Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:25]([N:29]([CH:37]=[O:38])[O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:26][CH2:27][CH3:28])[C:11]([O:13]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:39]1[CH:43]=[N:42][N:41]=[C:40]1[NH:44][C:45](=[O:63])[C@@H:46]([NH2:62])[CH2:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:53].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:55]([O:54][C:52]([NH:51][CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]([NH:62][C:11](=[O:13])[C@H:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@@H:25]([N:29]([CH:37]=[O:38])[O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[CH2:26][CH2:27][CH3:28])[C:45](=[O:63])[NH:44][C:40]1[S:39][CH:43]=[N:42][N:41]=1)=[O:53])[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Reactant: CCC[C@@H]([C@@H](CCCc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)N(C=O)OC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCC[C@@H]([C@@H](CCCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)Nc1nncs1)N(C=O)OC1CCCCO1
Temperature: 50 °C
Reaction time: 18 h
Yield: 20.1 %

Procedure:
To a solution of pentafluorophenyl (2R,3S)-2-(3-phenyl-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)hexanoate (90 mg, 0.166 mmol) in DMF (0.5 mL) is added (2S)-6-benzyloxycarbonylamino-2-aminohexanoic acid 1,3,4-thiadiazol-2-ylamide (78 mg, 0.215 mmol) and HOBt ( 2.2 mg, 0.017 mmol). The resulting solution is heated to 50° C. and is stirred for 18 h. The reaction mixture is cooled to 25° C., concentrated in vacuo, diluted with 20 mL of EtOAc, and washed with 1 M aqueous sodium carbonate solution. The organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 2:1 EtOAc-hexane) to provide (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(3-phenyl-1-propyl)hexanoic acid [(1S)-5-benzyloxycarbonylamino-1-(1,3,4-thiadiazol-2-ylcarbamoyl)-1-pentyl]amide as an oil (24.1 mg, 25% yield). APCI-MS m/z 745 (M+Na)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[OH:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.CCCCCCC=CCCC>O1CCCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:12]2[CH2:13][CH2:14][CH:10]([OH:9])[CH2:11]2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: OC1CCNC1
Agent: CCCC=CCCCCCC
Solvent: C1CCOC1
Product: OC1CCN(c2cccc(Br)n2)C1
Reaction time: 11 h
Yield: 100.9 %

Procedure:
A mixture of 5.7 g of 2,6-dibromopyridine, 2.5 g of 3-hydroxypyrrolidine, 3.6 ml of 1,8-diazbicyclo[5.4.0]-7-undecene (DBU) and 20 ml of tetrahydrofuran was heated under stirring for 11 hours in an oil bath kept at 70° C. The mixture was partitioned between ethyl acetate-water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography using 10-30% ethyl acetate/hexane, to give 5.9 g of 2-bromo-6-(3-hydroxypyrrolidine-1-yl)pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C[N+:13]1([O-])[CH2:18]COCC1.[CH3:20][Si:21](C#N)([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([O:11][Si:21]([CH3:23])([CH3:22])[CH3:20])([C:18]#[N:13])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: C[Si](C)(C)C#N
Reactant: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C[Si](C)(C)OC1(C#N)CCc2cc(Br)ccc21
Yield: 286.9 %

Procedure:
To a solution of 5-bromo-2,3-dihydro-1H-inden-1-one (10.0 g, 47.4 mmol) and N-methyl-morpholine N-oxide (1.67 g, 14.21 mmol) in CH2Cl2 (50 ml) was added trimethylsilylcyanide (7.05 g, 71.1 mmol), and the resultant solution was stirred at room temperature for 72 h, and then concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 5% EtOAc in hexanes as the eluent to give the title compound as a colorless liquid (12.65 g, 86%).
Reaction SMILES: [CH3:1][C:2]1(/[CH:10]=[CH:11]/[CH:12]=[O:13])[C:7](=[CH2:8])[CH:6]2[CH2:9][CH:3]1[CH:4]=[CH:5]2>CCO.O.[Ni]>[CH3:1][C:2]1([CH2:10][CH2:11][CH:12]=[O:13])[C:7](=[CH2:8])[CH:6]2[CH2:9][CH:3]1[CH2:4][CH2:5]2
Reactant: C=C1C2C=CC(C2)C1(C)/C=C/C=O
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: C=C1C2CCC(C2)C1(C)CCC=O
Yield: 85 %

Procedure:
Obtained in 85% yield by hydrogenation of 23 (2.0-mol-equiv. of H2) over Raney-Ni (5% by weight) at 0° in EtOH/H2O 95:5. (90% based on the recovered SM). For analyses, see H. Sonawane, R. Harikisan, N. S. Bellur, J. R. Ahuja, D. J. Kulkarni, J. Org. Chem. 1991, 56, 1434; M. Saito, M. Kawamura, K. Ogasawara, Tetr. Lett. 1995, 36, 9003; D. Solas, J. Wolinsky, J. Org. Chem. 1983, 48, 1988; P. A. Christenson, B. J. Willis, J. Org. Chem. 1979, 44, 2012.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([Br:11])=[CH:6][C:3]=1[CH:4]=O.C(N(CC)CC)C.[F:19][C:20]([F:29])([F:28])/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(OCC)(=O)C>CS(C)=O>[Br:11][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([Br:10])[CH:8]=1)[NH:1][CH:21]([C:20]([F:19])([F:29])[F:28])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:4]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: Nc1c(Br)cc(Br)cc1C=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(Br)cc(Br)c2NC1C(F)(F)F
Temperature: 25 °C
Yield: 42.9 %

Procedure:
The 2-amino-3,5-dibromobenzaldehyde (6.50 g, 23.3 mmol), triethylamine (6.96 g, 69.9 mmol) and ethyl 4,4,4-trifluorocrotonate (7.85 g, 46.6 mmol) were mixed in dimethylsulfoxide (12.0 mL) at 90° C. for 48 h. The solution was cooled to room temperature and the solution poured into ethyl acetate (100 mL). The solution was extracted with saturated aqueous ammonium chloride (2×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The ethyl 6,8-dibromo-2-(trifluoromethyl)-1,2-dihydroquinoline-3-carboxylate (4.3 g, 10.0 mmol) was isolated as a yellow solid by flash silica chromatography (43% yield): MS m/z 428 (M−H, calcd 428).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([O:9][C@@H:10]1[CH:15]2[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]2)[CH2:11]1)=[O:8])=[O:4].[Br:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>CCOC(C)=O.CC#N>[Br-:24].[CH3:1][O:2][C:3]([NH:5][CH:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([O:9][C@@H:10]1[CH:15]2[CH2:16][CH2:17][N+:12]([CH2:25][C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:13][CH2:14]2)[CH2:11]1)=[O:8])=[O:4]
Reactant: COC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.3 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(methoxycarbonylamino)-2-phenylacetate (C26) (58.0 mg, 0.18 mmol) in EtOAc (3 ml) and CH3CN (1 ml), was added 2-bromo-1-phenylethanone (39.9 mg, 0.20 mmol). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5 to 92/8) and the resulting product was triturated with i-Pr2O to obtain (3R)-3-(2-(methoxycarbonylamino)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (55.2 mg; 58.6% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].[CH:20]1([CH2:25]Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[CH:20]1([CH2:25][N:4]2[C:5]3=[N:6][C:7]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([CH3:1])=[N:3]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1n[nH]c2nc(-c3ccncc3)nc(N)c12
Reactant: BrCC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(CC2CCCC2)c2nc(-c3ccncc3)nc(N)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To a solution of 3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine (6.0 g, 0.027 mol) in DMF (50 ml) at 0° C. was added 60% NaH/mineral oil dispersion (1.06 g, 0.027 mol) in one portion. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled to 0° C. and cyclopentylmethyl bromide (4.3 g, 0.027 mol) was added dropwise over 5 minutes. The reaction mixture was warmed to room temperature and stirred for 50 hours. The solvent was removed in vacuo, the yellow slurry was added to water (100 ml) and acidified with acetic acid. The resulting paste was stripped to dryness and the residue was slurried with ethanol. A tan solid was collected by filtration and purified by column chromatography on silica eluting with ether/ethanol/water (97.5/2/0.5) followed by recrystallization from cyclohexane to afford 2.2 g (26%) of 1-cyclopentylmethyl-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d] -pyrimidin-4-amine, m.p. 177°-178° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.[CH:59]1[C:71]2[CH:70]([CH2:72][O:73][C:74](=[O:94])[NH:75][C@H:76]3[CH2:80][C@@H:79]([C:81](=[O:93])[NH:82][C@H:83]4[C:92]5[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=5)[CH2:86][CH2:85][CH2:84]4)[NH:78][CH2:77]3)[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[C:63]=2[CH:62]=[CH:61][CH:60]=1>CN(C=O)C>[CH:68]1[C:69]2[CH:70]([CH2:72][O:73][C:74](=[O:94])[NH:75][C@H:76]3[CH2:80][C@@H:79]([C:81](=[O:93])[NH:82][C@H:83]4[C:92]5[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=5)[CH2:86][CH2:85][CH2:84]4)[N:78]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[CH2:77]3)[C:71]3[C:63](=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:64]=2[CH:65]=[CH:66][CH:67]=1
Reactant: O=C(N[C@@H]1CN[C@H](C(=O)N[C@@H]2CCCc3ccccc32)C1)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1
Temperature: 0 °C

Procedure:
To a solution of (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (Aldrich) (4.529 g, 17.622 mmol) in DMF (100 mL) were added HATU (6.7 g, 17.622 mmol) followed by DIPEA (13.87 mL, 80.101 mmol). The mixture was cooled to 0° C. and ({(3S,5S)-5-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-pyrrolidin-3-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester trifluoroacetate (Intermediate 22) (9.5 g, 16.02 mmol) in DMF (50 mL) was added dropwise and then the cooling bath removed. After 4 h the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated to give the title compound as an off white solid (10 g) which was used without purification. LC-MS: 721 (M+H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]1([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14](=[O:22])[CH:13]2[C:23]#N)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:25]([OH:27])[CH3:26]>>[C:6]1([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14](=[O:22])[CH:13]2[C:23]([O:27][CH2:25][CH3:26])=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCO
Reactant: O=S(=O)(O)O
Reactant: N#CC1C(=O)Nc2ccccc2C1c1ccccc1
Product: CCOC(=O)C1C(=O)Nc2ccccc2C1c1ccccc1

Procedure:
80 g of concentrated sulphuric acid were dropped into a suspension of 4-phenyl-1,2,3,4-tetrahydro-2-oxo-3-quinoline carbonitrile (15 g) in ethanol (70 ml) and the whole was heated to reflux for 1 hour. After cooling the reaction mixture was poured onto ice and the aqueous layer was extracted with ethylacetate. After the usual workup 20 g of raw material were obtained. After purification by flash chromatography technique (Silicagel eluted with methylene dichloride/ethylacetate 85:15) 8.3 g of title compound were obtained. M.p. 178°-180° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:22]=[CH:21][C:13]2[O:14][C:15]([CH3:20])([CH3:19])[C:16]([CH3:18])=[CH:17][C:12]=2[CH:11]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C.ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:22]=[CH:21][C:13]2[O:14][C:15]([CH3:19])([CH3:20])[C:16]([CH3:18])=[CH:17][C:12]=2[CH:11]=1
Reactant: COc1ccccc1Sc1ccc2c(c1)C=C(C)C(C)(C)O2
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CC1=Cc2cc(Sc3ccccc3O)ccc2OC1(C)C
Temperature: 150 °C
Yield: 35.9 %

Procedure:
6-(2-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (3.5 g) (see Preparation 7) was dissolved in dry 2,4,6-collidine (15 ml), anhydrous lithium iodide (9.0 g) was added and the mixture was heated at 150° C for 40 hours. After cooling, the mixture was taken up in dichloromethane and washed with 2N aqueous hydrochloric acid solution (×3). The organic layer was dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the residue was chromatographed on silica using 1:1 hexane:dichloromethane as the eluent to yield 6-(2-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (1.2 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(N=C=NCCCN(C)C)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Nc1ccccn1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
To a solution of 4-methoxyphenyl acetic acid (5 g; 30.08 mmol) in 30 ml of dichloromethane, under nitrogen, it was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (6.34 g; 33.09 mmol) in small portions. After 10 minutes 2-aminopyridine (2.83 g; 30.08 mmol) was added and stirred for 4 hours at rt. The reaction mixture was concentrated and partitioned between ethyl acetate and 0.5N HCl. The organic phase was washed with 0.5N HCl (2×) and 0.5N NaOH (2×). The pH of the acidic/aqueous phase was adjusted to ˜7 with 0.5N NaOH and extracted twice with ethyl acetate. The basic/aqueous phase was also extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to afford 2-(4-methoxyphenyl)-N-pyridin-2-ylacetamide (7 g; 92% yield), which was used in the next step without further purification. MS: m/z 243 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH3:7][C:8]1([CH3:18])[C:12]([CH3:13])=[CH:11][CH2:10][CH:9]1[CH:14]([CH3:17])[CH:15]=[O:16].C(Cl)C(=C)C.O>CN(C=O)C>[CH3:17][C:14]([CH:9]1[CH2:10][CH:11]=[C:12]([CH3:13])[C:8]1([CH3:18])[CH3:7])([CH2:3][C:2]([CH3:5])=[CH2:1])[CH:15]=[O:16]
Reactant: CC(C)(C)[O-]
Reactant: CC1=CCC(C(C)C=O)C1(C)C
Agent: C=C(C)CCl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CC(C)(C=O)C1CC=C(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
A 4 neck 2 liter round bottomed flask was charged with 600 ml of DMF and 160 g of potassium t-butoxide (1.35 moles). Under nitrogen the flask was cooled to 0° C. and 200 g of 2-(2,2,3-trimethylcyclopent-3-en-1-yl)propanal (from Example 5) at 90% purity (1.08 moles) in 100 ml of DMF were added over 40 minutes at 0°-5° C. The reaction was stirred 30 minutes at 0° C. Then 140 g of methallyl chloride (1.54 moles) in 100 ml of DMF were added dropwise over 40 minutes at 5°-15° C. The batch was stirred 30 minutes at 10°-15° C. With good stirring the reaction mixture was poured onto 1 liter of water and extracted with 3×100 ml of hexane. The hexane extract was washed with 2×500 ml of water and 1 liter of brine. The extract was dried and concentrated in vacuo. The crude mixture of C- and O-alkylates, 261.4 g, was heated in a 500 ml 3 neck flask under nitrogen at 165° C. for 6.5 hours. Fractional distillation afforded 239.5 g of purified product (86.8% yield). BP 84° C./0.15 mmHg; 1H-NMR (300 MHz), δ 0.89 (3H, s), 1.03 (3H, s), 1.11 (3H, s), 1.55 (3H, s), 1.63 (3H, s), 2.20-2.27 (4H, m), 2.53 (1H, m), 4.67 (1H, s), 4.84 (1H, s), 5.27 (1H, s), 9.79 (1H, s); 13C-NMR (75 MHz), δ 12.34, 15.27, 22.25, 24.31, 28.11, 30.89, 46.11, 48.20, 52.83, 56.17, 115.57, 120.98, 141.43, 148.00, 207.01; m (Neat), 2980, 2700, 1725, 1645, 1450, 1380, 895 cm-1 ; MS (m/e), 220 (M+), 205, 191, 121, 108 (Base), 93, 55, 41;
Reaction SMILES: [C:1]([OH:6])#[C:2][CH2:3][CH2:4][CH3:5].[Si:7](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:20]([Si:7]([O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCCC#CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
A mixture of pentynol (8.0 g, 95 mmol), t-butyldiphenylsilylchloride (28 g, 114 mmol) and Et3N (14 g, 138 mmol) in CH2Cl2 is stirred at room temperature for 16 h, treated with 1M K2CO3 and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo. The residue is purified by filtration on a silica pad to obtain 30 g of t-butylpent-4-ynyloxy diphenyl silane (yield: 98%
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Br:22])[CH:20]=3)[NH:15][C:14](=[O:23])[C@@H:13]2[CH2:24][CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.I[CH2:31][CH3:32].C([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>>[Br:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:31][CH3:32])[C:14](=[O:23])[C@H:13]([CH2:24][CH3:25])[N:12]2[S:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: CCI
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(Br)ccc3NC(=O)[C@@H]2CC)cc1
Agent: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Product: CC[C@H]1C(=O)N(CC)c2ccc(Br)cc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-7-Bromo-2-ethyl-3-oxo-3,4-dihydroquinoxalin-1(2H)-yl]sulfonyl}phenyl ethyl carbonate was treated with iodoethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-6-bromo-1,3-diethyl-4-[(4-hydroxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−190° (c=0.0052 G/ML, DMSO); MS (ESI) m/z 439/441 ([M+H]+); MS (ESI) m/z 437/439 ([M−H]−); Anal. Calcd for C18H19BrN2O4S: C, 49.21; H, 4.36; N, 6.38. Found: C, 50.41; H, 5.02; N, 6.00.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C@H]5COCCN5)[CH:27]=4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:5]=[C:6]([F:15])[C:7]=1[CH2:8][N:9]1[CH2:14]CO[CH2:11][CH2:10]1.[CH:38](=[O:40])[CH3:39].[CH3:41][OH:42]>C([BH3-])#N.[Na+]>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([C@H:8]5[CH2:7][O:40][CH2:38][CH2:39][N:9]5[CH2:10][CH3:11])=[CH:30][CH:31]=4)[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17]2)[CH:5]=[C:6]([F:15])[C:7]=1[CH2:8][N:9]1[CH2:10][CH2:11][O:42][CH2:41][CH2:14]1
Reactant: CO
Reactant: CC=O
Reactant: Fc1cc(-n2ccc3cnc(Nc4cccc([C@H]5COCCN5)c4)nc32)cc(F)c1CN1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN1CCOC[C@@H]1c1ccc(Nc2ncc3ccn(-c4cc(F)c(CN5CCOCC5)c(F)c4)c3n2)cc1

Procedure:
The compound is obtained by treating [7-(3,5-difluoro-4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-((S)-3-morpholin-3-yl-phenyl)-amine (Example 507) with acetaldehyde in methanol and sodium cyanoborohydride at rt to 60° C. HPLC: tR=0.63 min (Method G); MS-ES: (M+H)+=535
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH2:6][NH:5]2.[N+:14]([O-])([OH:16])=[O:15]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2
Reactant: O=C1CNc2cc(Br)c(Cl)cc2N1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=c1cnc2c([N+](=O)[O-])c(Br)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a stirred suspension of 6-bromo-7-chloro-3,4-dihydroquinoxaline-2(1H)-one (0.06 g, 0.23 mmol, as obtained above) in CF3COOH (0.5 mL) was added fuming HNO3 (0.02 mL, 0.46 mmol) and the resulting reddish yellow suspension was stirred at room temperature overnight. The cream colored suspension so obtained was poured into ice (2.5 mL) and the precipitated solid was filtered, washed with water (1.0 mL), and dried under vacuum to afford 0.049 g (70%) of the title compound as a cream colored powder. 1H NMR (DMSO-d6): δ7.577 (s, 1H), 8.251 (s, 1H), 12.879 (s, 1H). The crude product was used as such for the final reaction.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C@@H:15]([NH:18]S(C(C)(C)C)=O)[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.O1CCOCC1>CO>[C:1]1([CH3:25])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C@@H:15]([NH2:18])[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](N)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {(S)-1-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-propyl}-amide (1.00 g, 2.61 mmol) in MeOH was added a 4 M solution of HCl in dioxane (1 mL, 4 mmol). After 2 hours, the solvent was concentrated in vacuo. The residue was made basic with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=1.[OH-].[Na+].CO.Cl>O>[CH3:26][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][O:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCCOc1ccc(OCc2cnccc2N(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)c1ccncc1COc1ccc(OCCCC(=O)O)cc1
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture containing ethyl 4-[4-[(4-dimethylaminopyrid-3-yl)methoxy]phenoxy]butanoate (25 mg), aqueous sodium hydroxide (1M, 0.2 ml), methanol (0.5 ml) and water (0.5 ml) was stirred for 3 hours then neutralised with hydrochloric acid (1M, 0.2 ml) and concentrated. The residue was dissolved in dichloromethane (5 ml), filtered, and the filtrate was concentrated to give the title compound (17 mg) as a colourless gum. NMR (d6DMSO+d4AcOH): δ2.0(2H,q); 2.4(2H,t); 3.35(6H,s); 3.95(2H,t); 5.1(2H,s); 6.8-7.0(4H, dd +1H,m); 8.15(1H,dd); 8.3(1H,d); m/e 331(M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][C@H:4]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH3:32][I:33]>>[I-:33].[CH2:9]([O:8][C:6](=[O:7])[CH2:5][C@@H:4]([NH:16][S:17]([C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:3][N+:2]([CH3:32])([CH3:1])[CH3:31])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1
Reactant: CI
Product: CCCCCc1ccc(S(=O)(=O)N[C@H](CC(=O)OCc2ccccc2)C[N+](C)(C)C)cc1
Product: [I-]

Procedure:
According to the method described in example S20b, (R)-benzyl 4-(dimethylamino)-3-(4-pentylphenylsulfonamido)butanoate was reacted with methyl iodide to give the title compound as a white solid in quantitative yield.