Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(CC2C=CC(OCC)=CC=2)=CC([C@H]2[C@H](OCC3C=CC=CC=3)[C@@H](OCC3C=CC=CC=3)[C@H](OCC3C=CC=CC=3)[C@@H](COCC3C=CC=CC=3)O2)=C(O)C=1.C([O:61][C:62]1[CH:63]=[C:64]([C@H:76]2[C@H:81]([O:82][CH2:83][C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=3)[C@@H:80]([O:90][CH2:91][C:92]3[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=3)[C@H:79]([O:98][CH2:99][C:100]3[CH:105]=[CH:104][CH:103]=[CH:102][CH:101]=3)[C@@H:78]([CH2:106][O:107][CH2:108][C:109]3[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=3)[O:77]2)[CH:65]=[C:66]([CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:67]=1[Cl:68])C=C>>[CH2:69]([C:66]1[C:67]([Cl:68])=[C:62]([OH:61])[CH:63]=[C:64]([C@H:76]2[C@H:81]([O:82][CH2:83][C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=3)[C@@H:80]([O:90][CH2:91][C:92]3[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=3)[C@H:79]([O:98][CH2:99][C:100]3[CH:101]=[CH:102][CH:103]=[CH:104][CH:105]=3)[C@@H:78]([CH2:106][O:107][CH2:108][C:109]3[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=3)[O:77]2)[CH:65]=1)[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1
Reactant: C=CCOc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(Cc2ccccc2)c1Cl
Agent: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Product: Oc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(Cc2ccccc2)c1Cl

Procedure:
Similar procedure with preparation of 27 proceeded except for using compound 169 to obtain the compound 170.
Reaction SMILES: [CH3:1][C:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:4]=2[N:3]=1.Br[C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=1[CH2:26]C>>[CH3:1][CH:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7]([C:19]3[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=3[CH3:26])[CH:8]=[CH:9][C:4]=2[NH:3]1
Reactant: CC1=Nc2ccc(Br)cc2C2(CCCCC2)O1
Reactant: CCc1cc(C#N)sc1Br
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C1(CCCCC1)OC(C)N2

Procedure:
The title compound was prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,1-benzoxazine-4,1′-cyclohexane] and 5-bromo-4-ethyl-2-thiophenecarbonitrile. A brown solid: 1H-NMR (DMSO-d6) δ 7.78 (s, 1H), 7.17 (d, 1H, J=1.8 Hz), 7.14 (dd, 1H, J=8.4, 2.2 Hz), 6.64 (s, 1H), 6.63 (d, 1H, J=82 Hz), 4.74 (m, 1H), 2.26 (s, 3H), 2.14 (m, 1H), 1.87 (m, 1H), 1.4-1.7 (m, 8H), 1.31 d, 3H, J=5.3 Hz); MS (ESI) m/z 337 [M−-H]−.
Reaction SMILES: [CH2:1]([C@@H:4]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH:2]=C.C1(C)C=CC=CC=1.I([O-])(=O)(=O)=[O:31].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:4]([CH2:1][CH:2]=[O:31])[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@H](CCCCOCc1ccccc1)CCC(=O)OC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](CC=O)CCCCOCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of methyl (S)-4-allyl-8-(benzyloxy)-octanoate (2.37 g, 7.8 mmol) in tetrahydrofuran (70 ml) and water (24 ml) is added a solution of 10 mg/ml of osmium tetroxide in toluene (9.4 ml, 0.37 mmol). Sodium periodate (3.57 g, 16.7 mmol) is added in small portions over a period of 0.5 hour. The mixture is allowed to stir for 1 hour and then poured on water and extracted with ether (3×30 ml). The combined organic extracts are dried, filtered and evaporated to give crude methyl (S)-8-(benzyloxy)-4-(formylmethyl)octanoate; IR (CH2Cl2): 2727, 1724, 1202, 1100 cm-1.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[K+:17]>C(O)C>[O:1]=[C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][C:4]([O-:6])=[O:5].[K+:17]
Reactant: CCCCCCCC(=O)CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCC(=O)CC(=O)[O-]

Procedure:
A solution of ethyl 3-oxodecanoate (25.7 g) in ethanol (360 ml) and aqueous potassium hydroxide (260 ml, 1M) was stirred at room temperature for 18 hours. The solvent was removed in vacuo to give crude potassium 3-oxodecanoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[CH2:17]([N:24]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC>O1CCOCC1>[CH2:35]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]1[N:26]=[CH:27][N:28]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=[CH:6][CH:7]=2)[C:30]=1[N+:31]([O-:33])=[O:32])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)c1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a solution of tert-butyl 3-aminophenyl(methyl)carbamate (20) (4.6 g, 20.8 mmol) and N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (7 g, 19.8 mmol) in dioxane (100 mL) was added Et3N (6 mL) and the reaction mixture was stirred at 60° C. overnight. The mixture was cooled to room temperature, the solvent was evaporated before water (200 mL) and EA (100 mL) was introduced. Organic layer was separated and extracted with EA (60 mL×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by column chromatography (silica gel, 0 to 30% ethyl acetate in petroleum ether) to give tert-butyl 3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenyl(methyl)carbamate (21) 6.7 g as yellow solid (yield 63%). LC-MS (ESI): m/z (M+1) 541.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([O:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Reactant: OCC(F)(F)F
Product: O=C(OCC(F)(F)F)c1csnc1-c1cccc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of 2.50 g (0.00856 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride and 50 ml of 2,2,2,-trifluoroethanol was held at reflux for 40 minutes, was allowed to stand overnight, and was concentrated under vacuum (to 90° at 0.1 torr) to give 2.68 g (88%) of oil, nD24 =1.4976.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(C(C)C)C(C)C)C.[F:33][CH:34]([F:38])[C:35](O)=[O:36].N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F>CN(C)C=O>[F:33][CH:34]([F:38])[C:35]([NH:2][C@H:3]1[CH2:4][C:5](=[O:23])[N:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:12][CH:13]=2)[CH2:7]1)=[O:36]
Reactant: O=C(O)C(F)F
Reactant: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1)C(F)F
Reaction time: 6 h
Yield: 18.5 %

Procedure:
A solution of 103 mg (0.3 mmol) of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 2g)] in 0.5 ml of N,N-dimethylformamide is treated successively with 180 μl (1.0 mmol) of N-ethyl-diisopropylamine, 20 μl (0.3 mmol) of difluoroacetic acid, and 102 mg (0.3 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TBTU) at RT, and thereafter, stirred for 6 hours. For the working-up, the reaction mixture is evaporated under reduced pressure. The resulting residue is dissolved in 3 ml of dichloromethane and the solution is washed with 1.5 ml of a saturated solution of sodium hydrogenate and with 1.5 ml of hydrochloric acid (0.1 N). The organic phase is dried over sodium sulfate and evaporated. For purification, the crude material is chromatographed on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent. There are obtained 21 mg (18% of theory) of (S)-2,2-difluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=396 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](OC)=[O:16])=[N:8][C:4]=2[CH:3]=1.[NH2:21][OH:22].[OH-].[K+]>C1COCC1>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:21][OH:22])=[O:16])[NH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)CCCCCCc1nc2cc(Br)ccc2[nH]1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCCCCCc1nc2ccc(Br)cc2[nH]1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of methyl 7-(5-bromo-1H-benzimidazol-2-yl)heptanoate (100 mg, 0.295 mmol) in THF at 0° C. was added 50% hydroxylamine solution (0.17 mL, 2.70 mmol). To this was added KOH (0.74 mL, 1M in MeOH, 0.74 mmol) dropwise. The reaction was stirred at 0° C. for 2 hr, briefly concentrated and neutralized by adding 1 N HCl solution until pH was 7. The light yellow precipitate was collected by filtration and pump-dried to give 7-(6-bromo-1H-benzimidazol-2-yl)-N-hydroxy heptanamide 15 (53 mg). The filtrate was extracted with ethyl acetate, dried and concentrated. The residue was purified by column to give another portion of the desired product 15 (16 mg). LCMS (M+1@retention time): 340@1.283 min (LC conditions: 1. Column: YMC, C-18 ODS, 50×4.6 mm 0.5 u; 2. Mobile phase: A 0.05% TFA in water and B 0.05% TFA in acetonitrile; 3. Flow rate 1.2 mL/min; Gradient program: 20% B to 100% B in 3 min).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH2:7][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:38]1([CH2:43][CH2:44]O)[CH:42]=[CH:41][N:40]=[CH:39]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N:38]1([CH2:43][CH2:44][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:18])[CH2:7][CH:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[O:9]3)=[CH:4][CH:3]=2)[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: OCCn1ccnc1
Reactant: O=C1CC(c2ccccc2)Oc2cc(O)ccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CC(c2ccccc2)Oc2cc(OCCn3ccnc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
A solution of 5.0 g (20.8 mmol) of 7-hydroxy-2-phenyl-4-chromanone in 200 mL of THF was treated with 6.22 g (23.7 mmol) of triphenylphosphine and 2.65 g (23.7 mmol) of 2-(1H-1-imidazolyl)-1-ethanol. A solution of 4.13 g (23.7 mmol) of diethyl azodicarboxylate in 25 mL of THF was added dropwise and the solution allowed to stir at room temperature overnight. The solvent was removed under pressure, and the residue taken up in 1N citric acid and washed three times with Et2O. The aqueous phase was adjusted to pH 7 with 50% NaOH and extracted with EtOAc. The EtOAc was washed with saturated NaCl and dried over MgSO4. Treatment with charcoal and removal of the solvent under pressure gave 3.0 g (43% yield) of the product as a white solid, mp 139-140° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 335 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]3[C:21]4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:22]=4[N:23]=[C:17]3[CH:16]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:36]>>[ClH:36].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][N:18]3[C:21]4[CH2:27][NH:26][CH2:25][CH2:24][C:22]=4[N:23]=[C:17]3[CH:16]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3cc(-n4ccc(OCc5ccccc5)cc4=O)ccn3c2C1
Agent: Cl
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccn2c3c(nc2c1)CCNC3
Yield: 82 %

Procedure:
tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydropyrido[4′,3′:4,5]imidazo[1,2-a]pyridine-2(1H)-carboxylate (482 mg, 1.02 mmol) was deprotected and converted to the hydrochloride according to Example 18 (step h) to provide the title compound (340 mg, 82%) as a white solid: mp 280° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 2H), 8.54 (d, J=7.2 Hz, 1H), 7.77 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.47-7.34 (m, 5H), 7.23 (d, J=6.6 Hz, 1H), 6.19 (dd, J=7.6, 2.5 Hz, 1H), 6.02 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 4.57 (s, 2H), 3.51 (s, 2H), 3.08 (t, J=5.4 Hz, 2H); ESI MS m/z 373 [M+H]; HPLC (Method B) 98.8% (AUC), tR=10.6 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].C1C=C[NH+]=CC=1.[Br:17][Br-]Br>C1COCC1>[Br:17][C:3]1[C:2]([F:1])=[CH:8][C:6]([NH2:7])=[C:5]([O:9][CH3:10])[CH:4]=1
Reactant: COc1ccc(F)cc1N
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COc1cc(Br)c(F)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a THF (20 mL) solution of 5-fluoro-2-methoxyaniline (1.76 g), a THF (30 mL) solution of pyridinium bromide perbromide (4.36 g) was added dropwise under ice-cooling, and the reaction solution was agitated for 30 minutes at room temperature. The solid which deposited from the reaction mixture was separated by filtering and the solid was washed by THF. After the obtained solid was dissolved with water and ethyl acetate, the aqueous layer was neutralized with a saturated sodium bicarbonate water, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate system), and 1.83 mg of the title compound was obtained.
Reaction SMILES: NC1C(CC)=C(Cl)C=C2C=1N=C(Cl)C(Cl)=N2.[NH2:17][C:18]1[C:27]([Cl:28])=[C:26]([CH2:29][CH3:30])[CH:25]=[C:24]2[C:19]=1[N:20]=[C:21](Cl)[C:22](Cl)=[N:23]2.[CH3:33][O-:34].[Na+].[CH3:36][OH:37]>O1CCCC1.C(OCC)(=O)C>[NH2:17][C:18]1[C:27]([Cl:28])=[C:26]([CH2:29][CH3:30])[CH:25]=[C:24]2[C:19]=1[N:20]=[C:21]([O:37][CH3:36])[C:22]([O:34][CH3:33])=[N:23]2
Reactant: CO
Reactant: CCc1cc2nc(Cl)c(Cl)nc2c(N)c1Cl
Reactant: C[O-]
Agent: CCc1c(Cl)cc2nc(Cl)c(Cl)nc2c1N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2nc(OC)c(OC)nc2c(N)c1Cl
Reaction time: 3.5 h
Yield: 26 %

Procedure:
A mixture of 5-amino-2,3,7-trichloro6-ethylquinoxaline and 5-amino-2,3,6-trichloro-7-ethylquinoxaline (169 mg, 0.611 mmol) in anhydrous tetrahydrofuran (6 ml) was treated with a 25% solution of sodium methoxide in methanol (0.84 ml, 1.47 mmol) at 0° C. with stirring. After 3.5 hours, the solution was diluted with ethyl acetate, washed with water (2×10 ml), saturated aqueous sodium chloride (10 ml), dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (eluting with hexane/ethyl acetate 19:1) gave two products. The first eluted compound, 5-amino-6-chloro-7-ethyl-2,3-dimethoxyquinoxaline (42 mg, 26%), was obtained as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([Cl:29])[CH:16]=1)[C:10]([O:12]C)=[O:11].C(N(CC)CC)C.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[OH-].[Li+].Cl>FC(F)(F)C(O)=O.CO>[Cl:29][C:17]1[CH:16]=[C:15]([CH2:14][C@H:9]([NH:8][S:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:45])=[O:44])[C:10]([OH:12])=[O:11])[CH:20]=[CH:19][C:18]=1[CH:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C1CC(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2Cl)S(=O)(=O)N1
Temperature: 130 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Methyl (2S)-2-amino-3-[3-chloro-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)-phenyl]-propanoate trifluoroacetate (145 mg, 0.314 mmol) was dissolved in trifluoroacetic acid (3 mL) and heated in the microwave at 130° C. for 180 s. The reaction was concentrated in vacuo and azetroped with toluene (5 mL). The product was dissolved in methanol (2 mL), was treated with triethylamine (170 μL, 1.2 mmol) and then benzenesulfonyl chloride (60 μL, 0.47 mmol). The solution stirred at rt for 1 h. 4 M aqueous lithium hydroxide solution (0.782 mL) was added and the solution stirred 3 h at rt. The solution was acidified with aqueous hydrochloric acid solution (1.0 N, 4.0 mL), diluted with methanol to 10 mL volume, and then purified by reverse phase HPLC to afford product as a white solid (108 mg, 73%). 1H NMR (400 MHz, CD3OD): δ 7.66–7.64 (m, 2H), 7.63–7.51 (m, 1H), 7.44–7.38 (m, 3H), 7.31–7.16 (m, 2H), 5.65–5.61 (m, 1H), 4.10–4.03 (m, 1H), 3.48–3.42 (m, 1H), 3.29–3.27 (m, 1H), 3.12–3.07 (m, 1H), 2.88–2.81 (m, 1H); LCMS found for C18H21ClN3O7S2 (M+H)+: m/z=490.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)([CH3:6])[CH2:3][CH2:4][OH:5].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:5][CH2:4][CH2:3][C:2]([CH3:1])([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH3:6])(=[O:24])=[O:23]
Reactant: CC(C)(CCO)n1cc(-c2ncnc3[nH]ccc23)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(CCOS(C)(=O)=O)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A solution of 3-methyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butan-1-ol (6.61 g, 0.0244 mol) in DCM (300 mL) at 0° C. was treated with TEA (3.74 mL, 0.0268 mol), followed by methanesulfonyl chloride (2.07 mL, 0.0268 mol). The reaction was stirred for 1 hour, and was then concentrated in vacuo. The crude residue was purified by flash column chromatography to afford the desired product (4.9 g, 57%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2N=N1.C(N(CC)CC)C.[C:30]([O:34][C:35]([NH:37][CH2:38][C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]>ClCCl.C(OCC)(=O)C>[C:18]1([NH:14][C:39]([CH2:38][NH:37][C:35](=[O:36])[O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:40])[CH:17]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.27 g (1.19 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 681 mg (5.04 mmol) of 1-hydroxybenzotriazole and 0.95 ml (6.82 mmol) of triethylamine were added to 1.15 g (6.56 mmol) of t-butoxycarbonylglycine in 20 ml of dichloromethane under cooling in an ice bath, and they were stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the product was washed with 0.1 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([NH:10][C:11]([C:13]1[N:17]2[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])[C:16]2=[N:15][C:14]=1[CH3:32])=[O:12])[CH2:6][CH2:7][CH2:8][CH3:9])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C@H:5]([NH:10][C:11]([C:13]1[N:17]2[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]3[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=3[F:30])[C:16]2=[N:15][C:14]=1[CH3:32])=[O:12])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCC[C@H](CN=[N+]=[N-])NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](CN)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
42 mg of N-[(2R)-1-azidohexan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]-pyridine-3-carboxamide (Example 44A, 0.095 mmol) were initially charged in 0.78 ml of THF/water (10:1.5), 28.3 mg of triphenylphosphine (0.108 mmol) were added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and the residue was purified by preparative thick-layer chromatography (mobile phase ethyl acetate:dichloromethane:diethylamine=2:1:0.1). The combined product fractions were purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated. This gave 17 mg of the title compound (41% of theory).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([C:12](=[O:14])[CH3:13])[CH2:3]1.[Cl:16][S:17](O)(=[O:19])=[O:18].O>ClCCl>[C:12]([N:4]1[CH2:3][C:2]([CH3:15])([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1Cc2ccccc2C(C)(C)C1
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(S(=O)(=O)Cl)ccc2C(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
A solution of 1-(4,4-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-ethanone (D2) (0.5 g, 2.5 mmol) in dry dichloromethane (2 ml) was added over 15 minutes to an ice-cooled, stirred solution of chlorosulfonic acid (1.7 ml, 25 mmol) in dry dichloromethane (6 ml). After stirring the solution at 0° C. for 1 h, it was warmed to ambient temperature and stirred for a further 3 h. The solution was then carefully poured onto a mixture of ice (30 g) and water (30 ml) with stirring. The layers were separated and the aqueous layer was extracted with dichloromethane (30 ml). The combined organic layers were dried (MgSO4) and concentrated in vacuo to an oil which was stirred at room temperature for 15 minutes with diethyl ether (30 ml) to afford the title compound (D3) as a white solid (0.21 g, 27%), δH (CDCl3, rotamers observed)/ppm 1.33, 1.37 (6H, 2×s), 2.21, 2.24 (3H, 2×s), 3.47, 3.66 (2H, 2×s), 4.77, 4.88 (2H, 2×s), 7.55-7.62 (1H, m), 7.77-7.90 (2H, m).
Reaction SMILES: [C-]#N.[K+].C([O:7][CH2:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([S:16](=[O:23])(=[O:22])[N:17]=[CH:18][N:19]([CH3:21])[CH3:20])=[CH:11][C:10]=1[Cl:24])(=O)C>CO>[Cl:24][C:10]1[CH:11]=[C:12]([S:16]([N:17]=[CH:18][N:19]([CH3:21])[CH3:20])(=[O:22])=[O:23])[CH:13]=[C:14]([F:15])[C:9]=1[CH2:8][OH:7]
Reactant: CC(=O)OCc1c(F)cc(S(=O)(=O)N=CN(C)C)cc1Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CN(C)C=NS(=O)(=O)c1cc(F)c(CO)c(Cl)c1
Yield: 80.8 %

Procedure:
To a solution of KCN (82 mg, 1.26 mmol) in MeOH (80 mL) was added 2-chloro-4-(N-((dimethylamino)methylene)sulfamoyl)-6-fluorobenzyl acetate (850 mg, 2.52 mmol) at 0° C. The mixture was allowed to attain room temperature and then refluxed 1 h. After cooling, the reaction mixture was quenched with H2O, concentrated, and extracted with EtOAc. The combined extracts were washed with brine, dried over anhyd MgSO4, filtered and concentrated under reduced pressure to give N′-(3-chloro-5-fluoro-4-(hydroxymethyl)phenylsulfonyl)-N,N-dimethylformimidamide (600 mg, 80%) as ivory solid. 1H NMR (400 MHz, CDCl3) δ 8.10(s, 1H), 7.74 (s, 1H), 7.55 (d, 1H), 4.86 (d, 2H), 3.17 (s, 3H), 3.05 (s, 3H), 2.07 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1>>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:20][CH:21]=1)#[N:26]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(CN(c2ccc([N+](=O)[O-])cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-nitrophenyl) amino]pyrimidine and α-bromo-p-tolunitrile