Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].ClC(N(C)C)=C(C)C.N1C=CC=CC=1.O[C@H:25]([C@@H:47]([NH:55][C:56](=[O:75])[C@H:57]([CH2:71][C:72](=[O:74])[NH2:73])[NH:58][C:59]([C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[N:62]=1)=[O:60])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:26][N:27]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH:28][C:29](=[O:39])[C@H:30]([CH:36]([CH3:38])[CH3:37])[NH:31][C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl.O1CCOCC1.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9][C@H:25]([C@@H:47]([NH:55][C:56](=[O:75])[C@H:57]([CH2:71][C:72](=[O:74])[NH2:73])[NH:58][C:59]([C:61]1[CH:70]=[CH:69][C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[N:62]=1)=[O:60])[CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:26][N:27]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[NH:28][C:29](=[O:39])[C@H:30]([CH:36]([CH3:38])[CH3:37])[NH:31][C:32]([O:34][CH3:35])=[O:33])=[O:8]
Reactant: O=C(O)c1ccccn1
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)C(C)C
Agent: CC(C)=C(Cl)N(C)C
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccccc1)C[C@H](OC(=O)c1ccccn1)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1)C(C)C
Reaction time: 18 h

Procedure:
Analogously to Example 108, 51 mg (0.416 mmol) of 2-picolinic acid in 0.8 ml of methylene chloride are converted with 59 μl (0.416 mmol) of 1-chloro-N,N,2-trimethyl-1-propenamine into the acid chloride. After the addition of 0.5 ml of dioxane and 0.4 ml of pyridine to the latter, the mixture is reacted with 148 mg (0.208 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(quinoline-2-carbonyl)-(L)-asparaginyl)amino-4-phenyl-butyl]-1-[phenylmethyl]-2-[N-(methoxycarbonyl)-(L)-valyl]-hydrazine (Example 109) in 5 ml of dioxane in the presence of 0.5 mg of DMAP. Since, after 18 h, not all of the educt has been acylated according to HPLC, further acid chloride is added. Column chromatography (SiO2, methylene chloride→methylene chloride/methanol 15:1) yields the title compound: FAB-MS (M+H)+ +817.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[OH-].[Li+].O.C(OCC)(=O)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:36]=[CH:35][CH:34]=[CH:33][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([C:19]([NH:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=3)[C:26]([OH:28])=[O:27])=[O:20])=[CH:17][N:18]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cccc(C(=O)OC)c3)cn2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cccc(C(=O)O)c3)cn2)C1
Temperature: 22.5 °C
Reaction time: 72 h
Yield: 92.6 %

Procedure:
A solution of (R)-methyl 3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoate (21.3 g, 43.5 mmol) in THF (100 mL) was cooled to 5° C. Aqueous 1.9M lithium hydroxide solution (50 mL, 96 mmol) was added via addition funnel, maintaining the temperature below 14° C., followed by a 30-mL water rinse of the addition funnel. The reaction mixture was warmed to 20-25° C. and was stirred at that temperature for 72 hours. The mixture was concentrated to remove THF, and then was cooled to 8° C. Hydrochloric acid (1N, 80 mL) was added dropwise, and a precipitate began to form. Ethyl acetate (200 mL) was added to dissolve the solids, and the layers were separated, and the aqueous phase was further extracted with ethyl acetate (2 times with 100 mL). The combined organics were washed with brine (4 times with 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid (20.4 g) was slurried in ethanol (250 mL) and heated to 75° C., resulting in a yellow solution. Water (250 mL) was added slowly, forming a precipitate, and the mixture was heated to 90° C. to dissolve the solids. The solution was then cooled to 30° C. and was held at that temperature for 16 hours. The mixture was further cooled to −1.5° C. for 3 hours. The resulting crystals were collected by filtration, rinsed with water (50 mL), and then dried to afford (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)benzoic acid (19.2 g). 1H NMR (500 MHz, CD3OD) δ 8.73 (s, 2H), 8.03 (s, 1H), 7.94 (d, 1H), 7.59 (d, 1H), 7.45 (t, 1H), 7.01 (dd, 1H), 6.92 (m, 2H), 6.86 (m, 1H), 4.60 (s, 2H), 4.37 (m, 1H), 4.14 (dd, 1H), 4.06 (dd, 1H), 3.92 (m, 4H), 2.07 (m, 1H), 1.97 (m, 2H), 1.58 (m, 1H), 1.29 (t, 3H). Chiral SFC: Chiralcel OJ-H, 4.6 mm×25 cm, 70:30 CO2:methanol, 0.2% isopropylamine, 2.5 mL/min, 210/254 nM; retention time (R)-enantiomer (Example 1) 4.13 min, (S)-enantiomer 2.35 min. MS (ES+) 477.3 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41](C=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1([C:56](OC(C)(C)C)=O)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.[C:63](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[C@H:55]12[CH2:63][C@H:52]([NH:53][CH2:54]1)[CH2:51][N:50]2[CH2:56][C:41]1[CH:40]=[C:39]([C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([CH2:32][NH:31][C:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:21]([NH:20][CH2:19][C:10]4[C:11]([NH:12][CH:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)=[C:6]5[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]5=[N:8][C:9]=4[CH2:48][CH3:49])=[O:22])[CH:24]=3)=[O:30])[C:34]=2[CH3:47])[CH:44]=[CH:43][CH:42]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4C[C@@H]5C[C@H]4CN5)c3)c2C)c1
Reaction time: 3 h
Yield: 19 %

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL), 1,1-dimethylethyl 1-piperazinecarboxylate (44.6 mg, 0.00024 mol) and sodium triacetoxyborohydride (68 mg., 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The crude product was taken up in 1,2-dichloroethane (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on a Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a beige colored solid [21.4 mg (19%)]. LC-MS m/z 741.7 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=O)([O-:13])=[O:12].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+].C(O)(=O)C>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C@@H:4]1[N:28]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:19])[CH2:16][CH2:15][C@H:14]1[N+:11]([O-:13])=[O:12]
Reactant: O=Cc1cc(F)ccc1F
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: NCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2cc(F)ccc2F)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2,5-difluorobenzaldehyde (1.09 g, 7.67 mmol) in ethanol (20 mL) were added methyl 4-nitrobutyrate (1.13 g, 7.04 mmol), benzylamine (0.98 mL, 7.67 mmol), sodium acetate (1.26 g, 15.3 mmol) and acetic acid (0.88 mL, 15.4 mmol). The mixture was stirred at rt for 12 h and then heated at reflux temperature overnight. After evaporation, the residue was purified by column chromatography (silica gel Biotage 40M™) eluting with ethyl acetate/hexane (gradient from 3% to 50%) to give the title compound as the racemic trans isomer. LC-MS: 347.1 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[N:3]=1.[CH2:28]([OH:31])[C:29]#[CH:30].O>N(CC)CC.[Cu]I.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][C:13]3[N:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)[N:3]=[C:2]([C:30]#[C:29][CH2:28][OH:31])[C:10]=12
Reactant: Nc1ncnc2c1c(I)nn2Cc1nc2ccccc2n1-c1ccccc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCNCC
Product: Nc1ncnc2c1c(C#CCO)nn2Cc1nc2ccccc2n1-c1ccccc1
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A mixture of 3-iodo-1-((1-phenyl-1H-benzo[d]imidazol-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 141 (1.5 g, 3.2 mmol), prop-2-yn-1-ol (0.4 g, 6.4 mmol), CuI (0.2 g, 0.64 mmol) and Pd(PPh3)2Cl2 (0.25 g, 0.32 mmol) in Et2NH (30 mL) was stirred at 25 for 2 hrs. Then the mixture was added H2O (50 mL) and extracted with CH2Cl2 (30 mL×3). The combined organic layers were concentrated in vacuo. The residue was treated with CH2Cl2 and filtered to give 152 (400 mg, yield 32%) as a yellow solid. LCMS (ESI), M+H+=394.15. 1HNMR (400 MHz, DMSO) δ 4.322-4.337 (d, J=6 Hz, 2H), 5.395-5.425 (t, J=6 Hz, 1H), 5.710 (s, 2H), 5.735 (s, 2H), 7.090-7.107 (d, J=6.8 Hz, 1H), 7.223-7.249 (m, 2H), 7.414-7.491 (s, 5H), 7.643-7.663 (d, J=8 Hz, 1H), 8.092 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.[N:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl.O>[N:18]1([C:24]([O:10][C:8]2[CH:9]=[C:2]([F:1])[C:3]([CH:4]=[O:5])=[C:6]([F:11])[CH:7]=2)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=Cc1c(F)cc(O)cc1F
Reactant: O=C(Cl)N1CCOCC1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1c(F)cc(OC(=O)N2CCOCC2)cc1F
Yield: 93.8 %

Procedure:
To a 250 mL dry round bottom flask were added 2,6-difluoro-4-hydroxybenzaldehyde (5.53 g, 35.0 mmol), anhydrous CH2Cl2 (40 mL) and pyridine (3.68 mL, 45.5 mmol). The mixture was stirred in an ice-water bath, then 4-morpholinecarbonyl chloride (4.4 mL, 37.4 mmol) was added. After stirring at 0° C. for 1 hour, the mixture was stirred at room temperature overnight. Water (80 mL) and CH2Cl2 (50 mL) were added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (50 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 3,5-difluoro-4-formylphenyl morpholine-4-carboxylate (8.90 g) as white solid. Yield: 94%. 1H NMR (CDCl3, 300 MHz): δ=10.28 (s, 1H), 6.91 (dd, J=10.8, 1.5 Hz, 2H), 3.77-3.58 (m, 8H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): δ=183.7, 163.8 (dd, J=263.1, 8.53 Hz), 157.0 (t, J=15.3 Hz), 151.8, 111.7 (t, J=11.5 Hz), 106.6 (dd, J=25.1, 3.70 Hz), 66.6, 66.5, 45.2, 44.5.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:11]1[C:49](=[O:50])[N:13]2[C:14]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])=[C:15]([S:18]([CH2:20][CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=O)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:51][N:52]([CH3:74])[C:53]([C@@H:55]1[CH2:59][C@H](S)CN1C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[O:54]>>[CH3:51][N:52]([CH3:74])[C:53]([C@@H:55]1[CH2:59][C@H:20]([S:18][C:15]2[C@H:16]([CH3:17])[C@@H:12]3[C@@H:11]([C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH3:10])[C:49](=[O:50])[N:13]3[C:14]=2[C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH2:21][N:22]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])=[O:54]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)CCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 18, but using 101 mg of 4-nitrobenzyl (1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-[2-(4-nitrobenzyloxycarbonyl)aminoethylsulfinyl)-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 48) and 61 mg of (2S,4S)-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine, the title compound was obtained in a yield of 83%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]#[CH:26])[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C.C(#N)C.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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]#[C:25][CH2:24][CH2:23][N:20]2[CH2:19][CH:18]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C#CCCN1CC=C(c2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2-bromo-5-nitropyridine (4.23 g, 0.02 mol) and the alkyne prepared in Step (a) (4.0 g, 0,019 mol) in 7.9 mL of triethylamine and 100 mL of acetonitrile is degassed by bubbling in dry nitrogen for 15 minutes, and 0.27 g (0.0004 mol) of bis(triphenylphosphine)palladium chloride and 0.07 g (0.0004 mol) of cuprous iodide are added. The flask is flushed with nitrogen and the mixture is stirred at room temperature for 6 hours. The solvent is removed under reduced pressure and the residue is partitioned between 100 mL of dichloromethane and 100 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 50 mL of dichloromethane and the combined organic layers are washed with 50 mL of water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound, containing 0.3 mol of water; mp 133°-134° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12.[C:28]([Zn]C#N)#[N:29]>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>[C:28]([C:2]1[CH:3]=[C:4]([C:24]([F:26])([F:25])[F:27])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]3)[C:6]=12)#[N:29]
Reactant: N#C[Zn]C#N
Reactant: CN1CCn2c(C(F)(F)F)cc(Br)c2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN1CCn2c(C(F)(F)F)cc(C#N)c2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 150 °C
Yield: 34.6 %

Procedure:
A mixture of tert-butyl 8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (1.67 g, 3.7 mmol) and dicyanozinc (234.9 μL, 3.7 mmol) in DMF (10 mL) was purged with N2 for 5 min. Pd(PPh3)4 (427.6 mg, 0.37 mmol) was added. The mixture was heated in a sealed microwave vial at 150° C. overnight. The mixture was partitioned between ethyl acetate and water. The layers were separated. The aqueous layer was extracted with ethyl acetate (3×). All organic layers were combined, washed with water (3×), brine, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (10-20% EtOAc/hexanes) to provide tert-butyl 8-cyano-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (510 mg, 35%) as a white solid. ESI-MS m/z calc. 398.2, found 399.3 (M+1)+; Retention time: 1.56 minutes (3 minute run).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(N(CC)CC)C.C1C=CC=CC=1.[CH3:19][Si:20]([CH3:23])([CH3:22])Cl>CCCCCC>[CH3:19][Si:20]([CH3:23])([CH3:22])[N:5]([Si:20]([CH3:23])([CH3:22])[CH3:19])[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: C[Si](C)(C)Cl
Reactant: CS(N)(=O)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C[Si](C)(C)N([Si](C)(C)C)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
A glass reactor equipped with a stirrer, nitrogen inlet, reflux condenser and addition funnel was purged with nitrogen and charged with 29.1 g (0.30 mol) of methanesulfonamide, MeSO2NH2, where Me represents the methyl radical, 84.9 ml (0.605 mol) of triethylamine and 240 ml of dry benzene. Trimethylchlorosilane (129.5 ml, 1.00 mol) was then added through the addition funnel over a period of 15 minutes to the stirred mixture, followed by heating at the boiling point for three hours. The mixture was then diluted with 200 ml of hexane and stirring was continued for 30 minutes.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH3:18][C:19]1[CH:20]=[C:21]([SH:25])[CH:22]=[CH:23][CH:24]=1>>[CH3:18][C:19]1[CH:20]=[C:21]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Reactant: Cc1cccc(S)c1
Product: Cc1cccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)c1

Procedure:
Prepared analogous to Example 1 from 6-(4-chloro-butoxy)-3,4-dihydro-carbostyril (m.p. 147°-148° C.) and 3-methyl-thiophenol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]1=2)#[N:2].[O:38]1[C:42]([NH2:43])=[CH:41][CH:40]=[N:39]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(O)(=O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([NH:43][C:42]3[O:38][N:39]=[CH:40][CH:41]=3)(=[O:24])=[O:25])[CH:21]=[CH:22][C:14]1=2)#[N:2]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccno1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3ccno3)ccc21
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A round bottom flask was charged with perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (44.1 mg, 0.080 mmol), isoxazol-5-amine (10.1 mg, 0.12 mmol, Matrix Scientific, Columbia, S.C.) and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (168 μl, 0.168 mmol) was added dropwise over 30 s to give a light-yellow solution. After 10 min, the flask was lowered into an ice bath for 45 min. Glacial acetic acid (1 drop) was added, and the mixture was concentrated under a vacuum. The product was purified by chromatography on silica gel (12 g column with 0 to 10% MeOH/DCM) to give 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(isoxazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (25.2 mg, 0.056 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.18 (br. s., 1 H), 8.42 (d, J=2.1 Hz, 1 H), 8.34 (d, J=2.0 Hz, 1 H), 8.11 (dd, J=2.0, 8.9 Hz, 1 H), 7.76 (d, J=8.6 Hz, 1 H), 7.30 (d, J=2.2 Hz, 1 H), 7.23 (dd, J=2.2, 8.7 Hz, 1 H), 6.80 (d, J=8.6 Hz, 1 H), 5.77 (d, J=1.9 Hz, 1 H), 4.40-4.35 (m, 2H), 3.89-3.86 (m, 2 H). m/z (ESI) 451.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.[BH4-].[Na+]>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3-amino-phenyl)-carbamic acid tert-butyl ester (1 g, 4.8 mmol), benzaldehyde (0.54 ml, 5.3 mmol) and acetic acid (0.41 ml, 7.2 mmol) in dry tetrahydrofuran (30 ml) were stirred at room temperature for 2 hrs. Sodium borohydride (0.172 g, 4.5 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water (50 ml) and extracted with dichloromethane (3×50 ml). The combined organics were dried (magnesium sulphate), concentrated in vacuo and the crude residue purified by flash column chromatography (SiO2) eluting with ethyl acetate to afford the title compound as an off white solid (1.27 g, 89%) HPLC retention time 6.4 min. Mass spectrum (ES+) m/z 198 (M+H-BOC)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:12]([C:4]3[CH:3]=[C:2]([OH:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)=[O:14])[CH2:34][CH2:35]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Agent: Cl
Product: O=C(c1cc(O)c2ccccc2n1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 4 except for the use of 4-hydroxyquinoline-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.