Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[CH:4][CH:3]=1.[CH:17](O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]=[CH:17][N:8]([CH2:9][CH:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[C:6]=2[CH:7]=1
Reactant: O=CO
Reactant: Nc1ccc(Br)cc1NCC1CCOCC1
Product: Brc1ccc2ncn(CC3CCOCC3)c2c1

Procedure:
A solution of the crude product of Example 5B (8.41 g, 29.5 mmol) in formic acid (10 mL, 261 mmol) was heated at 95° C. for 1 hour. After cooling, the mixture was concentrated and dissolved in ethyl acetate. The mixture was washed with 10% aqueous potassium carbonate and brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (Isco®, Redi-Sep® column) eluting with a gradient of 50-100% ethyl acetate/hexane then 10% 2:1 methanol/water in ethyl acetate, followed by recrystallization from ethyl acetate/hexane, afforded the title compound. MS (ESI) m/z 297 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][C@@H:10](O)[CH2:11][C@H:12]([OH:14])[CH3:13].C(=O)([O-])O.[Na+]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:9][C@@H:10]1[CH2:11][C@@H:12]([CH3:13])[O:14][C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])[O:8]1
Reactant: CC1CCCCC1=O
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1CCCCC12O[C@H](C)C[C@@H](C)O2
Yield: 77.7 %

Procedure:
A mixture of 2-methylcyclohexanone (13.1 g), (2R,4R)-2,4-pentanediol (12.2 g), pyridinium p-toluene sulfonate (119 mg) and toluene (120 ml) was refluxed with heating for 8 hours. The reaction mixture was added with a saturated aqueous solution of sodium hydrogen carbonate, extracted with diethyl ether, the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane/ethyl acetate=100/0 to 0/100 gradient) to obtain 18.0 g of (2R,4R)-2,4,7-trimethyl-1,5-dioxaspiro[5.5]undecane
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[N:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](S(C)(=O)=O)[N:16]=3)=[CH:11][C:10]2=[O:25])=[CH:4][C:3]=1[F:32].[O:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[N:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:39][CH:36]4[CH2:37][CH2:38][O:33][CH2:34][CH2:35]4)[N:16]=3)=[CH:11][C:10]2=[O:25])=[CH:4][C:3]=1[F:32]
Reactant: NC1CCOCC1
Reactant: Cn1cc(C(c2ccc(Cl)c(F)c2)n2ccc(-c3ccnc(S(C)(=O)=O)n3)cc2=O)cn1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cn1cc(C(c2ccc(Cl)c(F)c2)n2ccc(-c3ccnc(NC4CCOCC4)n3)cc2=O)cn1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
1-((4-Chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridin-2(1H)-one (343 mg, 0.724 mmol) as a solution in DMA (5 mL) was added to a microwave tube equipped with a stir bar. Tetrahydro-2H-pyran-4-amine (366 mg, 3.62 mmol) was then added neat by syringe. The solution was heated in a microwave apparatus with stirring to 120° C. for 1 hour. After 1 hour, the solution was diluted to 30 mL with ethyl acetate and washed with a water/brine mixture (4×30 mL). The organics were isolated, dried (MgSO4), filtered and concentrated. TLC in 5/95 methanol/ethyl acetate showed complete loss of starting material and a new spot of nearly the same rf. The crude product was loaded onto a Biotage 40S column with 2.5/97.5 methanol/ethyl acetate and eluted. Product containing fractions were pooled and concentrated to a foam, 1-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (225 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 8.39 (d, 1H), 7.37 (m, 4H), 7.23 (s, 1H), 7.18 (br s, 1H), 7.00 (m, 2H), 6.90 (d, 1H), 6.79 (dd, 1H), 5.15 (br d, 1H), 4.11 (m, 1H), 4.00 (m, 2H), 3.91 (s, 3H), 3.56 (m, 2H), 2.06 (m, 2H), 1.57 (m, 2H); m/z (APCI-pos) M+1=496.1.
Reaction SMILES: [I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:6].[O-2].[O-2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:42]([CH3:43])=[CH:41][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](C4C=C5C(C=NN5C)=CC=4)[CH:26]=3)[S:24][C:20]=2[C:19]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[CH2:16][OH:17])([CH3:13])([CH3:12])[CH3:11].[C:51](#[N:53])[CH3:52]>>[I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:14].[O-2:6].[O-2:2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:42]([CH3:43])=[CH:41][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:18]4[CH:15]=[C:52]5[C:21](=[CH:20][CH:19]=4)[N:22]([CH3:23])[N:53]=[CH:51]5)[CH:26]=3)[S:24][C:20]=2[C:19]=1[C:44]1[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=1)[C:16]([OH:6])=[O:17])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC#N
Reactant: Cc1cc2nc(-c3ccnc(-c4ccc5cnn(C)c5c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: [Cr+6]
Agent: [O-2]
Agent: [O-][I+3]([O-])([O-])O
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H2O) to a volume of 114 mL. This stock solution (0.6 mL) was added to a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-6-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)ethanol (25 mg, 0.049 mmol) in ACN (3 mL) at room temperature and stirred for one hour. The reaction mixture was quenched with saturated Na2SO3 solution and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, concentrated and purified by reverse phase HPLC (H2O/ACN+0.1% TFA) to give the desired product after lyophilization. LCMS-ESI+: calc'd for C33H30ClN4O3S: 597.2 (M+H+); found: 597.2, 599.2. 1H NMR (400 MHz, CD3OD) δ 8.72 (d, J=5.3 Hz, 1H), 8.46 (s, 1H), 8.43 (s, 1H), 8.14-8.08 (m, 2H), 7.94-7.87 (m, 2H), 7.73-7.63 (m, 2H), 7.61-7.54 (m, 3H), 5.26 (s, 1H), 4.10 (s, 3H), 2.63 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]3[O:15][CH2:14][CH2:13][N:9]3[C:10](=[O:12])[NH:11][C:6]=2[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[C:32]([F:35])([F:34])[F:33])=[CH:19][CH:18]=1.Cl.O1CCOCC1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:2]3[C:7]4[CH:8]5[O:15][CH2:14][CH2:13][N:9]5[C:10](=[O:12])[NH:11][C:6]=4[N:5]=[CH:4][CH:3]=3)=[CH:22][CH:21]=2)=[O:36])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:27]=1
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2C(F)(F)F)cc1
Reactant: O=C1Nc2nccc(Cl)c2C2OCCN12
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Nc2ccnc3c2C2OCCN2C(=O)N3)cc1)c1ccc(F)cc1C(F)(F)F
Reaction time: 1 h

Procedure:
42 (16 mg, 0.07 mmol), N-(4-aminophenyl)-4-fluoro-2-(trifluoromethyl) benzamide (22 mg, 0.07 mmol), and 4.0M HCl in dioxane (18 μl, 0.07 mmol) were suspended in a sealed tube, and placed in microwave at 140° C. for 1 h. The crude product was purified directly via HPLC to provide 43. LC-MS (M+H=488, obsd.=488).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32](O)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32]([NH:35][CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[C:15]=23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c5) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [I:1]I.ClCl.[OH:5][C:6]1[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]=[CH:8][N:7]=1>C(O)(=O)C>[OH:5][C:6]1[C:11]([I:1])=[C:10]([CH2:12][CH3:13])[N:9]=[CH:8][N:7]=1
Reactant: II
Reactant: CCc1cc(O)ncn1
Agent: ClCl
Solvent: CC(=O)O
Product: CCc1ncnc(O)c1I

Procedure:
50.8 g of iodine (0.20 mol) are introduced into 850 ml of acetic acid, and 14.8 g (0.21 mol) of chlorine are introduced at 30°-33° C., whereupon the iodine dissolves. 49.7 g (0.4 mol) of 4-hydroxy-6-ethylpyrimidine in solution in 150 ml of acetic acid are then added dropwise at 20° C., the crystalline end product separating out. Filtration with suction and recrystallisation from ethyl acetate yield 24.4 g of pure substance, m.p. 191°-192° C.
Reaction SMILES: O1[C:3]23[C@:16]([CH3:21])([CH2:17][CH2:18][C:19](=[O:20])[CH:2]12)[C@@H:15]1[C@H:6]([C@H:7]2[C@@:11]([CH2:13][CH2:14]1)([CH3:12])[C@@H:10]([C:22]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:9][CH2:8]2)[CH2:5][CH2:4]3.[N-:29]=[N+]=[N-].[Na+].[N-]=[N+]=[N-].S(=O)(=O)(O)O>CS(C)=O>[NH2:29][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([NH:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A solution of 4,5-epoxy-N-(1,1-dimethylethyl)-3-oxoandrostane-17β-carboxamide (3.0 g, 7.7 mmole) in dimethyl sulfoxide (40 mL), under a nitrogen atmosphere, was placed in an oil bath heated at 60° C. The solution was stirred vigorously as sodium azide (8.11 g, 0.338 mole) was slowly added. After the addition of the azide was complete, concentrated sulfuric acid (0.54 mL) was added. The bath temperature was raised to 100° C. and the reaction was stirred at this temperature for 90 minutes. The reaction was removed from the oil bath and cooled to room temperature and the resulting solid mass was broken up and poured into cold water (550 mL). The mixture was stirred for 30 min and the solids were collected by filtration, washed with water and dried to a yellow solid. The crude product was purified by flash chromatography (hexane-30% ethyl acetate) to give 4-amino-N-(1,1-dimethylethyl)-3-oxoandrosta-4,6-diene-17β-carboxamide as a crystalline, yellow solid (0.90 g, 30%) (aq methanol). IR 3442, 3372, 1662, 1616, 1592, 1570, 1512 cm-1 ; MS (CI) m/z 385 (100%, M+ +1); (EI) m/z 384 (35%, M+), 150 (100%); 1H NMR (CDCl3) δ 0.77 (3H, s, C18 -Me), 1.06 (3H, s, C18 -Me), 1.37 (s, tBu-Me's), 2.44-2.54 (1H, pr dd), 2.58-2.72 (1H, pr dd), 3.70 (1.6H, br, NH2), 5.13 (1H, s, NH), 5.97 (1H, dd), 6.30 (1H, dd); 13C NMR (CDCl3) δ 132.27, 132.44, 135.90, 171.51, 194.27. This compound has the following structure: ##STR3##
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Cl>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([O:5][CH3:1])=[O:18])=[C:10]([C:16]#[CH:17])[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C#Cc1cc(Cl)ccc1OCC(=O)OC
Temperature: 60 °C

Procedure:
A solution of (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3; 500 mg; 1.87 mmol) in MeOH (10 ml) was treated with an 1.25 N solution of HCl in methanol (1.5 ml). The solution was heated at 60° C. for 24 hours. The solvents were removed under reduced pressure to give the title compound as an oil which solidifies upon standing (445 mg, quantitative yield).
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]2[N:8]3[CH:26]=[CH:25][CH:24]=[C:9]3[C:10]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[O:11][C:6]=2[CH:5]=1)(=O)[NH2:2].N1C(Cl)=NC(Cl)=NC=1Cl.O>CN(C=O)C>[C:1]([C:4]1[CH:28]=[CH:27][C:7]2[N:8]3[CH:26]=[CH:25][CH:24]=[C:9]3[C:10]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[O:11][C:6]=2[CH:5]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C(N)=O)ccc1-n1cccc12
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cc(C#N)ccc1-n1cccc12
Yield: 42.4 %

Procedure:
A solution of tert-butyl 7′-carbamoylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (2.7 g, 7.1 mmol) and cyanuric chloride (1.3 g, 7.1 mmol) in DMF (10 mL) was stirred at room temperature for 1 hour. The reaction was poured into water and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to yield a crude mixture that was purified by silica gel chromatography eluting with 0-100% EtOAc in Hexanes. Pure fractions were combined and concentrated to yield tert-butyl 7-cyanospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate (1.1 g, 44%). ESI-MS m/z calc. 365.4. found 366.3 (M+1)+. Retention time: 2.00 minutes (3 min run).
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:29]\[OH:30])/[C@:18]5([OH:28])[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:51])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:28][C@:18]12[CH2:19][C:20](=[O:51])[CH2:21][CH2:22][C@:23]1([CH3:24])[C@@H:25]1[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]1)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16]/[C:17]/2=[N:29]\[OH:30]
Reactant: C[C@]12CC[C@H]3[C@@H](C/C(=N\O)[C@@]4(O)CCCC[C@]34C)[C@@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CC[C@H]3[C@@H](C/C(=N\O)[C@@]4(O)CC(=O)CC[C@]34C)[C@@H]1CCC2=O
Yield: 80 %

Procedure:
The title compound II-bm was prepared in 80% yield from 3,3:17,17-bis(ethylendioxy)-5α-hydroxy-6-(E)-hydroxyiminoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone/CH2Cl2 60/20/20). 1H-NMR (300 MHz, acetone-d6, ppm from TMS: δ 10.72 (s, 1H), 5.35 (s, 1H), 3.12 (dd, 1H), 2.85-1.09 (m, 18H), 0.94 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: [N:1]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:50]([O:52][C:53](=[O:74])[C@H:54]([O:56][C:57]1[CH:62]=[C:61](Cl)[N:60]=[C:59]([S:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[C:67]=2[F:73])[N:58]=1)[CH3:55])[CH3:51]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:50]([O:52][C:53](=[O:74])[C@H:54]([O:56][C:57]1[CH:62]=[C:61]([NH:9][S:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])[N:60]=[C:59]([S:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[C:67]=2[F:73])[N:58]=1)[CH3:55])[CH3:51]
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)N1CCCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1, step iv) using a mixture of 1-pyrrolidinesulfonamide (prepared according to patent WO 2004/011443, 0.19 g), tris(dibenzylideneacetone)dipalladium (0) (71 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (52 mg), cesium carbonate (0.38 g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of Example 23 step i) (0.30 g) and dioxane (10 mL). Purification was by column chromatography on silica gel using EtOAc/isohexane (1:1) as eluent to give the subtitle compound as an oil. Yield: 0.38 g
Reaction SMILES: [IH:1].[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(O)C>C(OCC)C>[IH:1].[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([F:17])=[CH:19][CH:20]=1)=[NH:11]
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1ccc(F)cc1
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: N=C(NCc1ccc(F)cc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide (U.S. Pat. No. 3,657,337) and 3.75 g. of p-fluorobenzylamine in 25 ml. of absolute ethanol is heated under reflux for 24 hours and then evaporated under reduced pressure, giving a mixture of gum and crystals. This mixture is dissolved in 50 ml. of absolute ethanol and diluted with 175 ml. of diethyl ether. The colorless plates which form are removed by filtration and discarded. The filtrate is diluted with petroleum ether (b.p. 30°-60° C), causing colorless needles to separate. These needles are removed by filtration and recrystallized from a mixture of ethanol-diethyl ether-petroleum ether (b.p. 30°-60° C), giving the desired product as colorless crystals, m.p. 162.5°-164° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][N:9]2[C:13](=[O:14])/[C:12](=[CH:15]/[C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[C:33]([F:36])([F:35])[F:34])[N:20]=[CH:19]4)/[S:11][C:10]2=[O:37])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl[C:39]([O:41][CH3:42])=[O:40]>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:21]2[C:22]3[C:18](=[CH:17][C:16](/[CH:15]=[C:12]4/[C:13](=[O:14])[N:9]([CH2:8][C:2]5([NH:1][C:39](=[O:40])[O:41][CH3:42])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]5)[C:10](=[O:37])[S:11]/4)=[CH:24][CH:23]=3)[CH:19]=[N:20]2)=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:28]=1
Reactant: NC1(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CCOCC1
Reactant: COC(=O)Cl
Product: COC(=O)NC1(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CCOCC1

Procedure:
Methyl (4-{[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}tetrahydro-2H-pyran-4-yl)carbamate was prepared from (5Z)-3-[(4-aminotetrahydro-2H-pyran-4-yl)methyl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (Example 308) and methyl chloroformate following General Procedure R3.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:20])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:19])=[C:14]([C:16](=[O:18])[CH3:17])[CH:15]=1.[CH:21](OCC)=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:20][N:4]([CH3:3])[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[C:14]2[C:13](=[CH:12][CH:11]=1)[O:19][CH:21]=[CH:17][C:16]2=[O:18]
Reactant: CC(=O)c1cc(CCOCCN(C)C)ccc1O
Reactant: CCOC=O
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)CCOCCc1ccc2occc(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 3.0 mL of toluene is suspended 0.44 g of sodium hydride (60% mineral oil suspension), to which is dropwise added, at an ice-cooled temperature, a mixture of 0.93 g of 1-(5-{2-[2-(dimethylamino)ethoxy]-ethyl}-2-hydroxyphenyl)-1-ethanone, 6.0 mL of toluene and 9.0 mL of ethyl formate. The resulting mixture is stirred at ambient temperature for one hour. Ice water and ethyl acetate are added to the reaction mixture, pH is adjusted to 11 with anhydrous potassium carbonate, and the organic layer is separated. The aqueous layer is twice extracted with ethyl acetate, and then the aqueous layer is salted out and further extracted once with ethyl acetate and four times with chloroform. The organic layers are collected and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in 13 mL of acetic acid, 6.5 mL of 12 mol/L aqueous hydrochloric acid is added, and the resulting mixture is stirred at 60° C. for 15 minutes. After cooling, chloroform and water are added, pH is adjusted to 7.0 with anhydrous potassium carbonate, and the organic layer is separated. The organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=50:1 to 5:1) to obtain 6-{2-[2-(dimethylamino)ethoxy]-ethyl}-4H-chromen-4-one as an oily product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[C:9]([CH3:18])=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)=[C:5]([CH3:7])[N:6]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[NH:42]1[CH2:47][CH2:46][CH:45]([C:48]2[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][CH:49]=2)[CH2:44][CH2:43]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:1][C:2]1[NH:3][C:4]([C:8]2[C:9]([CH3:18])=[CH:10][C:11]([CH3:17])=[C:12]([CH:16]=2)[C:13]([N:42]2[CH2:47][CH2:46][CH:45]([C:48]3[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[CH:50][CH:49]=3)[CH2:44][CH2:43]2)=[O:15])=[C:5]([CH3:7])[N:6]=1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1nc(C)c(-c2cc(C(=O)O)c(C)cc2C)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C)[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
A mixture of 5-(2,4-dimethyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 1.8, 280 mg, 1.15 mmol), EDC.HCl (330 mg, 1.72 mmol), 4-dimethylaminopyridine (420 mg, 3.44 mmol), and HOBT (180 mg, 1.33 mmol) in N,N-dimethylformamide (6 mL) was stirred at room temperature. After 5 min, 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 230 mg, 1.03 mmol) was added and the resulting solution was stirred at room temperature for 15 h, then quenched with ice water (20 mL). The aqueous was extracted with ethyl acetate (50 mL) and the combined organics was washed with brine (2×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (22% CH3CN up to 37% in 7 min, up to 100% in 2 min, down to 22% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (214 mg, 50%). m/z (ES+) 413 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.68 (d, J=7.8 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.36 (br s, 1H), 7.27 & 7.16 (2 singlets, rotamers, Ar—H, 1H), ˜4.9-4.82 (m, 1H partially obscured by water peak), 3.72-3.55 (m, 1H), ˜3.35-3.20 (m, 1H partially overlapped with methanol solvent peak), 3.08-2.92 (m, 2H), 2.65 (s, 3H), 2.44 & 2.34 (2 singlets, rotamers, Ar—CH3, 3H), 2.29 (s, 3H), 2.22 (s, 3H), 2.10-1.96 (m, 1H), 1.93-1.53 (m, 3H).