Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:21]([O:22][C@H:23]2[O:55][C@H:54]([CH2:56][O:57][C:58](=[O:65])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C@@H:44]([O:45][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:34]([O:35][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:24]2[O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:20]([O:66][C:67](=[O:74])[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C@@H:19]([CH2:75][O:76]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:9][C@H:10]1[C@@H:21]([O:22][C@H:23]2[O:55][C@H:54]([CH2:56][O:57][C:58](=[O:65])[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C@@H:44]([O:45][C:46](=[O:53])[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C@H:34]([O:35][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:24]2[O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:20]([O:66][C:67](=[O:74])[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C@@H:19]([CH2:75][OH:76])[O:18][C@@H:11]1[O:12][CH2:13][CH2:14][N:15]=[N+:16]=[N-:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCCO[C@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H](O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NCCO[C@H]1O[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H](O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 50 mL round bottom flask was added 2-azidoethyl 2,4-di-O-benzoyl-3-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl)-6-O-trityl-α-D-mannopyranoside (450 mg, 0.352 mmol) and CH2Cl2 (3 mL). To the above solution was added TFA (3 mL, 38.9 mmol). After stirring at 25° C. for 1 hr, the reaction mixture was diluted with CH2Cl2 (10 mL), washed with water (3×15 mL) and brine (10 mL). The organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (40 g), eluting with 0-100% EtOAc in hexanes, to give the title product. LC-MS Method A: m/e=1053.57 [M+18]; Rt=2.73 min. 1H NMR (CDCl3) δ 7.0-8.5 (m, 45H), 6.1 (t, 1H), 6.0 (t, 1H), 5.7 (m, 2H), 5.4 (s, 1H), 5.3 (s, 1H), 5.25 (s, 1H), 4.6 (m, 2H), 4.5 (m, 1H), 4.3 (m, 1H), 4.0-4.2 (m, 3h), 3.8 (m, 1H), 3.3-3.5 (m, 3H).
Reaction SMILES: [CH2:1](N)C.Cl[C:5]1[C:14]([C:15]([C:17](=[CH:23][N:24](C)[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([Cl:28])=[C:10]([F:27])[CH:11]=2)[N:6]=1.C1CCN2C(=NCCC2)CC1>C(O)C>[Cl:28][C:9]1[C:10]([F:27])=[CH:11][C:12]2[C:7]([CH:8]=1)=[N:6][C:5]1[N:24]([CH2:25][CH3:1])[CH:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:15](=[O:16])[C:14]=1[CH:13]=2
Reactant: CCN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc3cc(Cl)c(F)cc3cc2c1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
Ethylamine (16 g) is added in the course of 5 minutes at between 10° and 15° C. to a stirred suspension of ethyl 2-(2,7-dichloro-6-fluoro-3-quinolinecarbonyl)-3-(dimethylamino)acrylate (13.5 g) in ethanol (135 cc), the temperature is allowed to rise to approximately 20° C., DBU (0.5 g) is added and the mixture is heated with stirring for 2 hours to a temperature in the region of 75° C. After cooling to a temperature in the region of 20° C., the precipitate is drained and washed with ethanol (2×100 cc) and ethyl ether (2×100 cc). 8-Chloro-3-ethoxycarbonyl-1-ethyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1, 8]naphthyridine (10.4 g) is obtained in the form of a yellow solid, m.p. 300°-301° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [C:1]1(C)C=CC=C[CH:2]=1.[C:8]1([CH:15]=[CH:14][CH:13]=[C:11]([OH:12])[CH:10]=1)[OH:9].[C:16]([OH:24])(=O)[C:17]([CH2:19][C:20]([OH:22])=[O:21])=[CH2:18]>CCCCCC.C(OCC)(=O)C>[OH:9][C:8]1[CH:10]=[C:11]2[C:13]([CH2:18][CH:17]([CH2:19][C:20]([O:22][CH2:1][CH3:2])=[O:21])[C:16](=[O:24])[O:12]2)=[CH:14][CH:15]=1
Reactant: Oc1cccc(O)c1
Reactant: Cc1ccccc1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)CC1Cc2ccc(O)cc2OC1=O
Reaction time: 2 h
Yield: 46 %

Procedure:
100 ml of toluene were admixed with 4.4 g (0.04 mol) of resorcinol and 6.32 g (0.04 mol) of the ethyl monoester of itaconic acid, and also 8.8 g of Amberlyst 15 resin from Aldrich. The reaction mixture was stirred for 2 hours and then filtered off to cooling. The filtrate was concentrated and purified by flash chromatography on a silica column (eluent CH2Cl2: MeOH=50:1), to give, following recrystallization from a 3/1 hexane/ethyl acetate mixture, 4.6 g (46% yield) of the expected lactone C2 in the form of a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])C(OCC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].CS(C)=O>O>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[N:16]=[CH:17][C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:1]2[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=CNc1ccc(Cl)cc1C(=O)c1ccccc1)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cnc2ccc(Cl)cc2c1-c1ccccc1
Yield: 70 %

Procedure:
A mixture of diethyl (2-benzoyl-4-chlorophenyl)aminomethylenemalonate (7.0 g), lithium chloride (3.7 g) and dimethyl sulfoxide (70 ml) was heated for 1.5 hrs. at 180° C. The mixture was diluted with water to give ethyl 6-chloro-4-phenyl-3-quinolinecarboxylate as crystals (3.8 g, 70.0%), which was recrystallized from ethanol as needles. m.p. 123°-124° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CN(C)C=O.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>O>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: ClCCN1CCOCC1
Reactant: Sc1ccccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1SCCN1CCOCC1
Temperature: 100 °C

Procedure:
Potassium carbonate (10.95 g) and 2-chloroethylmorpholine hydrochloride (5.9 g) were mixed with dimethylformamide (56 ml) and 2-bromothiophenol was added before the mixture was heated to 100° C. for 3 days. The mixture was allowed to cool before water (500 ml) was added. The product was extracted into diethyl ether (×3). The combined extracts were dried over sodium sulphate and filtered before evaporation. The product was purified by column chromatography eluting with ethyl acetate/hexane mixtures to give a red/brown oil (6.024 g).
Reaction SMILES: [SH:1][CH:2](O)C.[NH2:5][C:6]1[CH:11]=[N:10][C:9](Br)=[CH:8][N:7]=1.CN(C)[CH:15]=[O:16]>O.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>[NH2:5][C:6]1[N:7]=[CH:8][C:9]([S:1][CH2:2][CH2:15][OH:16])=[N:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: Nc1cnc(Br)cn1
Reactant: CC(O)S
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Nc1cnc(SCCO)cn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
Based on the method described in WO2004/052869, mercaptoethanol (0.93 mL) and tetrakis(triphenylphosphine)palladium (3.39 g) were added to a solution of 1.00 g of 2-amino-5-bromopyrazine (5.75 mmol) in N,N-dimethylformamide (15.1 mL), and the resulting mixture was heated and stirred in a sealed tube for about 3 hours at 120° C. After cooling, the reaction mixture was diluted with water, and then extracted (100 mL×6) with a mixed liquid (methylene chloride:ethanol=5:1). The organic layer was dried over anhydrous sodium sulfate, then filtered, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate, and then ethyl acetate:methanol=10:1), then recrystallized (chloroform) to obtain 470 mg of the title compound (yield 44%) as yellow needle-like crystals.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8](COCCOC)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][CH2:30][N:31]([CH3:41])[C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:11])=[O:10])[O:4][N:3]=1.[Si](Cl)(C)(C)C.[Na+].[I-].O>CC#N.CCOC(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:20][C:19]=2[CH2:29][CH2:30][N:31]([CH3:41])[C:32](=[O:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:10])=[O:11])[O:4][N:3]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CCN(C)C(=O)Cc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CCN(C)C(=O)Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title compound of Step (B) in 1.5 ml of CH3CN, Me3SiCl (34 mg, 0.32 mmol) was added and followed by NaI (48 mg, 0.32 mmol). The mixture was stirred at room temperature for 0.5 hr. Additional Me3SiCl (46 mg, 0.42 mmol) and NaI (63 mg, 0.42 mmol) were added in three portions and the reaction mixture was stirred for additional 1 hr and 45 min. The mixture was then added to 2 ml H2O and 20 ml EtOAc. The organic layer was washed with 1 ml sat. Na2 S2O3, brine, dried and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 30% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 70% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (7 mg, 23% for two steps) as a white solid, m.p. 98°-106° C. (amorphous).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>O1CCCC1.C(Cl)Cl>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:17][CH3:16])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)N1CC(Oc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 129.3 %

Procedure:
A solution of 4.6 g (0.02 mole) of 3-(4-fluorophenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was stirred while 6.2 g (0.08 mole) of 40% aqueous methylamine was added. The reaction mixture was exothermic and was allowed to cool to ambient temperature while stirring for 18 hr. The reaction mixture was diluted with 200 ml of ice water and the oil droplets which separated quickly crystallized. Filtration yielded 6.6 g of crude product. The solid was dissolved in 100 ml of methylene chloride, treated with 15 g of silica gel and stirred for 2 hr. The silica gel was removed by filtration and washed with 200 ml of 50/50 ethyl acetatemethylene chloride. The combined filtrates were concentrated on a rotary evaporator, yielding 5.8 g of solid residue. The solid was recrystallized by dissolving in 22 ml of acetone and adding 88 ml of isopropyl ether. The volume was reduced to 40 ml by boiling under nitrogen atmosphere and upon cooling the product crystallized. Filtration yielded 2.95 (66.7%) of white crystals, m.p. 140°-142° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[O:39]=[S:40]1(=[O:49])[CH2:45][CH2:44][N:43]([CH2:46][CH2:47]O)[CH2:42][CH2:41]1>>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:47][CH2:46][N:43]1[CH2:44][CH2:45][S:40](=[O:49])(=[O:39])[CH2:41][CH2:42]1)[CH:5]=2
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: O=S1(=O)CCN(CCO)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Reaction time: 2 h
Yield: 29 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(1,1-dioxothiomorpholin-4-yl)ethanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 2 h to obtain the title compound (29%).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:12]1[CH2:38][CH2:37][CH2:36][C:14]2([O:18][CH2:17][CH:16]([C:19]3[CH:24]=[C:23]([N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[C:30]([F:33])([F:32])[F:31])[CH:22]=[CH:21][C:20]=3[O:34][CH3:35])[CH2:15]2)[CH2:13]1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].O>C(O)C>[OH:5][CH:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][N:12]1[CH2:38][CH2:37][CH2:36][C:14]2([O:18][CH2:17][CH:16]([C:19]3[CH:24]=[C:23]([N:25]4[CH:29]=[CH:28][N:27]=[C:26]4[C:30]([F:32])([F:33])[F:31])[CH:22]=[CH:21][C:20]=3[O:34][CH3:35])[CH2:15]2)[CH2:13]1
Reactant: COc1ccc(-n2ccnc2C(F)(F)F)cc1C1COC2(CCCN(CC(=O)c3ccccc3)C2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-n2ccnc2C(F)(F)F)cc1C1COC2(CCCN(CC(O)c3ccccc3)C2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
Sodium borohydride (12 mg, 0.32 mmol) was added to a solution of (±)-(3R*, 5R*)-7-phenacyl-3-(2-methoxy-5-(2-trifluoromethyl-1H-imidazol-1-yl)phenyl)-1-oxa-7-azaspiro[4,5]decane (105.9 mg, 0.212 mmol) in ethanol (2 ml) and the mixture stirred at room temperature for 4 hours. The mixture was poured into water (50 ml) and extracted with ethyl acetate (2×20 ml). The extracts were washed with brine (20 ml), combined, dried (MgSO4) and concentrated. The residue was purified by flash chromatography, eluting with 5% then 7.5% methanol in dichloromethane to give (±)-(3R*, 5R*, 12S*/R*)-7-(2-hydroxy-2-phenylehtyl)-3-(2-methoxy-5-(2-trifluoromethyl-1H-imidazol-1-yl)phenyl)-1-oxa-7-azaspiro[4,5]decane (86.0 mg, 81%). The free base was dissolved in ether and treated with oxalic acid (15.7 mg) in ether. The resulting precipitate was collected under suction, washed with ether and dried in vacuo to afford the title compound (75.1 mg); (Found: C, 58.89; H, 5.11; N, 6.87. C27H30F3N3O3. C2H2O4 requires C, 58.88; H, 5.45; N, 7.10%; δH (360 MHz, D2O) 1.72-2.37 (6H, m), 3.11 (2H, m), 3.34-3.96 (10H, m), 4.27 (1H, m), 5.25 (1H, m), 7.13 (1H, d, J 9.3 Hz, 3'-H), 7.22 (1H, br s, imidazole H), 7.36 (3H, m, ArH), 7.47 (5H, m, ArH); m/z (ES+) 502 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[Cl:12].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C)C=O.O>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:5]2[CH:4]=[C:3]([Cl:12])[C:2]([Cl:1])=[CH:7][C:6]=2[N+:8]([O-:10])=[O:9])[CH:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNC(CC(=O)O)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)c(Cl)cc2[N+](=O)[O-])C(CC(=O)O)C1
Temperature: 50 °C

Procedure:
1,2-Dichloro-4-fluoro-5-nitrobenzene (0.125 mL, 0.952 mmol) and 2-(4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (256 mg, 1.048 mmol) were dissolved in N,N-dimethylformamide (2 mL) and water (1 mL). Triethylamine (0.398 mL, 2.86 mmol) was slowly added. The resulting mixture was heated at 50° C. overnight. The mixture was concentrated and ethyl acetate was added. 1N HCl was then added slowly until the pH=6. The water layer was separated and washed multiple times with ethyl acetate. The organic layers were then combined and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 10% to 50% of ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.32 (br, 1H), 8.17 (s, 1H), 7.69 (s, 1H), 3.36-3.90 (m, 4H), 2.97-3.29 (m, 2H), 2.88 (dd, J=8.92, 3.37 Hz, 1H), 2.18-2.47 (m, 2H), 1.41 (s, 9H); MS (DCI+) m/z 434.1 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:28][CH2:27]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NC2CC2)nn1
Yield: 82 %

Procedure:
As described for example 69, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.29 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (85 mg, 82%) which was obtained as a light brown solid. MS: m/e=352.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[C:14]1([CH2:20][C:21](O)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>>[OH2:12].[ClH:9].[CH2:20]([C:21]1[NH:4][C:3]2[CH:5]=[C:6]([S:10](=[O:12])(=[O:13])[NH2:11])[C:7]([Cl:9])=[CH:8][C:2]=2[N:1]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: Cl
Product: NS(=O)(=O)c1cc2[nH]c(Cc3ccccc3)nc2cc1Cl
Product: O
Yield: 80.5 %

Procedure:
A mixture of 12.0 g of 2-amino-4-chloro-5-sulfamylaniline, 29.5 g of phenylacetic acid, and 54.5 ml of a 15% hydrochloric acid solution was refluxed for 6 hours and the blue precipitate collected by filtration. The crude product was dissolved in hot methanol and the organic solvent then treated with charcoal. Filtration followed by conc. in vacuo gave crystals which upon trituration with methanol and drying provided 8.2 g of pink crystals, m.p. 176°-180° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([O-])=O.Cl.[CH2:9]([C:11]1[N:12](C(OCC(C)C)=O)[C:13]2[C:14]([N:30]=1)=[N:15][CH:16]=[C:17]([C:19]1[CH:20]=[CH:21][C:22]3[O:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]=3[CH:29]=1)[CH:18]=2)[CH3:10].Cl[C:39]1[C:48]2[CH2:47][C:46]([CH3:50])([CH3:49])[CH2:45][CH2:44][C:43]=2[N:42]=C[N:40]=1>>[CH2:9]([C:11]1[NH:12][C:13]2[C:14]([N:30]=1)=[N:15][CH:16]=[C:17]([C:19]1[CH:20]=[CH:21][C:22]3[O:28][CH2:27][CH2:26][N:25]([C:39]4[C:48]5[CH2:47][C:46]([CH3:50])([CH3:49])[CH2:45][CH2:44][C:43]=5[N:42]=[C:3]([CH3:2])[N:40]=4)[CH2:24][C:23]=3[CH:29]=1)[CH:18]=2)[CH3:10]
Reactant: O=C([O-])C(F)(F)F
Reactant: CC1(C)CCc2ncnc(Cl)c2C1
Reactant: CCc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Agent: Cl
Product: CCc1nc2ncc(-c3ccc4c(c3)CN(c3nc(C)nc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared as trifluoroacetate salt according to the method of example 6 by using 2-methylpropyl 2-ethyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate hydrochloride (reagent preparation 19) and 4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin (reagent preparation 8) in step 3. 1H NMR (400 MHz, methanol-d4): 8.67 (d, 1H), 8.19 (d, 1H), 7.76 (s, 1H), 7.57 (d, 1H), 7.09 (d, 1H), 5.13 (s, 2H), 4.45 (m, 2H), 4.31 (m, 2H), 3.09 (m, 2H), 2.81 (m, 2H), 2.57 (s, 2H), 2.50 (s, 3H), 1.68 (m, 2H), 1.48 (m, 3H), 0.94 (s, 6H); MS (EI) for C28H32N6O: 469 (MH+).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[CH2:12]([N:14]([CH2:18][CH3:19])[C:15](=[S:17])[S-:16])[CH3:13].[Na+]>C1COCC1>[CH3:13][CH2:12][N:14]([C:15]([S:17][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[S:16])[CH2:18][CH3:19]
Reactant: BrCc1ccccc1
Reactant: CCN(CC)C(=S)[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=S)SCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Benzyl bromide (2.05 g, 12 mmol) in THF (10 mL) was added dropwise over 15 minutes to a supension of sodium N,N-diethyldithiocarbamate trihydrate (2.25 g, 10 mmol) in 25 mL of THF at room temperature. The solution was allowed to stir at room temperature for 3 hours when the solids were filtered off and the filtrate concentrated. The crude residue was purified by column chromatography (silica gel, 20% ethyl acetate in petroleum spirits) to obtain the title compound (2.25 g, 94%). 1H-nmr (CDCl3) δ 1.3 (6H), 3.7 (2H), 4.1 (2H), 4.6 (2H), 7.3 (5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=1[F:22].C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:19]2[CH:18]=[CH:17][C:16]([F:22])=[C:15]([Cl:14])[CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(I)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(F)c(Cl)c2)C1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a 50 ml of isopropyl alcohol solution containing 15.0 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (80.5 mmol) and 24.8 g of 2-chloro-1-fluoro-4-iodobenzene (96.7 mmol) were added 1.54 g of copper (I) iodide (8.1 mmol), 9.0 ml of ethylene glycol (10.1 mmol) and 34.2 g of potassium phosphate (161 mmol), and heated under reflux under a nitrogen atmosphere for 46 hours. The reaction solution was cooled to room temperature and filtered using Celite. The substance remained in the filter was washed with ethyl acetate and the filtrate was concentrated under reduced pressure together with the washings, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether to thereby obtain 15.9 g of white powdery 3(S)-(3-chloro-4-fluorophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:17])[N:6]([CH2:13][C:14]([OH:16])=[O:15])[C:7]2=[O:12].[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:15][C:14](=[O:16])[CH2:13][N:6]1[C:5](=[O:17])[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[C:7]1=[O:12]
Reactant: COc1cccc2c1C(=O)N(CC(=O)O)C2=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cccc2c1C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Yield: 41.4 %

Procedure:
To a solution of 2-(4-methoxy-1,3-dioxoisoindolin-2-yl)acetic acid (30 mg, 0.128 mmol) in DCM (3 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (53.6 mg, 0.128 mmol), EDC (73.4 mg, 0.383 mmol) and DMAP (15.58 mg, 0.128 mmol) were added, and the mixture was reacted overnight at room temperature. The solvent was removed, and the resulting crude was purified by flash chromatography on silica gel (DCM:MeOH=98:2) recovering the title compound (33.7 mg, 0.053 mmol, 41% yield). MS/ESI+ 637.34 [MH]+; [αD]=−12.96, c=0.25 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.85 (dd, 1H), 7.54 (d, 1H), 7.46 (dd, 1H), 7.18 (d, 1H), 7.06 (d, 1H), 6.95 (dd, 1H), 7.08 (t, 1H), 5.99 (dd, 1H), 4.36 (s, 2H), 3.99 (s, 3H), 3.94 (dd, 1H), 3.90 (dd, 1H), 3.38 (dd, 1H), 3.22 (dd, 1H), 1.07-1.36 (m, 1H), 0.50-0.68 (m, 2H), 0.24-0.45 (m, 2H).