Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.ClCCl>[C:9]1([S:15]([N:1]([C:2]2[C:6]([Br:7])=[C:5]([CH3:8])[O:4][N:3]=2)[S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1onc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1onc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 25 h
Yield: 72.9 %

Procedure:
3-Amino-4-bromo-5-methylisoxazole (5.31 g, 30 mmol) was dissolved in dry pyridine (30 ml). Benzenesulfonyl chloride (5.24 ml, 42 mmol) was added dropwise with stirring at ambient temperature. N,N-(Dimethyl)aminopyridine (100 mg) was added and stirring was continued at 50° C. for 25 h. The reaction mixture was diluted with dichloromethane (200 ml), washed with 1N HCl (6×100 ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product which was purified by column chromatography using 9:1, hexanes/ethyl acetate as eluent to give N-(benzenesulfonyl)-N-(4-bromo-5-methyl-3-isoxazolyl)benzenesulfonamide (7 g, 51% yield, Rf=0.27 using 3:1, hexanes/ethyl acetate as eluent) as a solid.
Reaction SMILES: [C:1]([C:3]([CH:9]1[CH2:11][CH2:10]1)([CH3:8])[CH2:4][C:5]([OH:7])=O)#[N:2].Cl.[NH2:13][C:14]1[N:19]=[C:18]([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][N:26](C(OC4CCNCC4)=O)[CH2:27]3)=[CH:22][CH:21]=2)[CH:17]=[C:16]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)[N:15]=1>>[NH2:13][C:14]1[N:19]=[C:18]([C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][N:26]([C:5](=[O:7])[CH2:4][C:3]([CH:9]4[CH2:11][CH2:10]4)([CH3:8])[C:1]#[N:2])[CH2:27]3)=[CH:22][CH:21]=2)[CH:17]=[C:16]([N:39]2[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]2)[N:15]=1
Reactant: CC(C#N)(CC(=O)O)C1CC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC(C)(C#N)C3CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 4 starting from 3-cyano-3-cyclopropylbutanoic acid and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=460.1.
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][C@@H:34]2[C:39]3[CH:40]=[CH:41][S:42][C:38]=3[CH2:37][CH2:36][C@@H:35]2[CH2:43][CH2:44][CH3:45])=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][C@@H:34]2[C:39]3[CH:40]=[CH:41][S:42][C:38]=3[CH2:37][CH2:36][C@@H:35]2[CH2:43][CH2:44][CH3:45])=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCC[C@H]1CCc2sccc2[C@H]1Nc1nc(CC)cnc1CC
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCC[C@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(Br)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-[Cis-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.06, 6.88, 5.61, 4.28, 2.97–2.80, 2.54, 2.05–1.92, 1.74, 1.49–1.21, 0.87; HRMS (FAB) calcd for C19H26BrN3S+H 408.1109, found 408.1108.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=[N:7][C:6]=12.[CH3:17][N:18](C)C=O>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2[N:5]3[N:4]=[CH:3][C:2]([C:17]#[N:18])=[C:6]3[N:7]=[CH:8][CH:9]=2)[CH:12]=1
Reactant: CN(C)C=O
Reactant: Brc1cnn2c(-c3cccnc3)ccnc12
Product: N#Cc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 1.0 g. of 3-bromo-7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine and 0.50 g. of cuprous cyanide in 25 ml. of N,N-dimethylformamide is heated at reflux temperature for 16 hours. The solvent is removed in vacuo and the residue is triturated with dichloromethane. The dichloromethane solution is passed through a column of hydrous magnesium silicate. The eluent is concentrated and hexane added to give the product of the example as tan crystals, m.p. 258°-260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:25]2[CH2:27][CH2:26]2)=[CH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1>[Ni].C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:25]2[CH2:26][CH2:27]2)[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(=CCCc2cccc(Oc3ccccc3)c2)C2CC2)cc1
Agent: [Ni]
Solvent: CCO
Product: Clc1ccc(C(CCCc2cccc(Oc3ccccc3)c2)C2CC2)cc1
Yield: 78.6 %

Procedure:
This compound was prepared in a manner analogous to that of Example 4, Step E, by hydrogenation of 1.0 gram (0.0027 mole) of 1-(4-chlorophenyl)-1-cyclopropyl-4-(3-phenoxyphenyl)-1-butene in the presence of 0.35 gram of Raney nickel in 75 mL of ethanol. This procedure yielded 0.8 gram of 1-(4-chlorophenyl)-1-cyclopropyl-4(3-phenoxyphenyl)butane as an a oil. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [I-:1].[Na+].Cl/[CH:4]=[CH:5]/[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>CC(C)=O>[I:1]/[CH:4]=[CH:5]/[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(=O)/C=C/Cl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(=O)/C=C/I

Procedure:
A mixture of 54.5 g. (0.364 mole) of sodium iodide and 40 g. (0.249 mole) of 1-chloro-trans-1-octen 3-one (Example 723) in 360 ml. of acetone is stirred and refluxed for 24 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between water and ether. The organic phase is washed with dilute sodium bicarbonate solution, brine, dried (MgSO4) and evaporated to an oil. This material is used directly without purification.
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[CH:15]=[C:14]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(=O)([O-])[O-].[K+].[K+].BrC1C=CC(S(O[CH2:52][C:53](=[O:75])[C@@H:54]2[C@:71]3([CH3:72])[C@H:57]([C@H:58]4[C:68](=[CH:69][CH2:70]3)[C@:66]3([CH3:67])[C:61](=[CH:62][C:63](=[O:73])[CH:64]=[CH:65]3)[CH2:60][CH2:59]4)[CH2:56][C@H:55]2[CH3:74])(=O)=O)=CC=1>C(#N)C>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[CH:15]=[C:14]([N:29]4[CH2:30][CH2:31][N:32]([CH2:52][C:53](=[O:75])[C@@H:54]5[C@:71]6([CH3:72])[C@H:57]([C@H:58]7[C:68](=[CH:69][CH2:70]6)[C@:66]6([CH3:67])[C:61](=[CH:62][C:63](=[O:73])[CH:64]=[CH:65]6)[CH2:60][CH2:59]7)[CH2:56][C@H:55]5[CH3:74])[CH2:33][CH2:34]4)[N:13]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: c1c(NC23CC4CC(CC(C4)C2)C3)nc(NC23CC4CC(CC(C4)C2)C3)nc1N1CCNCC1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(NC34CC5CC(CC(C5)C3)C4)nc(NC34CC5CC(CC(C5)C3)C4)n2)CC1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
After adding 1.88 g (4.07 mmoles) of 2,4-bis(1-adamantylamino)-6-(1-piperazinyl)pyrimidine and 0.56 g of potassium carbonate to a solution containing 2.00 g (3.57 mmoles) of 21-(4-bromobenzenesulfonyloxy)-16α-methylpregna-1,4,9(11)-triene-3,20-dione in 100 ml of acetonitrile, the reaction mixture is stirred at a temperature of 65° C. for 5 hours, then evaporated. The residue is distributed between 40 ml of chloroform and 10 ml of water. After separation the chloroform layer is dried and evaporated. The residue is purified by chromatography on a silica gel column by using a 98:2 mixture of chloroform/methanol as eluent. After recrystallization from ether the title compound is obtained in a yield of 2.48 g (88.5%), m.p.:210°-220° C.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[S:16][C:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1>[Cu]I>[N:23]1[CH:22]=[CH:21][C:20]([C:17]2[S:16][C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])=[N:19][N:18]=2)=[CH:25][CH:24]=1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1nnc(-c2ccncc2)s1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1nnc(-c2ccncc2)s1

Procedure:
The compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-bromo-5-(4-pyridyl)-1,3,4-thiadiazole using 5 equivalents of copper (I) iodide. The title compound was obtained as a beige solid, m/z 344 (MH+).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]12(O)[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.B(F)(F)F.CCOCC>CCCCC>[C:21]12([C:8]3[C:9]([OH:20])=[CH:10][C:11]4[CH2:12][CH2:13][C@@H:14]5[C@@H:5]([C:6]=4[CH:7]=3)[CH2:4][CH2:3][C@@:2]3([CH3:1])[C@H:15]5[CH2:16][CH2:17][C:18]3=[O:19])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCCCC
Product: C[C@]12CC[C@@H]3c4cc(C56CC7CC(CC(C7)C5)C6)c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
Estrone [3-hydroxyestra-1,3,5(10)-trien-17-one, 270 mg, 1 mmol) and 1-adamantanol (170 mg, 1 mmol) were added to anhydrous n-pentane (6 mL) and the stirred mixture was cooled with an ice bath. Boron trifluoride etherate (BF3.EtOEt, 0.4 mL) was added over a 10 minute period. After an additional 15 minutes, the ice bath was removed and stirring was continued for an additional 45 minutes at room temperature. During the 45 minute period, solids present in the reaction mixture were dissolved and a yellow oil formed. Crushed ice was then added while shaking and swirling the reaction flask and a pink solid was formed. The filtered, crude pink product was washed with water until the filtrate had a neutral pH, and then the solid was dried in a vacuum oven at 50° C. The crude pink powder (0.4 g) was purified by flash chromatography (silica gel eluted with 20% ethyl acetate in hexanes) to get the pure product (0.31 g, 76.7%). The product was recrystallized from a mixture of chloroform and isopropyl alcohol and characterized as follows: (i) melting point=322-324° C. (see, e.g., Lunn, W. H. W.; Farkas, E., Adamantyl Carbonium Ion as a Dehydrogenating Agent: Its Reactions with Estrone, Tetrahedron 1969, 24, 6773-76, citing melting point as 295-296° C.); (ii) 1H NMR (CDCl3, 300 MHZ) δ0.94 (s, 3H, C18—CH3), 2.8 (m, 2H, C6—CH2) 4.7 (s, 1H, C3—OH), 6.4 (s, 1H, C4—H), 7.12 (s, 1H, C1—H); (iii) 13C NMR (CDCl3, 300 MHZ) δ13.76, 21.47, 25.93, 26.41, 28.63, 28.95 (3×C), 31.56, 35.81, 36.56, 36.98 (3×C), 38.42, 40.69 (3×C), 44.25, 47.99, 50.35, 116.87, 124.11, 131.59, 134.00, 135.02, 152.44, 221.43. (Chemical Abstracts Registry Number [21003-01-0].)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:40])([F:39])[C:13]([CH2:34][NH:35][CH2:36][CH2:37][CH3:38])([OH:33])[CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:35]([CH2:36][CH2:37][CH3:38])[CH2:34][C:13]([CH2:14][NH:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)([OH:33])[C:12]([F:11])([F:40])[F:39])=[O:6]
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1Cl
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 1 from 2-chlorobenzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][O:28]COC)[CH:25]=3)[C:7]2=[O:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+:33]>O1CCOCC1.[Cl-].[Na+].O>[NH2:33][C:13]1[N:14]=[C:15]([CH3:16])[C:10]2[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=3)[C:7](=[O:32])[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:11]=2[N:12]=1
Reactant: COCOCCn1cc(-c2cc3c(C)nc(S(C)(=O)=O)nc3n(C3CCCC3)c2=O)cn1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(N)nc2c1cc(-c1cnn(CCO)c1)c(=O)n2C1CCCC1
Temperature: 100 °C
Yield: 54 %

Procedure:
To the solution of 8-cyclopentyl-6-(1-(2-(methoxymethoxy)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (80 mg, 0.17 mmol) in 5 ml 1,4-dioxane was babbled through ammonium gas for 10 minutes. The reaction tube was sealed and heated to 100° C. for 30 minutes. The reaction mixture was poured into brine and the precipitate was collected via filtration. The solid was then re-dissolved in 5 ml methanol and a few drop of concentrated HCl was added and the mixture was heated to 50° C. for 5 hours. The reaction mixture was cooled down to room temperature. Solvent was removed via rot vap and the residue was triturated with ethylacetate/hexane to give the title compound (33 mg, 54% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH2:25])=O>ClC(Cl)C.C(Cl)(Cl)(Cl)Cl>[F:20][C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]#[N:25]
Reactant: NC(=O)c1cccnc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cccnc1F
Temperature: 25 °C
Yield: 64.8 %

Procedure:
Add resin bound triphenylphosphine (4.0 g, 12.0 mmol) to a solution of 2-fluoro-nicotinamide (0.6 g, 4.3 mmol) in dichloroethane (20.0 mL) and carbon tetrachloride (20.0 mL). Reflux for 18 hours, cool to RT, filter, and concentrate the filtrate under vacuum. Purify by flash column on silica gel eluting with 10-60% EtOAc in hexanes to give the title compound (0.34 g, 64%). MS (ES) 123.1 (M+1)+. 1H NMR (400 MHz, CHCl3) δ 8.46 (m, 1H), 8.09 (m, 1H), 7.37 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([N:13]1[C:17]([CH3:18])=[C:16]([Cl:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[N:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[Li+].[OH-]>C1COCC1.O>[Cl:19][C:16]1[C:15]([C:20]([F:22])([F:21])[F:23])=[N:14][N:13]([CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[C:3]([OH:24])=[O:2])[C:17]=1[CH3:18]
Reactant: COC(=O)C(c1cccc(OC)c1)n1nc(C(F)(F)F)c(Cl)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(C(=O)O)n2nc(C(F)(F)F)c(Cl)c2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-acetic acid methyl ester was then dissolved in THF (20 ml) and LiOH (0.39 g) in water (5 ml) were added. The mixture was stirred at room temperature for 4 h. After this period the THF was completely evaporated from the reaction mixture under vacuum. The remaining aqueous layer was extracted with ethyl acetate (3×5 ml) and the organic layer was discarded. The aqueous layer was cooled in ice and neutralized by using concentrated HCl. This neutral aqueous layer was extracted with ethyl acetate (3×10 ml), the organic layer dried over Na2SO4, concentrated and purified by flash chromatography (CHCl3/MeOH) to yield (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-(3-methoxy-phenyl)-acetic acid
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CS(O[CH2:20][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)(=O)=O.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:21]1([CH2:20][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CS(=O)(=O)OCC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CC3CCCC3)c2)OC1(C)C
Temperature: 110 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol), cyclopentylmethyl methanesulfonate (0.10 g, 0.58 mmol), and sodium hydride (31 mg, 0.77 mmol) in N,N-dimethylformamide (1 mL) was stirred at 110° C. for 2 h. After cooling it was diluted with ethyl acetate, washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 0.11 g of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[CH:12]=O.Cl.[NH2:15]O.C([O-])=O.[Na+].C(O)=O>O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[C:12]#[N:15]
Reactant: NO
Reactant: O=Cc1coc2ccccc2c1=O
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1coc2ccccc2c1=O

Procedure:
A mixture of 26.1 g. (0.15 mole) of 4-oxo-4H-1-benzopyran-3-carboxaldehyde, 13.1 g. (0.19 mole) of hydroxylamine hydrochloride, 18.4 g. (0.27 mole) of sodium formate and 250 ml of 99% formic acid was heated with stirring at reflux for 21/2 hours. Water was added to 1-liter volume. The separated solid was filtered from the cooled mixture, washed well with water and dried to give 13 g. (51%) of crude nitrile melting at 138°-145°C. Recrystallization from ethylacetate gave pure, white crystals melting at 174°-176°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([NH:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:11][S:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)(=[O:22])=[O:21])[C:5]([NH:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNc1ncc(Br)cc1N
Product: CCNc1ncc(Br)cc1NS(=O)(=O)c1ccc(OC)cc1
Yield: 34.8 %

Procedure:
5-Bromo-N2-ethylpyridine-2,3-diamine (290 mg, 1.34 mmol, purchased from Aurora Building Blocks reference A01.414.067) was treated with 4-methoxybenzene-1-sulfonyl chloride (280 mg, 1.35 mmol) according to the method described in Preparation 15b to give 180 mg (35% yield) of the title compound as an oil. Purity 99%.
Reaction SMILES: [H-].[Na+].S([NH:13][N:14]=[C:15]([CH2:17]P(OCC)(OCC)=O)[CH3:16])(C1C=CC(C)=CC=1)(=O)=O.[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1>C1COCC1.CN(C=O)C>[C:26]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][C:29]([C:32]2[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=2)=[CH:28][CH:27]=1
Reactant: CCOP(=O)(CC(C)=NNS(=O)(=O)c1ccc(C)cc1)OCC
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(-c3ccccc3)cc2)[nH]n1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a stirred mixture of NaH (1.98 g, 0.049 mol, 60% oil dispersion) in dry THF (30 mL) was added a suspension of diethoxyphosphorylacetone tosyl hydrazone (8.97 g, 0.024 mol; N Almirante Syn. Lett. 1999, 302.) in a mixture of THF (35 mL) and DMF (5.0 mL) dropwise over 15 min. The yellow suspension was stirred at 0-5° C. for 30 min and was treated with a 4-biphenyl carboxaldehyde (3.10 g, 0.0169 mol) in dry THF (30 mL) at 0-5° C. over 15 min. The orange solution was heated and stirred at reflux for 4 h and stirred at ambient temperature overnight. The mixture was poured into 5% aq. NaH2PO4 (350 mL) and extracted with EtOAc (2×200 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated to a yellow semi-solid. This material was triturated with hot EtOAc (20 mL) and filtered. The solid was washed with EtOAc (2×10 mL) and dried under high vacuum to give the title compound (2.61 g, 47%): HRMS Calculated for C16H15N2: m/z 235.1235. Found: 235.1230.
Reaction SMILES: C([NH:9][C:10]1[O:11][C@H:12]([C:35]([F:38])([F:37])[F:36])[CH2:13][C@:14]([C:17]2[CH:18]=[C:19]([NH:24][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([O:33][CH3:34])[CH2:29][CH2:28]3)=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])([CH3:16])[N:15]=1)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[O:11][C@H:12]([C:35]([F:36])([F:38])[F:37])[CH2:13][C@:14]([C:17]2[CH:18]=[C:19]([NH:24][C:25]([N:27]3[CH2:28][CH2:29][CH:30]([O:33][CH3:34])[CH2:31][CH2:32]3)=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])([CH3:16])[N:15]=1
Reactant: COC1CCN(C(=O)Nc2ccc(F)c([C@]3(C)C[C@@H](C(F)(F)F)OC(NC(=O)c4ccccc4)=N3)c2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: COC1CCN(C(=O)Nc2ccc(F)c([C@]3(C)C[C@@H](C(F)(F)F)OC(N)=N3)c2)CC1
Temperature: 60 °C
Yield: 50.9 %

Procedure:
To a solution of N-(3-((4S,6S)-2-benzamido-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-4-methoxypiperidine-1-carboxamide (0.166 g, 0.309 mmol) in MeOH (3 mL) at room temperature was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.100 mL, 0.669 mmol). The reaction was heated at 60° C. for 4 h. Then the reaction was cooled to room temperature, diluted with MeOH, purified by reverse-phase HPLC (Gilson; Gemini-NX 10m C18 110A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O:0.1% TFA CH3CN (9:1→1:9). The fractions containing the desired product were combined and concentrated in vacuo. The material was dissolved in MeOH and eluted with MeOH, through an Silicycle carbonate cartridge to give the titled compound as a white crystalline solid (68 mg, 51%). MS m/z=433 [M+H]+. Calculated for C19H24F4N4O3: 432
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[CH3:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH:11]=1)(=[O:8])=[O:7]>C1(C)C=CC=CC=1>[CH3:5][S:6]([O:9][C:10]1[CH:15]=[CH:14][C:13]2[O:16][S:1](=[O:2])[O:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:12]=2[CH:11]=1)(=[O:8])=[O:7]
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)COS(=O)Oc2ccc(OS(C)(=O)=O)cc21
Temperature: 50 °C
Yield: 90 %

Procedure:
Thionyl chloride (12 parts) was added dropwise at room temperature to a suspension of 4-hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl methanesulphonate (5 parts) (from Example 1) in toluene (50 parts). The mixture was gently warmed to 50° C. when reaction commenced, then maintained at this temperature for 15 minutes. The temperature was then raised to boiling point and the mixture boiled under reflux for 2 hours. The solvent was then evaporated off under reduced pressure to give crude 4,5-dihydro-5,5-dimethyl-2-oxido-1,3,2-benzodioxathiepin-7-yl methanesulphonate (5.2 parts, 90% yield). Recrystallization from ethanol gave the pure product (2.4 parts), melting point 96°-98° C.
Reaction SMILES: B.[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](O)=[O:14]>O1CCCC1>[Br:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: O=C(O)CCCCCCCCCCBr
Agent: B
Solvent: C1CCOC1
Product: OCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A 250 ml. of solution of 1 M borane in tetrahydrofuran is cooled in an ice-water bath, and to this is slowly added 50 g. 11-bromoundecanoic acid in 150 ml. dry tetrahydrofuran. After stirring at room temperature for 19 hours the reaction is quenched by the addition of 300 ml. 10% hydrochloric acid. The aqueous solution is extracted three times with 150 ml. portions of ether, the organic layers are combined, washed with saturated brine, dried with anhydrous magnesium sulfate and evaporated. Distillation of the residue yields 11-bromoundecanol as a colorless liquid.