Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2(=[O:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=12.ClC1C(=O)[C:25](C#N)=[C:26]([C:31]#[N:32])C(=O)C=1Cl.C(N)CC>C1COCC1>[CH2:31]([NH:32][C:15]1[C:2](=[O:1])[C:3]2[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=2[C:5]2[C:14]=1[S:13](=[O:17])(=[O:16])[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[N:6]=2)[CH2:26][CH3:25]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=S1(=O)c2ccccc2Nc2c1cc(O)c1ccccc21
Solvent: C1CCOC1
Solvent: CCCN
Product: CCCNC1=C2C(=Nc3ccccc3S2(=O)=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 62.8 %

Procedure:
To a suspension of 5-hydroxy-12H-benzo[a]phenothiazine-7,7-dioxide (594 mg) in THF (10 ml) was added 2,3-dichloro 5,6-dicyano-1,4-benzoquinone (1.021 gram). The mixture was stirred at room temperature for 2 minutes, then there was added n-propyl amine (0.2 ml). The stirring was continued for 0.5 hour, then the mixture was evaporated to dryness. To the residue was added 50 ml dichloromethane and the mixture was stirred for 15 minutes and filtered. The filtrate was evaporated to dryness and the residue crystallized from a mixture of toluene and hexane to afford the title compound (442 mg) as a red-brown crystalline solid, m.p. 149°-151° C. (dec.).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C@@H:7]1[NH:11][C@H:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8]1)([CH3:4])[CH3:3].CN(C1C=CC=CN=1)C.CN1CCOCC1.O.[C:33]([O:37][C:38]([NH:40][C@H:41]([C:46](O)=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].Cl.CN(C)CCCN=C=NCC>ClCCl>[C:33]([O:37][C:38]([NH:40][C@H:41]([C:46]([N:11]1[C@@H:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH2:8][CH2:9][C@H:10]1[C:12]([O:14][CH3:15])=[O:13])=[O:47])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:39])([CH3:35])([CH3:36])[CH3:34]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl (5R)-5-((trimethylsilyl)ethynyl)-L-prolinate (1.6 grams, 7.48 mmol), dimethylaminopyridine (913 mg, 7.48 mmol), N-methylmorpholine (1.23 mL, 11.22 mmol), and N-(tert-butoxycabonyl)-L-leucine monohydrate (2.24 g, 8.98 mmol) in dichloromethane (30 mL) at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.72 g, 8.98 mmol). The resulting mixture was stirred 16 hours at room temperature, and partitioned between ethyl acetate (200 mL) and 1 M HCl (200 mL). The aqueous layer was further extracted with ethyl acetate (200 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated. The residue was chromatographed with a Biotage 40 M cartridge with 40% ethyl acetate/hexane provide the titled compound. MS (DCI/NH3) m/e 439 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[NH:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[O:16][CH3:17])[NH:7][C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].[Cl:21]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[C:14](=[NH:15])[C:13]2[C:8](=[C:9]([Cl:21])[CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[O:16][CH3:17])[NH:7][C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)[nH]c2ccc(OC)c(OC)c2c1=N
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CCCCn1c(=O)[nH]c2c(Cl)cc(OC)c(OC)c2c1=N

Procedure:
A solution of 0.5 g (1.77 mmol) of 3-butyl-5,6-dimethoxy-4-imino-2(1H)quinazolinone and N-chlorosuccinimide (0.45 g, 3.35 mmol) in 100 ml of CHCl3 was heated at reflux for 18 hours. The reaction mixture was cooled, washed with 10% aqueous sodium thiosulfate (3×35 ml), dried with anhydrous MgSO4 and evaporated to give the crude product as an orange-brown solid. Recrystallization from 2-propanol afforded the desired product in analytical purity; yield 0.30 g (54.5%) mp 155°-157°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[CH:6][CH:7]=1.[Cu](C#N)[C:11]#[N:12].O.Cl>CN1C(=O)CCC1.C(OCC)(=O)C>[C:11]([C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[CH:6][CH:7]=1)#[N:12]
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(Br)ccc1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C#N)ccc1O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 133.6 %

Procedure:
A mixed solution of 10.89 g (58 mmol) of 4-bromo-cresol and 10.39 g (116 mmol) of copper cyanide in 50 ml of NMP was stirred at 190° C. for 2 hours, followed by the addition of 43 g of FeCl3.6H2O, 65 ml of water and 11 ml of concentrated hydrochloric acid. The resulting mixture was stirred at 80° C. for 30 minutes and was then allowed to cool down. Water and ethyl acetate were added to the reaction mixture, followed by separation into a water layer and an organic layer. The organic layer was dried over Na2SO4, and the solvent was then distilled off under reduced pressure. The residue as purified by column chromatography (chloroform/methanol=40/1), whereby 10.32 g of 4-cyanocresol were obtained as a dark brown oil.
Reaction SMILES: [Cl:1][C:2]1[S:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClCCl>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:11][C:2]([Cl:1])=[CH:3][C:4]2=3)=[O:20])=[CH:18][CH:17]=1)=[O:32]
Reactant: Nc1ccc(C(=O)N2CCCCc3sc(Cl)cc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCCCc3sc(Cl)cc32)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (ice bath) solution of 0.245 g 15 (0.8 mmol) of 2-chloro-4-(4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 167 μl (1.2 mmol) of triethylamine in 5 ml of dichloromethane is added 140 μl (1 mmol) of 2,4-dichlorobenzoyl chloride. The solution is stirred under argon at room temperature overnight and diluted with 60 ml of dichloromethane. The mixture is washed with 20 ml each of 2N-citric acid, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue crystallized from ethyl acetate-hexane to give 0.315 g of white crystals, m.p. 187°-189° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:29])[CH3:28])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:31][CH3:30])([OH:29])[CH3:28])[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Reactant: COc1ccccc1[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1C(C)(O)c1cccc(-c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Reaction time: 3 h

Procedure:
A solution of 32 (1.5 g, 3.96 mmol) in anhydrous tetrahydrofuran (16 mL) was stirred under nitrogen at room temperature and 1M ortho-methoxyphenyl magnesium bromide in tetrahydrofuran (6 mL, 1.5 equiv.) was slowly added. Stirring was continued at room temperature for 30 min and at 60° C. for 3 hr. After cooling, the reaction mixture was poured on saturated ammonium chloride (100 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×100 mL), dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator and the crude 33 thus obtained was used in the next step without further purification.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:10][O:11][CH2:12][CH2:13][NH:14][C:15](=[O:18])[CH2:16]Cl.C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[C:4]([O:6][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12][O:11][CH3:10])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COCCNC(=O)CCl
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COCCNC(=O)COC(=O)/C=C/C(=O)OC
Yield: 7.4 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N-(2-methoxyethyl) chloroacetamide (0.69 g, 4.60 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.07 g (8% yield) of the title compound (5) as a white solid after purification by mass-guided preparative HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.94-6.92 (m, 2H), 6.46 (br s, 1H), 4.68 (s, 2H), 3.83 (s, 3H), 3.52-3.46 (m, 4H), 3.36 (s, 3H). MS (ESI): m/z 245.98 (M+H)+.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([Si:37]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].O>C1COCC1>[CH2:30]([Si:37]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:42][CH2:41][CH:40]([CH:2]=[O:4])[CH2:39][CH2:38]1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(=O)CC1
Reactant: CC(C)(C)[O-]
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC[Si]1(c2ccccc2)CCC(C=O)CC1
Reaction time: 2 h

Procedure:
12 g of potassium t-butoxide was added to a mixture of 35 g of methoxymethyltriphenylphosphonium chloride and 200 ml of THF to prepare an orange ylide solution. A solution of 28 g of 4-n-heptyl-4-phenyl-4-silacyclohexanone in 50 ml of THF was added to the solution. After agitation for 2 hours at room temperature, the mixture was poured into iced water and extracted with methylene chloride. The extract was washed, dried and concentrated by a usual manner. n-Hexane was added to the resultant concentrate, followed by removal of the resultant triphenylphosphine oxide crystals by filtration. The resultant filtrate was concentrated. The concentrate was hydrolyzed with 100 ml of 20% hydrochloric acid, followed by washing, drying and concentration by a usual manner to obtain 4-n-heptyl-4-phenyl-4-silacyclohexane carbaldehyde.
Reaction SMILES: Cl.[CH:2]1[C:14]2[CH:13]([CH2:15][O:16][C:17]([N:19]3[CH2:24][C@H:23]([C:25](=[O:48])[N:26]([CH:45]4[CH2:47][CH2:46]4)[C:27]4[CH:28]=[CH:29][C:30]5[O:35][C:34]([CH3:37])([CH3:36])[C:33](=[O:38])[N:32]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:31]=5[CH:44]=4)[CH2:22][C@H:21]([NH2:49])[CH2:20]3)=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:50]([C:52]1([C:55](O)=[O:56])[CH2:54][CH2:53]1)#[N:51].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:11]1[C:12]2[CH:13]([CH2:15][O:16][C:17]([N:19]3[CH2:24][C@H:23]([C:25](=[O:48])[N:26]([CH:45]4[CH2:47][CH2:46]4)[C:27]4[CH:28]=[CH:29][C:30]5[O:35][C:34]([CH3:36])([CH3:37])[C:33](=[O:38])[N:32]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:31]=5[CH:44]=4)[CH2:22][C@H:21]([NH:49][C:55]([C:52]4([C:50]#[N:51])[CH2:54][CH2:53]4)=[O:56])[CH2:20]3)=[O:18])[C:14]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](N)CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)C3CC3)cc21
Reactant: N#CC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](NC(=O)C4(C#N)CC4)CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)C3CC3)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (3S,5R)-3-Amino-5-{cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester hydrochloride salt (100 mg, 0.152 mmol) and 1-Cyano-cyclo-propanecarboxylic acid (20 mg, 0.182 mmol) in DMF (10 mL) is added EDC-HCl (45 mg, 0.227 mmol), HOAt (31 mg, 0.227 mmol) and diisopropylethylamine (0.04 mL, 0.227 mmol) at 0° C. The mixture is stirred for 14 h at r.t. and diluted with ethyl acetate, and washed with H2O. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by silica-gel column chromatography to afford the title compound as a white solid. MS: 746 [M+H]+; tR (CombiScreen ODS-AM, 50×4.6 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 2 min, flow 2.0 ml/min): 2.14 min.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N+:10]([CH3:13])([O-:12])=[O:11].[OH-].[Na+].C(O)(=O)C>CCO>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:13][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(C(O)C[N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A stirred solution of 4-methylbenzaldehyde (325 mg, 319 μL, 2.71 mmol) and nitromethane (531 μL, 9.89 mmol) in absolute EtOH (20 mL) at 0° C. was treated with 10% aq. NaOH (m/v) (1.14 mL, 2.84 mmol), stirred for 1 h and treated with 2% aq. acetic acid (m/v) (8.54 mL, 2.84 mmol). The reaction was stirred for 1 h at room temperature then partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts were washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo to afford 1-(4-methylphenyl)-2-nitroethanol as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.28 (d, J=8.1 Hz, 2H), 7.21 (d, J=8.1 Hz, 2H), 5.42 (dt, J=9.6, 3.3 Hz, 1H), 4.60 (dd, J=13.3, 9.7 Hz, 1H), 4.49 (dd, J=13.3, 3.1 Hz, 1H), 2.79 (d, J=3.7, 1H), 2.36 (s, 3H).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[Br:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([NH:19][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[N:15][NH:16]2)=[CH:12][CH:11]=1.C(OCC)(=O)C.O>C(#N)C>[Br:9][C:10]1[C:18]([N+:7]([O-:8])=[O:6])=[C:17]2[C:13]([C:14]([NH:19][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[N:15][NH:16]2)=[CH:12][CH:11]=1
Reactant: O=[N+]=O
Reactant: CCCC(=O)Nc1n[nH]c2cc(Br)ccc12
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC(=O)Nc1n[nH]c2c([N+](=O)[O-])c(Br)ccc12
Temperature: 3 °C
Reaction time: 14 h

Procedure:
235 mg of nitronium tetrafluoroborate are added in a single portion to 500 mg of N-[6-bromo-1H-indazol-3-yl]butanamide, described previously in Example 24, in 25 cm3 of acetonitrile, cooled to about 3° C. The mixture is maintained at about 3° C. for 1 hour and the resulting mixture is then allowed to return to about 19° C. over 14 hours. 15 cm3 of ethyl acetate and 15 cm3 of distilled water are added to the reaction medium. The medium is then evaporated under reduced pressure (2 kPa; 40° C.) and the residue is taken up in 20 cm3 of dichloromethane. The insoluble material is filtered off and washed with 20 cm3 of diisopropyl ether. The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with ethyl acetate/cyclohexane (30/70 by volume) and collecting 35 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 50° C.), 30 mg of N-[6-bromo-7-nitro-1H-indazol-3-yl]butanamide are thus obtained in the form of a white product melting at 248° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][CH2:9][C:10]([O:12][CH:13]2[CH:17]([OH:18])[CH2:16][O:15][CH2:14]2)=[O:11])=[CH:6][C:5]([N:19]=[C:20]2[N:28]3[N:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])[S:21]2)=[C:4]([F:30])[CH:3]=1.N1C=CC=CC=1.[Cl:37][CH2:38][C:39](Cl)=[O:40]>ClCCl>[Cl:1][C:2]1[C:7]([S:8][CH2:9][C:10]([O:12][CH:13]2[CH:17]([O:18][C:39](=[O:40])[CH2:38][Cl:37])[CH2:16][O:15][CH2:14]2)=[O:11])=[CH:6][C:5]([N:19]=[C:20]2[N:28]3[N:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])[S:21]2)=[C:4]([F:30])[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: O=C(CSc1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl)OC1COCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)OC1COCC1OC(=O)CSc1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
In 25 ml of dichloromethane were dissolved 1.19 g of 9-(4-chloro-2-fluoro-5-(4-hydroxytetrahydrofuran-3-yloxycarbonylmethylthio)phenylimino)- 8-thia-1,6diazabicyclo[4.3.0]nonan-7-one and 0.24 g of pyridine, followed by dropwise addition of a solution of 0.34 g of chloroacetyl chloride in dichloromethane. After stirring at room temperature overnight, the reaction mixture was washed with water, and subsequently with aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane =2/3), to obtain 1.02 g of a compound described in Table 1 (No. 32) (74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][OH:16])=[CH:12][CH:13]=2)[C:8]([S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[N:7]1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:57][CH2:58][CH2:59]O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][O:16][CH2:59][CH2:58][Cl:57])=[CH:12][CH:13]=2)[C:8]([S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[N:7]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2ccc(CO)cc12
Reactant: OCCCl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2ccc(COCCCl)cc12
Temperature: -20 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
[1-(3-Chlorobenzyl)-3-(1-naphthylsulfonyl)-1H-indazol-5-yl]-methanol (0.18 g, 0.4 mmol) and diisopropyl ethyl amine (1 mmol) in methylene chloride were treated at −20° C. with trifluoromethanesulfonic anhydride (0.14 g, 0.5 mmol). After stirring for 30 min an excess of 2-chloroethanol (2 mmol) was added and the mixture stirred for additional 2 hrs at −20° C. and at room temperature for 12 hrs. The reaction mixture was diluted with water, extracted with ethyl acetate and after evaporation of solvent, chromatographed on silica gel using 40% ethyl acetate/hexane as an eluent to afford the target material (0.08 g, 0.16 mmoles).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:24])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](Cc1ccccc1)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
A solution of {(R)-1-benzyl-2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-carbamic acid tert-butyl ester (1.12 g, 2.54 mmol) and trifluoroacetic acid (3 ml) in dichloromethane (6 ml) is stirred at ambient temperature for 3 hours. The solvent is evaporated and the residue takenup in hydrochloric acid (2M), washed with ethylacetate and basified with sodium hydroxide solution (4M) to pH8-9. The suspension is extracted with dichloromethane, the dichloromethane dried over magnesium sulphate and the solvent evaporated to afford [1-((R)-2-amino-3-phenyl-propyl)-piperidin-4-yl]-(4-fluoro-phenyl)-methanone. [MH]+341.7.
Reaction SMILES: [C:1]1([N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19]OC)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1>C(Cl)Cl>[C:1]1([N:7]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]([C:10]2[CH:11]=[C:12]3[N:18]=[C:17]([CH2:19][NH:33][C:34]4[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOC(=O)CCN(C(=O)c1cnc2sc(COC)nc2c1)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1cnc2sc(CNc3ccc(C#N)cc3)nc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.54 g (3.85 mMol) of 2-methoxymethyl-thiazolo[5,4-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and 4.3 ml (4.3 mMol) of a 1 molar solution of boron tribromide in methylene chloride was dissolved in a further 30 ml of methylene chloride and stirred for 5 hours at room temperature. Then the mixture was washed with 40 ml of saturated sodium hydrogen carbonate solution, the organic phase was dried with sodium sulphate and the solvent was distilled off. The crude product (1.9 g) was taken up in 15.0 ml of N,N-diisopropyl-ethylamine, mixed with 0.50 g (4.2 mMol) of 4-aminobenzonitrile and heated to boiling for one hour. Then the solvent was distilled off in vacuo, the crude product was taken up in 100 ml of methylene chloride, the organic phase was washed with 100 ml of water and dried with sodium sulphate. After the solvent had been removed in vacuo the crude product obtained was purified by flash chromatography (silica gel; ethyl acetate/petroleum ether=35:65 to 1:1) and evaporated down again in vacuo. Yield: 0.45 g (24% of theory) of yellow amorphous solid, Rf value: 0.34 (silica gel; ethyl acetate/petroleum ether=1:1)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)=O)[N:10]=2)[CH2:4][C:3]1([CH3:21])[CH3:20].O[C@@H]1CC[C@H](NC2C(C#N)=CN=C(S(C)(=O)=O)N=2)CC1(C)C.Cl.[CH3:45][C:46]1[N:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[CH2:57][NH2:58])[N:49]=[N:48][N:47]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:58][CH2:57][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=3[N:50]3[C:46]([CH3:45])=[N:47][N:48]=[N:49]3)[N:10]=2)[CH2:4][C:3]1([CH3:21])[CH3:20]
Reactant: CS(=O)c1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Reactant: Cc1nnnn1-c1ccccc1CN
Agent: CC1(C)C[C@@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@H]1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnnn1-c1ccccc1CNc1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a mixture of 4-(((1S,4R)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile and 4-(((1S,4R)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (1.0 equiv) in dioxane (0.4M) was added (2-(5-methyl-1H-tetrazol-1-yl)phenyl)methanamine hydrochloride (1.0 equiv.) and DIEA (2.0 equiv.). The mixture was stirred at 120° C. in microwave for 2 h. After completion of the reaction and standard work-up, the desired product was obtained (37% yield). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.12 (s, 1H), 7.82-7.78 (m, 1H), 7.63-7.61 (m, 1H), 7.58-7.51 (m, 3H), 7.02-6.92 (m, 1H), 4.32-4.17 (m, 3H), 4.01-3.99 (m, 1H), 3.21-3.14 (m, 1H), 2.41-2.36 (m, 3H), 1.65-1.47 (m, 1H), 1.36 (br, 1H), 1.23-1.17 (m, 2H), 0.81 (s, 3H), 0.73 (s, 3H); MS (ESI) m/z 434.2 [M+H]+.