Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl-].[NH4+].[N-:48]=[N+:49]=[N-:50].[Na+]>CN(C=O)C>[C:1]([O:7][CH2:8][C@H:9]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[NH:50][N:49]=[N:48][N:30]=5)[CH:24]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2nc(-c3ccnc(-c4cccc(C#N)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3ccnc(-c4cccc(-c5nnn[nH]5)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 120 °C

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(3-cyanophenyl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (17.2 mg, 0.027 mmol) in DMF (0.5 mL) was added ammonium chloride (7.2 mg, 0.135 mmol) and sodium azide (9.4 mg, 0.144 mmol). The reaction mixture was heated at 120° C. for 6 h then cooled. The crude reaction mixture was passed through a silica gel plug (hexanes/ethyl acetate eluent) to remove the DMF and salts, concentrated, and used without further purification. LCMS-ESI+: calc'd for C37H38ClN6O3S: 681.2 (M+H+); Found: 680.9 (M+H+).
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[CH3:8][C:9]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1.S(Cl)Cl>C(Cl)Cl.O>[CH3:8][C:9]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]1[N:17]([CH2:12][O:11][C:10]2[CH:9]=[CH:21][CH:20]=[C:19]([CH3:18])[C:6]=2[CH3:7])[CH2:16][CH2:15][N:14]=1
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Reactant: CCN(CC)CC
Agent: ClSCl
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(OCC2=NCCN2COc2cccc(C)c2C)c1C
Reaction time: 2 h

Procedure:
11 g of triethylamine are added slowly dropwise at 0° C. to a solution of 20.4 g of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline in 200 ml of methylene chloride, followed by the slow dropwise addition of 5.15 g of freshly distilled sulfur chloride. The reaction mixture is then stirred for about 2 hours in an ice bath, the resultant solution is diluted with water and the organic phase is washed repeatedly with water, dried over sodium sulfate and concentrated completely. The residue is stirred in hexane and recrystallisation of the solid precipitate yields bis-(2,3-dimethylphenoxymethyl)-2-imidazoline)-1,1'-sulfide (compound 1) of the formula ##STR5## in the form of a light beige-coloured powder with a melting point of 112°-114° C.
Reaction SMILES: C(/[C:11]1[CH:26]=[CH:25][C:14]([C:15](N(O)CCCC(O)=O)=[O:16])=[CH:13][CH:12]=1)=C/CCCCCCCC.[OH-:27].[CH2:28]([N+:32]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31].Cl.[O:46]1[CH2:51][CH2:50]OCC1>>[CH2:41]([N+:32]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:42][CH2:43][CH3:44].[CH2:15]([O:16][NH:32][CH2:28][CH2:29][CH2:50][C:51]([O-:46])=[O:27])[C:14]1[CH:13]=[CH:12][CH:11]=[CH:26][CH:25]=1
Reactant: [OH-]
Reactant: CCCCCCCC/C=C\c1ccc(C(=O)N(O)CCCC(=O)O)cc1
Reactant: C1COCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Product: O=C([O-])CCCNOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the compound prepared in Example 3 Part B (5.74 g, 30.0 mM) in dioxane (50 ml) was added tetrabutylammonium hydroxide (36 mM, 23.4 ml of a 40% solution) under argon and the mixture stirred at room temperature overnight. Excess base was neutralized with 1.0N HCl (6 ml, 6 mM) and then the crude mixture was evaporated. Residue was azeotroped (4×) with CH3CN to insure dryness, then stored under vacuum. TLC (9:1) CH2Cl2 --CH3OH, Rf product=0.48, UV and PMA, single spot.
Reaction SMILES: Cl.[NH2:2]O.[CH2:4]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25]([CH:28]=O)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:4]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH:25]([C:28]#[N:2])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NO
Reactant: CCCCCCc1ccc(-c2ccc([C@H]3CC[C@H](C=O)CC3)cc2)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc(-c2ccc(C3CCC(C#N)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.7 g of hydroxylamine hydrochloride in 1.58 g of pyridine is treated with 3.41 g of 5-hexyl-2-[p-(trans-4-formylcyclohexyl)phenyl]pyridine and stirred at room temperature for 5 minutes. The reaction mixture is then treated with 20 ml of toluene and heated to reflux for 4 hours under water separation. The cooled reaction mixture is filtered. The filtrate is diluted with diethyl ether, washed several times with water and dried over magnesium sulphate. After evaporation there is obtained 5-hexyl-2-[p- -(4-cyanocyclohexyl)phenyl]pyridine as a cis/trans mixture.
Reaction SMILES: [CH2:1]([NH:5][S:6](=[O:9])(=O)[OH:7])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)(Cl)[Cl:11]>C1C=CC=CC=1>[CH2:1]([NH:5][S:6]([Cl:11])(=[O:9])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNS(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCNS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of n-butyl sulfamic acid (1.92 gm, 12.53 mmoles) and phosphorus pentachloride (2.61 gm, 12.53 mmoles) in benzene (20 mL) was warmed gently to initiate gas evolution. The reaction mixture was stirred at room temperature for 0.5 h., during which time a cloudy solution resulted. The cloudy solution was heated to reflux for 0.5 h., then was concentrated. The product n-butyl sulfamoyl chloride was isolated by vacuum distillation (120 C., 300 millitorr), 730 mg (liq.) (34%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:29]12[N:36]([C:37]3[N:42]=[C:41](Cl)[N:40]=[C:39]([CH2:44][N:45]([CH3:47])[CH3:46])[CH:38]=3)[CH:33]([CH2:34][CH2:35]1)[CH2:32][O:31][CH2:30]2>COCCOC.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>[CH:33]12[N:36]([C:37]3[CH:38]=[C:39]([CH2:44][N:45]([CH3:47])[CH3:46])[N:40]=[C:41]([C:11]4[CH:10]=[CH:9][C:8]([NH:7][C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:6])=[CH:13][CH:12]=4)[N:42]=3)[CH:29]([CH2:35][CH2:34]1)[CH2:30][O:31][CH2:32]2
Reactant: CN(C)Cc1cc(N2C3CCC2COC3)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
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: COCCOC
Product: CN(C)Cc1cc(N2C3CCC2COC3)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 100 °C
Yield: 48.8 %

Procedure:
A microwave vial was charged with a solution of 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.496 mmol) in DME (3 ml). Sodium carbonate (2M in water, 0.530 ml, 1.061 mmol), tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.021 mmol), and 1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-dimethylmethanamine (0.100 g, 0.354 mmol) were added and the resulting solution was sparged with nitrogen for 5 minutes and then heated to 100° C. for 90 minutes via microwave. The vessel was then cooled to room temperature and the reaction mixture was filtered through Celite™. The filter cake was washed with ethyl acetate and the filtrate was washed with saturated sodium chloride and concentrated under reduced pressure to provide a brown oil. The crude product was added to a HPLC column and was eluted with 5-100% acetonitrile in water (0.05% TFA buffer) to provide the mono-TFA salt of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-cyclopropylurea (0.073 g, 49%) as a light yellow solid. MS; 423.2, M+H.
Reaction SMILES: O.NN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[C@@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:17][CH2:16]1.CO>C(Cl)Cl>[NH2:6][C@H:15]1[CH2:16][CH2:17][C@H:18]([O:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:19][CH2:20]1
Reactant: O=C(O[C@H]1CC[C@@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: N[C@H]1CC[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 8 h

Procedure:
35 wt % Hydrazine hydrate (0.93 g, 10.1 mmol) was added to a solution of compound 5 (2.0 g, 5.1 mmol) in CH2Cl2 (50 mL) followed by MeOH (50 mL) at room temperature. The reaction mixture was allowed to stir overnight. The resulting white precipitates were filtered off and the solvent was removed in vacuo. The resulting white solids were dissolved in aqueous 1N HCl solution and washed with CH2Cl2. Aqueous layer was basified with excess 1N NaOH solution and then extracted with CH2Cl2. After drying with MgSO4, the solvent was evaporated affording crude trans-4-nitro-benzoic acid 4-amino-cyclohexyl ester 6 as a white solid (1.1 g, 89% yield), which was used in the next step without further purification. 1H NMR (DMSO-d6): δ 8.26 (dd, J=44 and 9 Hz, 4H), 6.72 (d, J=7 Hz, 2H), 5.08 (s, 1H), 2.00-1.36 (m, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([F:13])=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[F:14])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:49][C:50]([C:52]1[C:53]2[CH:54]=[CH:55][N:56]=[CH:57][C:58]=2[CH:59]=[CH:60][CH:61]=1)=[NH:51]>CN(C)C=O>[CH2:1]([O:3][C:4]1[C:5]([F:14])=[CH:6][C:7]([C:8]2[O:10][N:51]=[C:50]([C:52]3[CH:61]=[CH:60][CH:59]=[C:58]4[C:53]=3[CH:54]=[CH:55][N:56]=[CH:57]4)[N:49]=2)=[CH:11][C:12]=1[F:13])[CH3:2]
Reactant: N=C(NO)c1cccc2cnccc12
Reactant: CCOc1c(F)cc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(F)cc(-c2nc(-c3cccc4cnccc34)no2)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 5.8 %

Procedure:
A mixture of 4-(ethyloxy)-3,5-difluorobenzoic acid (JRD Fluorochemicals Ltd; 130 mg, 0.641 mmol), HATU (244 mg, 0.641 mmol), Hunig's base (0.3 mL, 1.718 mmol) in N,N-dimethylformamide (DMF) (1 ml) was stirred at room temperature for 1 hr before the addition of N-hydroxy-5-isoquinolinecarboximidamide (D1; 100 mg, 0.534 mmol) in N,N-dimethylformamide (DMF) (1 ml). The reaction mixture was stirred at room temperature for 2-3 hrs and then heated in a microwave at 140° C. for 1.5 hr. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Waters Atlantis column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN+0.1% Formic acid)) to give the title compound (11 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+]>C1COCC1.C(O)C.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc5cc(Cl)ccc5n4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc2cc(Cl)ccc2n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To ethyl 6-chloro-7-(4-(6-chloroquinolin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (1.31 g, 2.44 mmol) in THF (12 mL) and ethanol (6 mL) was added NaOH (6.09 mL, 12.2 mmol) and the reaction stirred at ambient temperature for 3 hours. The reaction was diluted with ethyl acetate (25 mL) and 1N aqueous HCl (20 mL). THF was added as needed to keep the organic layer clear. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated. The residue was triturated with DCM and the resulting solids were collected by filtration to provide the desired product (0.98 g, 1.92 mmol, 78.9% yield). MS (APCI)=509.0 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.S1C=CC(C(N2CCOCC2)C#N)=C1.[C:22]([O:26]CC)(=[O:25])[CH:23]=[CH2:24].[OH-].[K+]>C(O)C.O1CCCC1>[CH:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([CH2:24][CH2:23][C:22]([OH:26])=[O:25])=[O:7]
Reactant: O=Cc1ccsc1
Reactant: C=CC(=O)OCC
Agent: N#CC(c1ccsc1)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccsc1

Procedure:
As for Example 6, 99 g. of 3-thiophenecarboxaldehyde is converted to α-(3-thienyl)-4-morpholineacetonitrile (137 g.; m.p. 85°-87° C.). The preceding compound 50.5 g. is reacted with 100 ml. of ethyl acrylate in 500 ml. of tetrahydrofuran in the presence of 50 ml. of 30% potassium hydroxide in ethanol. The solvent is removed from the reaction mixture and the residue is heated with 6 N hydrochloric acid to give 3-(3-thenoyl)propionic acid. As for Example 1, the preceding compound is converted to the product of the Example to give a glass.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[OH:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37](=O)[CH3:38]>O1CCCC1>[OH:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][C:37]([CH3:38])=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: CC(=O)CCCC(C)CCO
Reactant: O=C(O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=CCCCCCC(=O)O)CCCC(C)CCO
Yield: 53.4 %

Procedure:
95 g (0.2 mol) of (6-carboxyhexyl)triphenylphosphonium bromide in 600 ml of tetrahydrofuran were added to 48 g (0.42 mol) of potassium t-butylate in 200 ml of tetrahydrofuran. Thereafter, 29 g (0.18 mol) of 8-hydroxy-6-methyl-2-octanone were added. After work up and chromatography 26 g (48%) of 14-hydroxy-8,12-dimethyltetradec-7-enoic acid were obtained having the following characteristics: Z/E=58/42;
Reaction SMILES: N1([C:6](=[S:31])[O:7][CH:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])C=CN=C1.CO.[O:34]1CCOC[CH2:35]1>C(Cl)(Cl)Cl>[CH3:35][O:34][C:6]([O:7][CH:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[S:31]
Reactant: C1COCCO1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(OC(=S)n1ccnc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=S)OC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
4.3 g. (10mM) of α[(1H-imidazol-1-yl)thioxomethoxy]-benzeneacetic acid, diphenylmethyl ester together with 0.35 g. of methanol in 30 ml. of dioxane and one drop of a 10% sodium imidazole-dioxane solution, are held at 40° for 5 hours. After drawing off the solvent, the oily residue is dissolved in chloroform and washed three times, each time with 30 ml. of water. After drawing off the solvent, 2.3 g. of α-[(methoxycarbonothioyl)oxy] benzeneacetic acid, diphenylmethyl ester are obtained from the dried chloroform solution in the form of a pale yellow oil which crystallizes after 24 hours. Recrystallization from cyclohexane/petroleum ether yields 1.6 g. of white crystals, m.p. 74°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([OH:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl>CC(C)=O>[Br:1][C:2]1[C:3]([O:11][CH2:18][O:19][CH3:20])=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: COc1ccc(Br)c(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1c(Br)ccc(OC)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
To a stirring solution of 3-bromo-6-methoxybenzene-1,2-diol (500 mg, 2.28 mmol) in acetone (40 mL) at 0° C. was added potassium carbonate (314 mg, 2.28 mmol) and methoxymethyl chloride (184 mg, 2.28 mmol) and the resultant reaction mixture was stirred at RT for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure Purification by column chromatography (silica gel, 0-8% ethyl acetate in pet ether) afforded 3-Bromo-6-methoxy-2-(methoxymethoxy)phenol as a liquid (230 mg, 38%).
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[C:34]6[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=6)[N:28]([CH3:35])[CH:27]=5)[CH:23]=[CH:22][N:21]=4)=[C:12]([O:36][CH3:37])[CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.[NH4+].[Cl-].O>C(O)C.[Fe]>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:11]=[C:12]([O:36][CH3:37])[C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[C:34]6[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=6)[N:28]([CH3:35])[CH:27]=5)[CH:23]=[CH:22][N:21]=4)=[CH:14][C:15]=3[NH2:16])[CH2:6][CH2:7]2)[CH2:3]1
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Yield: 82.7 %

Procedure:
A mixture of N-[4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 124, 256 mg, 0.51 mmol), iron powder (172 mg, 3.07 mmol) and NH4Cl (19.19 mg, 0.36 mmol) were heated in ethanol (3 mL) and water (1 mL) at reflux for 18 h. The crude mixture was then purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and concentrated in vacuo. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (198 mg, 82%) as a yellow foam; 1H NMR (CDCl3) 1.78 (1H, td), 2.07-2.13 (1H, m), 2.15 (1H, dd), 2.29 (3H, s), 2.47 (1H, dd), 2.57-2.65 (2H, m), 2.82-2.95 (2H, m), 3.45 (1H, dt), 3.85 (3H, s), 3.88 (3H, s), 4.07 (1H, ddd), 6.74 (1H, s), 7.01 (1H, d), 7.27-7.35 (2H, m), 7.38 (1H, dd), 7.55 (1H, s), 7.79 (1H, s), 8.14 (1H, s), 8.33 (1H, d), 8.45-8.52 (1H, m); m/z: ES+ MH+ 470.29.
Reaction SMILES: [C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCO.[OH-].[Na+].Cl>C1COCC1>[C:1]1(=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1)C(=O)O
Yield: 74.6 %

Procedure:
The hydrolysis procedure described for 191 was employed. Ethyl 2-({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)-2-methylpropanoate (225) (0.150 g, 0.37 mmol) was dissolved in THF and EtOH (1:1, 6 mL) and then treated with 1 N NaOH (3 mL, excess) at 70° C. for 1 h. The reaction mixture was cooled and poured into 20% aqueous HCl (40 mL). Standard work-up and purification afforded 0.105 g (75%) of the title compound 226 as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 13.06 (br s, 1H), 9.26 (s, 1H), 6.98 (d, J=8.4 Hz, 2H), 6.90 (d, J=7.8 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.1 Hz, 2H), 2.21 (br s, 4H), 1.52 (br s, 8H), 1.48 (s, 6H). LCMS (ESI): m/z 379 (M−H)−. Anal. Calcd for C24H28O4, C, 75.76; H, 7.42. Found: C, 75.07, H, 7.52.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[F:18][C:19]([F:23])([F:22])[CH2:20][SH:21]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:21][CH2:20][C:19]([F:23])([F:22])[F:18])=[CH:11][CH:12]=1
Reactant: FC(F)(F)CS
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSCC(F)(F)F

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and 2,2,2-trifluoro-ethanethiol.
Reaction SMILES: N#N.C([Si](C)(C)[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[C:27]([CH3:37])[O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][N:17]2[N:21]=[C:20]([NH:22][C:23]([C:25]3[N:26]=[C:27]([CH3:37])[O:28][C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[O:24])[CH:19]=[N:18]2)=[CH:14][N:15]=1)[CH3:10]
Reactant: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O[Si](C)(C)C(C)(C)C)o3)n2)c(-c2cccc(F)c2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)Nc2cnn(Cc3cnc(C(C)O)o3)n2)c(-c2cccc(F)c2)o1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-carboxylic acid (2-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazol-5-ylmethyl}-2H-[1,2,3]triazol-4-yl)-amide (110 mg, 0.21 mmol) in dry THF (2.1 mL) was treated at 0° C. with TBAF (0.42 mL of a 1M solution in THF, 0.42 mmol). The reaction mixture was stirred at 0° C. for 45 min. The mixture was then diluted with EA (10 mL), washed with NaHCO3 (10 mL) followed by brine (3×10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (19:1 CH2Cl2-MeOH) gave the title compound as an orange oil. TLC:rf (19:1 CH2Cl2-MeOH)=0.21. LC-MS-conditions 02: tR=0.94 min; [M+H]+=412.86.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2>N.O.CO.[Ni]>[N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH2:13][NH2:14])[CH:15]=[CH:16][CH:17]=2)=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: N#Cc1cccc(-c2cn3ncccc3n2)c1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: O
Product: NCc1cccc(-c2cn3ncccc3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Raney-Ni (cat.) and NH3.H2O (4˜5 drops) were added to the solution of 3-(imidazo[1,2-b]pyridazin-2-yl)benzonitrile (25 mg) in MeOH. The mixture was stirred vigorously at room temperature for 1 h under hydrogen and the Raney-Ni was then removed. The filtration was concentrated in vacuo to give the (3-(imidazo[1,2-b]pyridazin-2-yl)phenyl)methanamine.