Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C@H:29]([OH:31])[CH3:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C@H:29]([OH:31])[CH3:30])(=[O:26])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: C[C@@H](O)CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: C[C@@H](O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
140 mg of (R)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (R)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 435 mg of (R)-methyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (R)-2-chloro-4-(2-hydroxypropylthio)benzoic acid. 403 mg of (R)-2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give (R)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 298 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.1 (M)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][CH2:13][CH2:14][OH:15].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:9][C:4]1[C:3]([NH:12][CH2:13][CH2:14][OH:15])=[C:2]([F:1])[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1NCCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(F)c1NCCO

Procedure:
To a solution of 2-[(2,3-difluoro-6-nitrophenyl)amino]ethanol (3.8 g, 17.4 mmol) in 70 ml of ethyl acetate and 30 ml of ethanol is added 10% Pd/C (380 mg). The reaction is shaken under 50 PSI of hydrogen for 3 hours. The pressure is periodically adjusted to 50 PSI. The reaction is filtered through celite, rinsed with ethanol and concentrated. The resulting material is used without further purification in the next step. 1H NMR (400 MHz, CDCl3) δ ppm 3.17-3.27 (m, 2H) 3.68-3.78 (m, 2H) 6.38 (ddd, J=8.89, 4.69, 2.05 Hz, 1H) 6.61-6.70 (m, 1H)
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[C:12](F)[C:11]=3[F:21])[CH:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([F:19])=[C:12]([NH:31][C@H:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH3:30])[C:11]=3[F:21])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1Nc1cc(C2CC2)[nH]n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1c(F)cc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A mixture of 5-cyclopropyl-N-(2,3,4-trifluoro-6-nitrophenyl)-1H-pyrazol-3-amine (Method 103, 0.300 g, 1.01 mmol), (S)-1-(4-fluorophenyl)ethylamine (0.154 g, 1.11 mmol) and DIEA (0.263 ml, 1.51 mmol) in n-BuOH (2 ml) was heated in a sealed tube placed in an oil bath set at 135° C. for 8 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography (hexane-EtOAc=3:1) to give the title compound as an orange solid (0.30 g, 71%). 1H NMR (400 MHz) 11.89 (s, 1H), 8.57 (s, 1H), 7.69 (d, 1H, J=13.6 Hz), 7.35 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 6.81 (d, 1H, 7.6 Hz), 5.39 (s, 1H), 5.00 (m, 1H), 1.80 (m, 1H), 1.49 (d, J=6.8 Hz, 3H), 0.90 (m, 2H), 0.62 (m, 2H). MS: Calcd.: 417; Found: [M+H]+ 418.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:26]1[C:36]2[C:35](=[C:37]3[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH2:39][CH2:38]3)[C:34]3[CH:48]=[CH:49][CH:50]=[CH:51][C:33]=3[CH2:32][S:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[CH:26]1[C:36]2[C:35](=[C:37]3[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:41][CH2:42]3)[C:34]3[CH:48]=[CH:49][CH:50]=[CH:51][C:33]=3[CH2:32][S:31][C:30]=2[CH:29]=[CH:28][CH:27]=1
Reactant: NCCCCN1CCC(=C2c3ccccc3CSc3ccccc32)CC1
Reactant: O=C(O)CCCCc1cccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(CCCCc1cccnc1)NCCCCN1CCC(=C2c3ccccc3CSc3ccccc32)CC1

Procedure:
Batch size: 1.6 g (9.0 mmol) 5-(3-pyridyl)-pentanic acid, 1.6 g (9.9 mmol) CDI and 3.0 g (8.2 mmol) 4-[4-(6,11-dihydro-dibenzo-[b,e]thiepin-11-yliden)-piperidin-1-yl]-butylamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@H:5]([CH:7]([C:11]([OH:13])=O)[C:8]([OH:10])=O)[CH3:6])[CH3:2].[NH2:15][C:16]([NH2:18])=[O:17]>C(OC(=O)C)(=O)C>[O:17]=[C:16]1[NH:18][C:8](=[O:10])[CH:7]([C@H:5]([CH3:6])[C:4]([O:3][CH2:1][CH3:2])=[O:14])[C:11](=[O:13])[NH:15]1
Reactant: NC(N)=O
Reactant: CCOC(=O)[C@@H](C)C(C(=O)O)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)[C@@H](C)C1C(=O)NC(=O)NC1=O
Temperature: 25 °C
Yield: 50 %

Procedure:
A suspension of (S)-2-(1-ethoxy-1-oxopropan-2-yl)malonic acid (5 g, 25 mmol) and urea (1.8 g, 29.4 mmol) in acetic anhydride (15 mL) was placed in a microwave reactor and allowed to react under microwave irradiation at 60° C. for 30 minutes. After cooled to room temperature, the mixture was quenched by sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography to afford the product (S)-ethyl 2-(2,4,6-trioxohexahydropyrimidin-5-yl)propanoate (2.85 g, yield 50%).
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([SH:11])[N:6]=1.I[CH3:13]>O>[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11][CH3:13])[N:6]=1
Reactant: Cc1ccnc(S)n1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nccc(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
To a solution of NaOH (7.46 g, 186.4 mmol) in water (120 mL), 4-methylpyrimidine-2-thiol hydrochloride (13.78 g, 84.7 mmol) was added and subsequently iodomethane (13.23 g, 93.2 mmol) was added dropwise under argon atmosphere. It was stirred at room temperature for 2 h. It was extracted with CH2Cl2 (×2). The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 10.26 g of the desired compound (yield: 86%).
Reaction SMILES: [O:1]([C:9]1[C:10]([CH3:46])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32]([C:34]3[S:44][C:43]4[N:45]5[C:36](=[CH:37][N:38]=[C:39]5[CH:40]=[CH:41][CH:42]=4)[CH:35]=3)=[O:33])[CH2:26][CH2:25]1)([CH3:21])[CH2:13][CH2:12]2)[Si](C(C)(C)C)(C)C.[ClH:47].CO>C(O)C>[ClH:47].[ClH:47].[OH:1][C:9]1[C:10]([CH3:46])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32]([C:34]3[S:44][C:43]4[N:45]5[C:36](=[CH:37][N:38]=[C:39]5[CH:40]=[CH:41][CH:42]=4)[CH:35]=3)=[O:33])[CH2:26][CH2:25]1)([CH3:21])[CH2:13][CH2:12]2
Reactant: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)CCC(C)(CCN1CCC(CNC(=O)C3=Cc4cnc5cccc(n45)S3)CC1)O2
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCN1CCC(CNC(=O)C3=Cc4cnc5cccc(n45)S3)CC1)O2
Temperature: 25 °C
Reaction time: 63 h

Procedure:
To a solution of 1.00 g (1.51 mM) of N-[1-[2-(6-tert-butyldimethylsiloxy-2,5,7,8-tetramethylchroman-2-yl)ethyl]piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (4 ml) was added 4.0 ml (16 mM) of 4N—HCl/methanol and the mixture was stirred at room temperature for 63 hours. After the solvent was distilled off under reduced pressure, ethanol was added and the mixture was stirred at room temperature for 1 hour. The resulting crystal crop was harvested by filtration and rinsed with ethanol and diethyl ether to provide the title compound as orange-colored crystals.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.O[CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:8][CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: N#Cc1ccc(S(=O)(=O)CCCO)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)CCCBr)cc1
Reaction time: 1 h

Procedure:
7.3 g of 4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure R to yield 4-(3-hydroxypropylsulfonyl)benzonitrile. 1.9 g of NBS was added to a solution of 2 g of 4-(3-hydroxypropylsulfonyl)benzonitrile and 2.8 g of triphenylphosphine in 10 mL of dichloromethane at 0° C. The reaction mixture was stirred at 0˜5° C. for 1 h. The mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (10-70% ethyl acetate/hexane) to afford 4-(3-bromopropylsulfonyl)benzonitrile. 300 mg of 4-(3-bromopropylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(allylsulfonyl)benzoic acid. 40 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(allylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(allylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 413.2 (M)+.
Reaction SMILES: [H][H].[Br:3][C:4]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>C(OCC)(=O)C.[Pt]>[Br:3][C:4]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(N)c1Br
Yield: 98.9 %

Procedure:
Hydrogen gas was passed through a solution of methyl 2-bromo-3-nitrobenzoate (0.20 g, 0.77 mM) and 0.1 g of 3% sulfided platinum on carbon in 25 mL ethyl acetate for 24 hours at room temperature. The catalyst was removed by filtration through celite. Concentration of the filtrate afforded 0.175 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil. 1H NMR (CDCl3) δ 7.15 (t, 1H, J=8 Hz), 7.1 (dd, 1H, J=1 and 8 Hz), 6.8 (dd, 1H, J=1 and 8 Hz), and 3.95 (s, 3H). IR (CHCl3, cm−1) 3550, 3380, 2980, 2900, 1729, 1613, 1465, 1451, 1434, 1324, 1266, and 1025. MS (FD) m/e 230, 232.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][F:33]>C(#N)C>[CH2:1]([N:3]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][F:33])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: FCCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCCCCF)CCCC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
According to Procedure B (Example 17, Step IV) a stirred mixture of N-[4-[4-(ethylamino)-1-hydroxybutyl]phenyl]methanesulfonamide (Example 7, Step II) and sodium bicarbonate in acetonitrile was allowed to react with 1-bromo-7-fluoroheptane (Step II) to give N-[4-[4-[ethyl(7-fluoroheptyl)amino]-1-hydroxybutyl]phenyl]methanesulfonamide, a compound of Formula I'. A mixture of this compound and 0.5 equivalents of fumaric acid was crystallized from acetone to give the titled product, mp 137°-138° C. Anal. calc'd for C22H37N2O5S: C, 57.36; H, 8.10; N, 6.08; S, 6.96. Found: C, 57.34; H, 8.08; N, 6.03; S, 6.95.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][O:17]S(C)(=O)=O)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]=2[CH:28]=1.[CH2:29](O)[CH2:30][OH:31]>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][O:17][CH2:29][CH2:30][OH:31])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]=2[CH:28]=1
Reactant: OCCO
Reactant: CS(=O)(=O)OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [Na]
Product: OCCOCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 6 h

Procedure:
A solution, prepared at 70°, of 2.83 g of sodium in 200 ml of ethylene glycol is treated with 24.8 g of 8-chloro-1-methylsulphonyloxymethyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (c.f. German Offenlegungsschrift 2,201,210, Example 1) and the mixture is stirred for 6 hours at 70°. The reaction mixture is partitioned between ethyl acetate and water. The organic phase is separated off, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and evaporated. Crystallisation from ethyl acetate gives 8-chloro-1-(2-hydroxyethoxy-methyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, melting point 162°-164°.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].C(Cl)Cl.[I:21]I>O>[I:21][C:12]1[CH:11]=[C:5]([CH:4]=[CH:3][C:2]=1[NH2:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N)c(I)c1
Reaction time: 72 h

Procedure:
Part A: Ethyl 4-aminobenzoate (5.0 gr, 30.27 mmol) and sodium bicarbonate (3.81 g, 45.40 mmol, 1.5 eq.) were added to a 50:50 mixture of methylene chloride and water. The mixture was chilled to 0 degrees and I2, (11.53 g, 45.40 mmol, 1.5 eq.) was added slowly. The reaction mixture was allowed to come to room temperature and was stirred for 72 hours. The layers were then separated and the aqueous layer washed with methylene chloride. All organics were combined and dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was chromatographed on silica using 30% ethyl acetate in hexanes as solvent to afford ethyl 3-iodo-4-aminobenzoate. C9H10NO2I MS 292 (M+H)+ 309 (M+NH4)+.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:10][CH2:9][C:7]([C:4]1[CH:5]=[CH:6][O:2][CH:3]=1)=[O:8])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC(=O)c1ccoc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccccc1)c1ccoc1
Yield: 91.6 %

Procedure:
6.0 g of (3-furylcarbonyl)methylamine hydrochloride, 7.8 g of sodium bicarbonate and 5.7 g of benzoyl chloride are treated in the same manner as described in Preparation 1-(1). 7.8 g of N-benzoyl-(3-furylcarbonyl)methylamine are thereby obtained. Yield: 91.8%
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]1[C:13](=[O:14])[N:12]([O:15][C:16](ON2C(=O)CCC2=O)=[O:17])[C:10](=[O:11])[CH2:9]1>C(#N)C>[O:11]=[C:10]1[CH2:9][CH2:8][C:13](=[O:14])[N:12]1[O:15][C:16](=[O:17])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Nc1ccccn1
Solvent: CC#N
Product: O=C(Nc1ccccn1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
A solution of 2-aminopyridine (2.0 g, 21.3 mmol) in acetonitrile (20 mL) was added to a stirred suspension of N,N-disuccinimidyl carbonate (5.4 g, 21.3 mmol) in acetonitrile (150 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in methylene chloride (120 mL). The methylene chloride solution was washed with sat. NaHCO3 (40 mL), water (2×40 mL), brine (40 mL) and dried (MgSO4). Solvent was removed, and the residue was slurried with ether (30 mL) to give pyridin-2-yl-carbamic acid 2,5-dioxo-pyrrolidin-1-yl ester (2.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][C@@H:10]([CH3:16])[C:9]1=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:18].[OH-].[Li+].O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:12]([C:13]([OH:15])=[O:14])[CH2:11][C@@H:10]([CH3:16])[C:9]([OH:17])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: C[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)O)C(=O)O
Yield: 98.8 %

Procedure:
A solution of (3R,5S)-1-t-Butoxycarbonyl-5-carboxy-3-methylpyrrolidine-2-one (6.2 g, 25.5 mmol) in THF (50 mL) was treated with lithium hydroxide monohydrate (3 eq, 3.20 g) and water (5 mL). After stirring for 16 hr at room temperature the THF was removed in vacuo and water (20 mL) was added. The pH was adjusted to 3 by the addition of glacial acetic acid, ether (100 mL) was added and the layers separated. The aqueous phase was extracted with ether (3 x 100 mL) and the combined organic phases were washed with brine (400 mL), dried over Na2SO4, filtered and evaporated to dryness, azeotroping with toluene (3 x 15 mL). The residue was dried under high vacuum to give 6.58 g of the product (99%) as a white foam which was used without further purification: Rf 0.8 (1% formic acid in ethyl acetate, developed with ninhydrin). 1H NMR (200 MHz, D2O): δ 3.80 (dd, J=10.4, 4.7 Hz, 1H), 2.45 (m, 1H), 2.0 (m, 1H), 1.60 (ddd, J=12.8, 4.2, 10.3 Hz, 1H), 1.25 (s, 9H), 1.0 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[N:34]=[C:35]=[O:36].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:35]([NH:34][C:28]3[C:29]([Cl:33])=[CH:30][CH:31]=[CH:32][C:27]=3[Cl:26])=[O:36])=[CH:16][CH:15]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1c(Cl)cccc1Cl)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (1.01 g; 3.04 mmol) in THF (25 mL) was added dropwise n-BuLi (1.2 mL; 2.5 mol/l in hexanes; 3.04 mmol), at −78° C. After 1 hour at −78° C., a solution of 2,6-dichlorophenyl isocyanate (0.63 g; 3.34 mmol) in THF (5 mL) was added dropwise. The mixture was allowed to warm to RT and then 5% aqueous NaHCO3 was added. Subsequently, the mixture was extracted with Et2O. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (Et2O:hexanes 1:1) to afford 4-(4-benzyl-morpholin-2-yl)-N-(2,6-dichloro-phenyl)-benzamide (0.68 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.CCN(CC)CC.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([N:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][OH:20])[CH2:24][CH2:25]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: OCCN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(c1ccccc1)N1CCN(CCO)CC1
Temperature: 25 °C

Procedure:
To a solution of racemic a-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of Et3N and 8 mL (66.0 mmol) of 1-(hydroxyethyl)piperazine. The reaction mixture was refluxed for three hours, cooled to rt. and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness to give a quantitative yield of the desired mixture of isomers as a yellow oil. MS (ion spray) 279.1 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][NH:15][CH3:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[C:22]1([S:28][CH2:29][CH2:30]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:16])[CH2:30][CH2:29][S:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCCN1CCc2cc(OC)c(OC)cc2CC1=O
Reactant: ClCCSc1ccccc1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCSc1ccccc1)CC2

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 2-phenylthioethylchloride analogously to Example 3.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[N:6]([C:8]([NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:9][N:10]=2)[N:7]=1.[O-:19][CH2:20][CH3:21].[Na+].O>C(O)C>[CH2:20]([O:19][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[N:6]([C:8]([NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:9][N:10]=2)[N:7]=1)[CH3:21]
Reactant: CC[O-]
Reactant: Cc1c(Cl)nn2c(NCC(F)(F)F)nnc2c1C
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nn2c(NCC(F)(F)F)nnc2c(C)c1C
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
(6-Chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)(2,2,2-trifluoroethyl)amine (W2.150; 330 mg) was initially charged in ethanol (25 ml) and admixed with sodium ethoxide (90 mg). The reaction mixture was stirred at 50° C. for 4 h, then further sodium ethoxide (10 mg) was added and the mixture was stirred further at 50° C. for 3 h. After standing overnight, the mixture was admixed with water and dried. The residue was taken up in EA and washed three times with water. The EA phase was dried over sodium sulfate, filtered and concentrated. 340 mg of the title compound were obtained. LC-MS rt: 0.82 min [M+H]+: 290.2 (met. b)
Reaction SMILES: C(C=C[C@@:8]1([N:16]2[CH:23]=[CH:22][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1)(OCC)=O.[OH-:24].[Na+]>>[C:10](/[CH:9]=[CH:8]/[C:22]1[C:20]([NH2:21])=[N:19][C:17](=[O:18])[N:16]([CH:23]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1)([OH:11])=[O:24]
Reactant: [OH-]
Reactant: CCOC(=O)C=C[C@]1(n2ccc(N)nc2=O)C[C@H](O)[C@@H](CO)O1
Agent: [Na+]
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbethoxyvinyldeoxycytidine (325 mg, 1mmol) is suspended in 0.5M NaOH solution (40 ml) and stirred at room temperature for 2 hrs. The clear solution is neutralised by addition of Dowex-50H+ -form to pH 7 and filtered. This solution is immediately used for the preparation of E-5-(2-bromovinyl)-2'-deoxycytidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([Si](C)(C)C)=[C:4]([F:15])[CH:3]=1.[I:16]Cl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([I:16])=[C:4]([F:15])[CH:3]=1
Reactant: C[Si](C)(C)c1c(F)cc(Cl)c(C=O)c1F
Reactant: ClI
Solvent: ClCCl
Product: O=Cc1c(Cl)cc(F)c(I)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 162.5 %

Procedure:
A solution of 6-chloro-2,4-difluoro-3-trimethylsilylbenzaldehyde (600 mg, 2.4 mmol) in methylene chloride (7 mL) was cooled to 0° C. and treated with solution of iodochloride (780 mg, 4.8 mmol) in methylene chloride (10 mL) and stirred at ambient temperature for 2 hours. Additional iodochloride (900 mg) was added and the solution heated under reflux for 40 minutes. The solution was allowed to cool and was washed with sodium bisulfite (15 ml, 5% solution), water (10 mL), and a saturated solution of sodium bicarbonate (10 mL). The organic phase was dried (sodium sulfate) and concentrated to give 6-chloro-2,4-difluoro-3-iodobenzaldehyde (620 mg, 3.9 mmol): LC/MS (m/z=302).