Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:32]N(C)C=O.IC>[Cl-].[Na+].O>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]([CH3:32])[C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[O:8])=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccccc2Nc2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1c2ccccc2CN(C(=O)c2ccc(-c3ccccc3)cc2)c2ccccc21

Procedure:
[1,1′-Biphenyl]-4-yl-(5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl)methanone of Example 6 (0.97 g) was added to sodium hydride (2 equivalents, 60% in oil, washed with hexane) and N,N-dimethylformamide (25 mL). Iodomethane (0.45 g) was added and after overnight stirring, the mixture was poured into brine. The precipitate was collected, redissolved in dichloromethane and the solution filtered through a short column of Magnesol®. The column was rinsed with several volumes of dichloromethane, and the combined eluate refluxed with the gradual addition of hexane until incipient crystallization. Cooling and filtration provided the title compound (0.89 g), m.p. 198-201° C.
Reaction SMILES: N1(C(N2C=CN=C2)=O)C=CN=C1.[C:13]([OH:17])(=O)[C:14]#[CH:15].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:36])[CH2:27][C:28]1[NH:29][C:30]([CH3:35])=[C:31]([CH2:33][CH3:34])[N:32]=1>C1COCC1>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([C:27]1[CH:15]=[CH:14][C:13](=[O:17])[N:29]2[C:30]([CH3:35])=[C:31]([CH2:33][CH3:34])[NH:32][C:28]=12)=[O:36]
Reactant: CCc1nc(CC(=O)c2ccc(F)cc2F)[nH]c1C
Reactant: C#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCc1[nH]c2c(C(=O)c3ccc(F)cc3F)ccc(=O)n2c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
552 mg (3.40 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole and 199 mg (2.83 mmol) of propiolic acid are dissolved in 25 ml THF. The mixture is stirred for 3 h at rt. To this solution are added 500 mg (1.89 mmol) of 1-(2,4-Difluorophenyl)-2-(4-ethyl-5-methyl-1H-imidazol-2-yl)ethanone (example XIII) and the mixture is refluxed for 24 h. The solvent is evaporated under vacuum and the crude is purified over preparative HPLC (RP18-Column, Eluent: acetonitrile-water-gradient). The regioisomers are isolated after purification over preparative HPLC (Daicel Chiralpak AD, eluent: iso-hexane-ethanol v/v 60:40).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:5]([O:4][CH2:3][CH2:2][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:6][CH2:7][CH3:8]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOCCOc1ccc(-c2ccc(O)cc2)cc1
Yield: 15.9 %

Procedure:
One gram (5.5 millimoles) of 1-bromo-2-butoxyethane was combined with 5.5 grams (30 millimoles) of 4,4'-dihydroxybiphenyl in 75 mls. of acetonitrile. To the reaction mixture were added 8.3 grams (60 millimoles) of finely ground potassium carbonate. Stirring was begun and the reaction mixture was brought to reflux and maintained for 48 hours. The reaction product was filtered, washed with acetonitrile and evaporated for removal of solvent. The product was passed through a silica gel chromatographic column using dichloromethane eluent, for recovery of 0.25 gram (20% yield) of a biphenol ether compound having the following formula confirmed by TLC, IR and mass spectral analyses: ##STR26##
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.Cl[Sn](Cl)(Cl)Cl.C(O[C@H:31]1[C@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][C@@H:45]([N:67]=[N+:68]=[N-:69])[CH2:46][CH2:47][C@H:48]([NH:56][S:57]([C:60]2[CH:65]=[CH:64][C:63]([CH3:66])=[CH:62][CH:61]=2)(=[O:59])=[O:58])[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[O:32]1)(=O)C>ClC(Cl)C>[C:37]([O:36][C@@H:35]1[C@H:34]([O:40][C:41](=[O:43])[CH3:42])[C@@H:33]([CH2:44][C@@H:45]([N:67]=[N+:68]=[N-:69])[CH2:46][CH2:47][C@H:48]([NH:56][S:57]([C:60]2[CH:65]=[CH:64][C:63]([CH3:66])=[CH:62][CH:61]=2)(=[O:58])=[O:59])[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[O:32][C@H:31]1[N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:21])=[N:10][C:2]=2[NH2:1])(=[O:39])[CH3:38]
Reactant: CC(=O)O[C@@H]1O[C@H](C[C@H](CC[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)N=[N+]=[N-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)(C)OC(=O)NCCNc1nc(N)c2nc[nH]c2n1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C[C@H](CC[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)N=[N+]=[N-])O[C@H]1n1cnc2c(N)nc(NCCNC(=O)OC(C)(C)C)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture consisting of Compound 27A (10 molar equivalents) in an appropriate solvent is added SnCl4 (equimolar) in dichloroethane. A mixture consisting of (2S,3R,4R,5R)-5-((2S,5S)-2-azido-6-(tert-butoxy)-5-(4-methylphenylsulfonamido)-6-oxohexyl)tetrahydrofuran-2,3,4-triyl triacetate (limiting reagent, prepared in the manner of Rapoport et. al. as 25β) is added and the mixture stirred at room temperature for 16 hours. The mixture is partitioned between ethyl acetate and 0.5N Na2HPO4 and the organics washed with brine, dried and evaporated. The residue is chromatographed on silica gel to obtain the title intermediate.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cccc(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate (1.826 g, 5.00 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.200 g, 5.00 mmol) dissolved in water (2.000 mL) was added during 20 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.306 mL, 5.00 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (25 mL, 150.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a brown semi-solid. The compound was purified by preparative HPLC in 2 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.141 g, 68%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.83-2.15 (m, 4H), 2.58-2.67 (m, 1H), 2.77-2.86 (m, 1H), 2.93-3.03 (m, 1H), 3.10-3.21 (m, 1H), 3.63 (s, 3H), 3.96-4.05 (m, 1H), 4.22-4.32 (m, 1H), 5.73 (s, 1H), 6.81-6.95 (m, 3H), 7.18-7.27 (m, 1H). MS m/z 335 (M+H)+
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:10]Br>>[Br:10][CH:8]([CH3:9])[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: BrBr
Reactant: CCC(=O)CC(=O)OC
Product: COC(=O)CC(=O)C(C)Br

Procedure:
reacting methyl 3-oxovalerate (commercially available) with bromine to give methyl 4-bromo-3-oxovalerate, or reacting ethyl 3-oxovalerate (commercially available) with bromine to give ethyl 4-bromo-3-oxovalerate,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: COc1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccnc(-c2ccc(OC)cc2)c1

Procedure:
4-Methoxyphenylboronic acid (179 mg) and ethyl 2-chloroisonicotinate (200 mg) were treated in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.Br[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH2:12]3)=[N:28][CH:29]=1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: Clc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(-c3ccc(Cl)cn3)cc2C1

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (1 g, 2.74 mmol) in dry 1,4 dioxane (15 ml), polymer supported Pd(PPh3)4 (54 mg, 0.5 mmol/g, 0.027 mmol) was added along with 2-bromo-5-chloropyridine (1.05 g, 5.48 mmol) and 3.5 ml of a 2M Na2CO3 solution in water and the resulting mixture was heated at 90° degrees for 3 hours. Then after cooling the resin was removed by filtration and then the solvent was removed under reduced pressure. The residue was taken up with AcOEt and water. The aqueous phase was separated and acidified with 3N HCl and extracted with AcOEt. Then pH was reverted to basic by addition of NaHCO3 and another extraction with AcOEt was performed. All the organic extracts were collected, dried on Na2SO4, filtered and evaporated. The crude was finally purified on a 40M+ silica cartridge eluting with a cyclohexane/AcOEt 80/20 mixture. 682 mg of title compound were recovered as whitish solid (71%). Due to the use of chiral Intermediate 7, the final compound is believed to be N-[(2S)-5-(5-chloro-2-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([NH:25][C:26](=O)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:26]([NH:25][C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CNc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
To a solution of N-(1-trityl-1H-imidazol-4-yl)-benzamide (0.36 g, 0.83 mmol) in tetrahydrofuran (10 ml) was added portionwise lithium aluminium hydride (0.16 g, 4.14 mmol). The reaction mixture was stirred at 80° C. for 16 hours, then cooled to room temperature and water added dropwise. The mixture was stirred at room temperature for 20 minutes and then extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: methanol/dichloromethane 0:100 to 10:90) to yield the title compound as a white solid (0.15 g, 44%); MS (ISP): 416.5 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:24]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[C:5]([O:7][CH3:24])=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a suspension of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (Synthech BC3558-001, 800 mg; 3.05 mmol; 1 eq.) in MeOH (16 mL) was added dropwise thionyl chloride (0.89 mL; 12.2 mmol; 4 eq.) and the reaction mixture was stirred at room temperature for 4 hours. The solvent evaporated in vacuo and the crude residue was diluted with Ethyl acetate (20 mL). The organic layer was washed with a sat. aq. NaHCO3 (5 mL), water (5 mL) and brine (5 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound (751 mg, 89%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].S(=O)(=O)(O)O.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C([BH3-])#N.[Na+]>CO>[CH:14]1([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C1CCCCC1
Agent: O=S(=O)(O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)[C@H](NC1CCCCC1)C(=O)O
Reaction time: 24 h

Procedure:
To the m-phenoxybenzyl ester of valine (2 g, 0.0067 mole) in methanol (30 ml) is added concentrated sulfuric acid to bring to about pH 6. Cyclohexanone (0.6 g, 0.006 mole) is then added followed by 3A molecular sieves and sodium cyanoborohydride (0.25 g, 0.004 mole). Additional sulfuric acid is added to keep pH at about 6. After about 24 hours, the reaction is worked up by removing methanol by rotoevaporation and the residue is poured into water and 10% sodium carbonate followed by extraction with ether. The combined ether extracts are filtered and concentrated and the product is isolated by preparatory TLC (10% ether/hexane) to yield the m-phenoxybenzyl ester of N-cyclohexylvaline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([N:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([N:33]([CH3:35])[CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)nc2ccccc12
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(Cl)cc3)nc3ccccc13)C2
Yield: 8 %

Procedure:
Reaction of 2-(4-chlorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 30 (8% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.74-3.10 (m, 8H), 3.58 and 4.21 (2t, 2H), 4.48 and 5.10 (2s, 2H), 6.34 and 6.88 (2d, 1H), 6.96 and 7.17 (2d, 1H), 7.48-8.16 (m, 7H), 8.57-8.62 (m, 2H); MS (ESI) m/z 459 ([M+H]+).
Reaction SMILES: COC1C=CC(C[N:10]2[C:15](=[O:16])[CH:14]=[C:13]3[CH2:17][CH2:18][CH2:19][O:20][C:12]3=[N:11]2)=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[N:11]1[NH:10][C:15](=[O:16])[CH:14]=[C:13]2[CH2:17][CH2:18][CH2:19][O:20][C:12]=12
Reactant: COc1ccc(Cn2nc3c(cc2=O)CCCO3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=c1cc2c(n[nH]1)OCCC2
Temperature: 70 °C
Yield: 88.5 %

Procedure:
2-{[4-(Methyloxy)phenyl]methyl}-6,7-dihydro-2H-pyrano[2,3-c]pyridazin-3(5H)-one (2.75 g, 10.1 mmol) was treated with anisole (10 ml) and TFA (100 ml) and heated at 70° C. for 24 hours. The solution was cooled and evaporated and the residue taken up in 2.5% methanol/dichloromethane. This was applied to a column of silica, and then elution with this solvent mixture followed by 5% methanol/dichloromethane gave the product as an off white solid (1.36 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH:25]([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH:25]([CH3:27])[CH3:26])[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C(C)C)c3c(C(F)(F)F)cccc23)cc1
Yield: 25.7 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.146 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.043 g) as a white solid.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:36]([O:35][CH2:34][C@@H:21]1[C@@H:20]([CH2:19][OH:18])[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO
Yield: 56.6 %

Procedure:
Compound 183 (2.00 g, 3.73 mmol) was dissolved in dry THF (36 ml) and tetrabutylammonium fluoride (8.8 ml, 1.0 M solution in THF, 2.4 equiv.) was added via syringe at room temperature under an atmosphere of argon. After completion of the reaction (1.5 hours), as was monitored by tlc in EtOAc (Rf 0.42), the solvent was removed in vacuo. The residue was purified by silica gel flash column chromatography in EtOAc/Hexane (4:6-9:1, v/v) to afford 184 (0.63 g, 57%) 1H NMR (CDCl3): δ8.89 (br, 1 H, NH), 7.55 (d, 1 H, J=1.1 Hz, H6), 6.13 (dd, 1 H, J=4.9, 6.6 Hz, H-1'), 4.17 & 4.09 (m, 2 H, CH2 -OAc), 4.07 (d, 1 H, J=11.7 Hz, H-5' & H-5'), 3.94-3.90 (m, 1 H, H-4'), 3.76 (d, 1H, J=11.7 Hz, H-5), 2.80-2.76 (m, 1 H, H-3'), 2.60 (br, 1 H, OH), 2.29-2.25 (m, 2 H, H2' & H-2"), 2.09 (s, 3 H, COCH3), 1.91 (s, 9 H, C(CH3)3); 13C NMR (CDCl3): 170.8 (C=O), 163.8 (C4), 150.3 (C2), 136.3 (C6), 110.8 (C5), 85.4 (C1'), 83.5 (C4'), 64.2 (C5'), 36.8 (C3'), 35 35.6 (C2'), 20.8, 12.5;
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1([C:15]([OH:17])=[O:16])[CH2:12][C:11]1([Cl:14])[Cl:13]>CN(C)C(=O)C>[Cl:9][C:10]1([C:15]([O:17][CH3:1])=[O:16])[CH2:12][C:11]1([Cl:14])[Cl:13]
Reactant: O=C(O)C1(Cl)CC1(Cl)Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(=O)N(C)C
Product: COC(=O)C1(Cl)CC1(Cl)Cl
Reaction time: 20 h

Procedure:
Potassium carbonate (4.14 grams) and methyl iodide (3.74 ml) were added to a solution of 1,2,2-trichlorocyclopropane carboxylic acid (5.68 grams) and N,N-dimethylacetamide (50 ml). The reaction mixture was stirred for approximately 20 hours and then filtered. Ethyl ether (250 ml) was added to the filtrate and the resultant mixture was washed, dried, and evaporated in vacuo to the desired product, methyl 1,2,2-trichlorocyclopropane carboxylate. Structure of the product was confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.Cl.[NH:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)[NH2:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[N:16][NH:15][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:19][CH:18]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: COc1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 5-methoxy-1H-indole-2,3-dione (Gassman, et al., Journal of Organic Chemistry 1977, 42, 1344–8) and 4-hydrazinobenzenesulfonamide hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 3.80 (s, 3H), 6.87 (s, 2H), 7.20 (s, 1H), 7.28 (s, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.8 Hz, 2H), 10.93 (s, 1H), 12.85 (s, 1H); APCI-MS m/z 344.9 (M−H)−.
Reaction SMILES: [NH2:1][CH:2]1[NH:6][C:5](=[O:7])[N:4]([CH3:8])[C:3]1=[O:9].[N:10]1[C:17]([Cl:18])=[N:16][C:14](Cl)=[N:13][C:11]=1[Cl:12].C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:12][C:11]1[N:10]=[C:17]([Cl:18])[N:16]=[C:14]([NH:1][CH:2]2[NH:6][C:5](=[O:7])[N:4]([CH3:8])[C:3]2=[O:9])[N:13]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CN1C(=O)NC(N)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN1C(=O)NC(Nc2nc(Cl)nc(Cl)n2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
An ice-cold suspension of 5-amino-3-methyl-imidazolidine-2,4-dione (Example 1.3, Part C) (266 mg, 2.06 mmol), cyanuric chloride (415 mg, 2.27 mmol) and sodium bicarbonate (191 mg, 2.27 mmol) in acetonitrile (15 mL) was stirred over an ice bath under a nitrogen atmosphere for 1 h, and then allowed to stir at room temperature for 22 h. The solvent was evaporated, and the crude product was extracted with ethyl acetate. The organic layer was dried and evaporated, and the crude product was purified by column chromatography (PS with gradient elution to DCM:EtOAc 1:1) to afford the product as a cream solid (448 mg, 78%). δH (300 MHz, CD3CN) 7.50 (br s, 1H, NH), 6.56 (br s, 1H, NH), 5.60 (dd, J 7.8, 1.8 Hz, 1H, CH), 2.97 (s, 3H, CH3). Mass spectrum (ESI) m/z 259 [M+H(OH for Cl exchanged ion)].
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[O:11][C:10]([CH3:20])([CH3:19])[CH2:9]2.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23]>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:21])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:30](=[O:31])[C:27]4[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=4)[CH:16]=3)[O:11][C:10]([CH3:19])([CH3:20])[CH2:9]2)[N:4]=1
Reactant: CC1(C)C[C@@]2(N=C(N)OCC2(F)F)c2cc(N)ccc2O1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: CC1(C)C[C@@]2(N=C(N)OCC2(F)F)c2cc(NC(=O)c3ccc(C#N)cn3)ccc2O1
Yield: 78 %

Procedure:
The condensation of (R)-5′,5′-difluoro-2,2-dimethyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazine]-2′,6-diamine (intermediate B7.3) and 5-cyanopicolinic acid yielded the title compound (78% yield) as a yellow solid. MS (ISP): m/z=428.3 [M+H]+.