=8.8 Hz, 11H), 7.93 (d, J=8.4 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.8 Hz, 1H), 8.29-8.32 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=4.05 (2C, −), 11.31 (+), 48.99 (−), 100.98 (Cquart), 115.67 (Cquart), 118.96 (+), 123.30 (+), 125.94 (Cquart), 127.46 (+), 127.55 (2C, +), 128.23 (+), 128.47 (+), 128.87 (2C, +), 129.50 (+), 136.50 (Cquart), 136.55 (+), 139.45 (Cquart), 148.52 (Cquart), 150.97 (Cquart), 152.04 (+), 156.99 (Cquart), 158.12 (Cquart). MS (ES+): m/z 392.1 (100) [MH+], 338.2 (22) [MH+—C4H6]. HPLC: tR=2.9 min (OpenLynx, polar—5 min).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:25][CH:26](O)[CH2:27][NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([Br:24])=[CH:18][CH:17]=3>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH2:25][CH:26]([F:7])[CH2:27][NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][C:19]([Br:24])=[CH:18][CH:17]=3
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1cccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Solvent: ClCCl
Product: COc1cccc(NCC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 5.5 %

Procedure:
DAST [(Et2NSF3) 0.12 ml, 0.916 mmol] was added dropwise to a solution of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (0.102 g, 0.203 mmol) in 6.0 ml of anhydrous DCM at −78° C. The reaction was stirred at −78° C. for one hour before being slowly warmed to 0° C. over 5 hours. The reaction was quenched by addition of phosphate buffer (pH=8) and extracted with DCM. The aqueous phase was extracted twice with 10 ml DCM. The combined organics were dried over Na2SO4, filtered and concentrated. The crude reaction material was purified by flash chromatography on SiO2 (20% EtOAc/hexanes/0.2% TEA). Fractions containing the desired fluorinated product were further purified with 40% EtOAc/hexanes (+0.1% TEA). Isolated 5.7 mg desired product.