Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][C:6]1[S:13][CH2:12][CH2:11][CH:10]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=3)([CH2:9]2)[N:7]=1)(C)(C)C.FC(F)(F)C(O)=O.CS(O)(=O)=O.C([O-])(O)=O.[Na+]>>[N+:20]([C:16]1[CH:15]=[C:14]([C:8]23[CH2:9][CH:10]2[CH2:11][CH2:12][S:13][C:6]([NH2:5])=[N:7]3)[CH:19]=[CH:18][CH:17]=1)([O-:22])=[O:21]
Reactant: CC(C)(C)NC1=NC2(c3cccc([N+](=O)[O-])c3)CC2CCS1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: NC1=NC2(c3cccc([N+](=O)[O-])c3)CC2CCS1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
To a solution of (1SR,7SR)—N-tert-butyl-1-(3-nitrophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-amine (intermediate A4c) (990 mg, 3.1 mmol, Eq: 1.00) in trifluoroacetic acid (25.4 g, 17.2 ml, 223 mmol, Eq: 72) was added methanesulfonic acid (2.98 g, 2.01 ml, 31.0 mmol, Eq: 10) and the mixture was stirred at 23° C. for 20 hours. The light brown solution was poured cautiously into sat NaHCO3 solution, extracted with ethyl acetate, washed the organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left a light brown oil (910 mg, ca. 90% purity; 100%). The crude product either chromatographed on amine-coated silica gel using n-heptane and ethyl acetate or was used in the next step without further purification. MS (ISP): m/z=264.1 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:16]([O:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[C:22]=1B1OC(C)(C)C(C)(C)O1)[CH2:17][CH2:18][CH3:19]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:22]3[C:23]4[O:27][CH2:26][O:25][C:24]=4[CH:28]=[CH:29][C:21]=3[O:20][CH2:16][CH2:17][CH2:18][CH3:19])[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCCCOc1ccc2c(c1B1OC(C)(C)C(C)(C)O1)OCO2
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCCCOc1ccc2c(c1-c1ncnc3c(C(=O)OCC)c[nH]c13)OCO2

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 5-butoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole (example A33) the title compound is obtained as colorless solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:25]1[CH2:31][CH:30]2[NH:32][CH:27]([CH2:28][CH2:29]2)[CH:26]=1.C(O)(=O)C(O)=O>CCO>[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:25]1[CH2:26][CH:27]2[N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:7]=3[CH:8]=[CH:9][NH:10]4)[CH:30]([CH2:29][CH2:28]2)[CH:31]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: C1=C(c2ccc3ccccc3c2)CC2CCC1N2
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: C1=C(c2ccc3ccccc3c2)CC2CCC1N2CCCOc1cccc2[nH]ccc12

Procedure:
The title compound is prepared according to the procedure of Example 2, Step 3, except that 4-(3-chloropropoxy)-1H-indole is used in place of 4-(2-chloro-ethoxy)-1H-indole and 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-2-ene is used in place of 3-(8-aza-bicyclo[3.2.1]oct-2-en-3-yl)-1H-indole. The corresponding oxalate salt is prepared by treating the title compound with 1 equiv. of oxalic acid in EtOH. Yield: 35% of a white solid. mp: 118-123° C.; MS (ES) m/z: 409.3 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[S:16]([N:19]=C=O)(=[O:18])=[O:17].C1(C)C=CC=CC=1>C1C=CC=CC=1>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([O:1][S:16](=[O:18])(=[O:17])[NH2:19])=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)Oc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 77.6 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 10.4 g (0.05 mole) of 5-hydroxy-2-nitrobenzotrifluoride, 7.8 g (0.055 mole) of chlorosulfonyl isocyanate and 75 ml of toluene gave 11.1 g (78%) of tan solid, mp 95°-97° C. (benzene).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.O.[Na].Cl[C:15]1[N:20]=[C:19]([OH:21])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1>C(O)C.[Ni].O>[OH:21][C:19]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=[C:15]([NH:9][C:6]2[CH:5]=[N:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[N:20]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1O
Reactant: CSc1ccc([N+](=O)[O-])cn1
Agent: [Ni]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CSc1ccc(Nc2ncc([N+](=O)[O-])c(O)n2)cn1

Procedure:
4.5 gm (0.0264 mol) of 2-methylthio-5-nitro-pyridine were hydrogenated at 50° C. and 5 bars pressure in ethanol in the presence of Raney nickel as the catalyst. After the catalyst had been filtered off and after evaporation of the filtrate in vacuo an oil was obtained. A solution of 6.84 gm (0.032 mol) of the sodium monohydrate salt of 2-chloro-4-hydroxy-5-nitro pyrimidine in 150 ml of water was added to the solution of this oil in water. The aqueous solution was heated for 30 minutes on a steam bath, and the resulting precipitate suction-filtered off, washed with water and dried. 4-Hydroxy-2-(6'-methylmercapto-3-pyridyl)amino-5-nitro-pyrimidine was obtained.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[F-].[K+].O1CCOCC1.C([Sn](CCCC)(CCCC)[C:37]1[S:38][CH:39]=[CH:40][N:41]=1)CCC>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:37]3[S:38][CH:39]=[CH:40][N:41]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(-c3nccs3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine (49.0 mg, 0.117 mmol), KF (44 mg, 0.75 mmol), and Pd(PPh3)4 (13 mg, 0.011 mmol) in 1,4-dioxane (1.0 mL, 13 mmol) in a microwave reactor vial was evacuated and refilled with nitrogen (3×). 2-Tributylstannylthiazole (50 μL, 0.16 mmol) was added, and the reaction mixture was heated to 100° C. for 45 min in a microwave reactor. Further 2-tributylstannylthiazole (50 μL, 0.16 mmol) was added, and the reaction mixture was heated to 100° C. for 45 min. The reaction mixture was diluted with DCM and washed with water. The DCM solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was redissolved in MeOH and pre-purified by passing through a thiol SPE cartridge (500 mg/6 mL, PL-Thiol MP SPE+). The material from the thiol SPE treatment was chromatographed on silica gel [10 g/70 mL cartridge, eluting with DCM→10% EtOAc in DCM→15% EtOAc in DCM→20% EtOAc in DCM]. Fractions containing product were combined, concentrated in vacuo, chromatographed on a SCX column (1 g/6 mL cartridge), and the fraction that eluted with NH3/MeOH was concentrated and dried in vacuo to give the title compound as pale yellow film. 1H NMR (CDCl3, 400 MHz): δ=8.61 (s, 1H), 8.00 (s, 1H), 7.91 (d, J=3.2 Hz, 1H), 7.37 (d, J=3.2 Hz, 1H), 7.29 (dd, J=4.4, 8.4 Hz, 1H), 7.06 (dd, J=8.4, 9.2 Hz, 1H), 6.56 (q, J=6.8 Hz, 1H), 4.83 (brs, 2H), 1.89 (d, J=6.8 Hz, 3H). MS (ES+): m/z=423.96/425.90/427.93 (100/95/27) [MH+], 234.03 (30) [MH+−3-F-2,6-di-Cl-Ph-CH═CH2]. HPLC: tR=3.65 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:31])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][C:18]3[S:22][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[N:25]=4)=[N:20][CH:19]=3)[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:31])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][C:18]3[S:22][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[N:25]=4)=[N:20][CH:19]=3)[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(C(=O)c2cccc(Sc3cnc(Nc4cccc(Br)n4)s3)c2)CC1
Reactant: C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CCN(C(=O)c2cccc(Sc3cnc(Nc4cccc(N5CCCCC5)n4)s3)c2)CC1
Yield: 83.1 %

Procedure:
A solution of Example 4 (30 mg, 0.058 mmol), piperidine (86 μL, 0.87 mmol), 4-dimethylaminopyridine (7.1 mg, 0.058 mmol) in pyridine (300 μL) was heated to 134° C. in a sealed vial under nitrogen for 8.75 h. Most of pyridine was removed on a speed-vac at 40° C. The residue was purified using reversed phase automated preparative HPLC (conditions: YMC S5 ODS A 20×100 mm column, 15 min gradient starting from 10% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 90% solvent A (10% MeOH, 90% H2O, 0.1% TFA) to 90% solvent B and 10% solvent A, flow rate 20 mL/min, λ=220 nM) to obtain the titled compound (25.2 mg, 68%) as a light tan solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH2:11][F:12])[CH:10]=1)[CH2:6][OH:7].N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[Si:22]([O:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[C:9]([CH2:11][F:12])[CH:8]=1)[CH2:2][NH2:1])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCc1cc(CO)cc(CF)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(CN)cc(CF)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
3-Aminomethyl-5-fluoromethylbenzylalcohol (38) (520 mg, 3.07 mmol) and imidazole (923 mg, 13.6 mmol) were dissolved in DMF (15.5 mL). The air was evacuated from the reaction system, and then Ar was charged therein. To the solution was added TBDMSCl (1.03 g, 6.83 mmol), and dissolved. Again the air was evacuated from the reaction system, and then Ar was charged therein. The mixture was stirred for 18 hours at a room temperature. TLC was used to confirm the progress of the reaction. The reaction mixture was extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=1:1) to isolate 3-(t-butyldimethylsilyloxy)methyl-5-fluoromethylbenzylamine (41) (661 mg, 76%) as a colorless oil.
Reaction SMILES: C(OC([NH:8][C:9]([NH:23]C(OC(C)(C)C)=O)=[N:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][N:17]=2)[CH2:12]1)=O)(C)(C)C.[ClH:31]>ClCCl.O1CCOCC1>[ClH:31].[ClH:31].[CH3:22][C:20]1[CH:19]=[CH:18][N:17]=[C:16]([N:13]2[CH2:14][CH2:15][CH:11]([NH:10][C:9]([NH2:23])=[NH:8])[CH2:12]2)[CH:21]=1
Reactant: Cc1ccnc(N2CCC(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccnc(N2CCC(NC(=N)N)C2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(1-(4-methylpyridin-2-yl)pyrrolidin-3-yl)guanidine (210 mg) in dichloromethane (4 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at ambient temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 10% methanol in ethyl acetate (50 ml). The resultant precipitate was collected by filtration and dried under reduced pressure to give (1-(4-methylpyridin-2-yl)-pyrrolidin-3-yl)guanidine dihydrochloride (140 mg).
Reaction SMILES: C[O:2][C:3](=[O:42])[C@@H:4]1[CH2:8][CH:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:27]5[O:28][C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=6[C:26]=5[CH:25]=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:35]([O:37]C(C)(C)C)=[O:36].[OH-].[K+].Cl.[CH2:46]1[CH2:50]O[CH2:48][CH2:47]1>CO.C(OCC)(=O)C>[CH:25]1[C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][C:27]=2[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH:7]4[CH2:6][N:5]([C:35]([O:37][CH2:50][CH2:46][CH2:47][CH3:48])=[O:36])[C@H:4]([C:3]([OH:2])=[O:42])[CH2:8]4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H]1CC(Oc2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CN1C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CC(Oc2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)C[C@H]1C(=O)O
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-tert-butoxycarbonyl-proline methyl ester (400 mg, 0.71 mmol) in THF (3 mL) and methanol (4 mL) was cooled to 0° C. and treated with 2 N KOH (1.25 mL). After stirring at room temperature for 1 H the solution was acidified with 10% HCl to pH 2 and diluted with 25ml of ethyl acetate. After being separated, the aqueous layer was extracted with ethyl acetate (3×15 mL) and the combined organic layers were dried over MgSO4 and concentrated. Purification by flash column chromatography (2-5% methanol in dichloromethane) provided 4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-butoxycarbonyl-proline (320 mg, 82%) as pale yellow solid. 0.320 g (yield 82.1%). 1H NMR (DMSO-d6), δ 8.16 (dd, J=8, 12 Hz, 2H), 7.98 (d, J=9 Hz, 2H), 7.80 (m, 6H), 7.47 (m, 3H), 6.97 (d, J=9 Hz, 2H), 5.08 (m, 1H), 4.29 (t, J=9 Hz, 1H), 3.72 (m, 1H), 3.42 (dd, J=6, 9 Hz, 1H), 2.62 (m, 1H), 2.20 (m, 1H), 1.44 (s, 9H). LCMS 450 (M+−100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C([N:24](CC)CC)C.N>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:11]([NH2:24])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(Cl)nc2)CC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC(=O)C1(c2ccc(Cl)nc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 1-(6-chloropyridin-3-yl)cyclopropanecarboxylic from Step 4 (1.0 g) in chloroform (50 mL) were slowly added isobutyl chloroformate (800 μL) and triethylamine (920 μL). The reaction mixture was stirred at 0° C. for 2 hours. Then it was saturated with ammonia gas and stirred at 0° C. for 10 minutes. The reaction mixture was allowed to stand at room temperature for 1 hour then poured into water (80 mL) and partitioned. The aqueous layer was extracted with dichloromethane (2×80 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by swish using diethyl ether and hexanes to yield the title compound.
Reaction SMILES: [C:1]1([CH3:54])[CH:6]=[CH:5][C:4]([S:7]([S:10][C@H:11]2[N:14]([C:15](=[C:32](OS(C(F)(F)F)(=O)=O)[CH3:33])[C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[C:13](=[O:42])[C@H:12]2[NH:43][C:44](=[O:53])[CH2:45][O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C>O1CCCC1>[C:1]1([CH3:54])[CH:6]=[CH:5][C:4]([S:7]([S:10][C@H:11]2[N:14]([C:15](=[C:32]=[CH2:33])[C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[C:13](=[O:42])[C@H:12]2[NH:43][C:44](=[O:53])[CH2:45][O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: CC(OS(=O)(=O)C(F)(F)F)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1

Procedure:
Embodiment a: A solution of diphenylmethyl 2-[(3R,4R)-4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-trifluoromethanesulfonyloxy-2-butenoate (XXa, 0.300 g, 0.00036 mole) in dry tetrahydrofuran (3 mL) was treated with triethylamine (0.077 mL, 0.00036 mole) for 1 h at room temperature. Reverse-phase chromatography (C-18 column, eluting with 65% acetonitrile--35% of 0.01M phosphate pH 6.5 buffer) showed complete consumption of the starting material after 45 min with formation of a single, faster-eluting product. 0.05M sulfuric acid and ethyl acetate was added to the reaction mixture, followed by separating the two phases. The organic phase was dried with sodium sulfate and evaporated to give diphenylmethyl 2-[(3R,4R)-4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-2,3-butadienoate (Ia) as a colorless foam (0.245 g, quantitative).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]([CH:21]1[CH2:23][CH2:22]1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[NH2:24][CH:19]([CH:21]1[CH2:23][CH2:22]1)[C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=1
Reactant: O=c1c2ccc(Cl)n2nc(C(O)C2CC2)n1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 3-benzyl-7-chloro-2-(cyclopropyl-hydroxy-methyl)-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 17 G, 0.10 g, 0.29 mmol) and sodium azide (30 mg, 0.46 mmol) in DMF (2 mL) was stirred at rt under nitrogen overnight. The reaction mixture was diluted with EtOAc to 40 mL, washed with water and brine, dried over MgSO2 and concentrated to a pale oil. The oil was dissolved in THF (6 mL) and water (0.2 mL), flushed with nitrogen and treated with triphenylphosphine (0.15 g, 0.58 mmol). The reaction mixture was heated at 66° C. for 5 h. The solvents were removed under reduced pressure. Purification of the residue by flash column chromatography (SiO2, EtOAc/hexane/MeOH/NH4OH 500:500:50:5) gave the title compound as a colorless oil (69 mg, 73%): 1H NMR (CDCl3) δ 7.35 (m, 4H), 7.22 (d, 1H, J=7.7 Hz), 7.11 (m, 1H), 6.54 (m, 1H), 5.65 (m, 1H), 5.37 (m, 1H), 3.73 (m 1H), 2.00 (m, 1H),1.60 (m, 1H), 1.33 (m, 1H), 0.58 (m, 1H), 0.29 (m, 2H); MS (ESI+) 329.09, 331.07 (M++H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[O:32][N:31]=[C:30]([CH2:33][NH2:34])[CH:29]=2)[CH:23]=1>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:34][CH2:33][C:30]1[CH:29]=[C:28]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[O:32][N:31]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCc1cc(-c2cccnc2)on1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCc1cc(-c2cccnc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
4-Chloro-3-nitroquinoline (2.09 g, 9.99 mmol) and triethylamine (2.10 mL, 15.0 mmol) were sequentially added to a solution of (5-pyridin-3-ylisoxazol-3-yl)methylamine (2.09 g, 9.99 mmol) in dichloromethane, and the solution was stirred overnight at room temperature. The resultant red solution was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 2% to 5% methanol in dichloromethane) to provide 1.17 g of 3-nitro-N-[(5-pyridin-3-ylisoxazol-3-yl)methyl]quinolin-4-amine as a yellow-orange solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:33]2[CH2:36][CH:35]([N:37]([CH3:39])[CH3:38])[CH2:34]2)=[CH:9][C:10]([O:31][CH3:32])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[C:17]([C:29]#[N:30])=[CH:16][N:15]=2)[CH:12]=1>C(Cl)Cl.CO>[C:29]([C:17]1[C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:31][CH3:32])=[CH:9][C:8]([N:33]3[CH2:36][CH:35]([N:37]([CH3:38])[CH3:39])[CH2:34]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:30]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(C#N)c(-c2cnn3ccccc23)n1
Solvent: CO
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of acryloyl chloride (0.025 mL, 0.31 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 2-{[5-amino-4-(3-dimethylaminoazetidin-1-yl)-2-methoxyphenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile (Intermediate 122, 136 mg, 0.30 mmol) in CH2Cl2 (15 mL), which was cooled in an ice bath to approximately 0° C. The mixture was stirred for 1 h, and was then diluted with iii CH2Cl2 (50 mL) and methanol (to fully dissolve suspension). This solution was then washed with sat. NaHCO3 (100 mL) which had been diluted with water (10 mL). The aqueous wash solution was then extracted with CH2Cl2 (2×50 mL) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (136 mg, 89%) as a yellow solid; 1H NMR: 2.10 (6H, s), 3.05-3.13 (1H, m), 3.62 (2H, t), 3.74 (3H, s), 4.00 (2H, s), 5.67 (1H, d), 6.17 (1H, d), 6.27 (1H, s), 6.45 (1H, dd), 7.16 (1H, br s), 7.25 (1H, s), 7.42 (1H, br s), 7.95 (1H, br s), 8.68 (1H, s), 8.87 (1H, br s), 8.91 (1H, s), 9.28 (1H, s), 9.32 (1H, br s); m/z: ES+ MH+ 510.18.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:3]=1.C(Cl)Cl.CC(C[AlH]CC(C)C)C>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([O:12][CH2:13][CH2:14][O:15][CH3:16])[N:3]=1
Reactant: COCCOc1cc(C(=O)OC)nc(Cl)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: COCCOc1cc(C=O)nc(Cl)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 106 %

Procedure:
A 25 mL round bottomed flask was charged with methyl 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carboxylate [SAD105-047F1] (45 mg, 1 equiv.) and CH2Cl2 (1 mL). 1 M DIBAL-H (0.2 mL, 1.1 equiv.) was added at −78° C. over 2 min under argon. The reaction mixture was stirred for 3 h at −78° C. but the LC-MS still showed a lot of starting material. Additional 1 M DIBAL-H (0.27 mL, 1.4 equiv.) was added at −78° C. over 2 min under argon and after 0.5 h LC-MS showed no more starting material but mostly 1 peak at 1.20 min (M+1=217, M+1+MeOH=249). The reaction mixture was quenched with MeOH (0.5 mL) and then with 10% NH4Cl (1 mL). The reaction mixture was warmed to RT and then the solvent was concentrated under reduced pressure. The residue was diluted with 10% NH4Cl (4 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide 41.9 mg of the crude 2-chloro-6-(2-methoxyethoxy)pyrimidine-4-carbaldehyde as a yellow oil which was used in the next step without further purification, (H NMR δ: 9.91 (s, 1H); 7.23 (s, 1H); 4.59-4.64 (m, 2H), 3.7-3.8 (m, 2H); 3.44 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[C:4]([F:11])[CH:3]=1.P(Br)(Br)[Br:13]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Br:13])[CH3:9])=[C:4]([F:11])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc(Br)cc1F
Solvent: ClCCl
Product: CC(Br)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 145.6 %

Procedure:
A solution of 1-(4-bromo-2-fluorophenyl)ethanol (8.95 mmol) in dichloromethane (40 mL) at 0° C. was treated dropwise with a solution of phosphorus tribromide (3.58 mmol) in dichloromethane (10 mL). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solution was concentrated to a residue in vacuo. Purification of the residue by silica gel chromatography (hexanes) yielded the title compound as a clear oil (1.47 g, 58.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.00 (d, J=6.82 Hz, 3 H) 5.58 (q, J=7.07 Hz, 1 H) 7.47 (dd, J=8.34, 1.77 Hz, 1 H) 7.57-7.65 (m, 2 H).