Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](Cl)=[O:48])=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:47](=[O:48])[CH2:46][C:43]3[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=3)[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)Cc1ccc(F)cc1)CC2(C)C
Temperature: 25 °C
Yield: 11.8 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10.1 mg, 0.024 mmol) in CH2Cl2 (5 mL) was added Et3N (9.85 μl, 0.071 mmol) followed by 2-(4-fluorophenyl)acetyl chloride (6.10 mg, 0.035 mmol) and the resulting mixture stirred at room temperature. (Mixture became a clear, colorless solution within 30 min.) After 3 h, the solvent was removed and the residue was taken up in MeOH/DMF and purified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm). The product containing fractions were concentrated to remove the organic solvent and the resulting precipitate isolated by filtration and washed with water to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-6-(2-(4-fluorophenyl)acetyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (1.6 mg, 11.78% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.13-7.53 (5H, m), 6.88-7.09 (3H, m), 4.80-4.88 (1H, m), 4.32-4.46 (0.5H, m), 4.18-4.32 (1H, m), 3.97 (0.5H, d, J=16.56 Hz), 3.79-3.92 (1.5H, m), 3.55-3.68 (3H, m), 3.52 (0.5H, d, J=13.05 Hz), 1.37 (3H, d, J=6.53 Hz), 1.32 (3H, d, J=7.53 Hz), 1.27 (3H, dd, J=6.27, 5.02 Hz), 1.15 (3H, dd, J=6.53, 4.77 Hz), 0.91-1.06 (9H, m). 19F NMR (400 MHz, CD3OD) δ ppm −114.90, −115.19, −117.98, −118.41. LCMS (M+H) calcd for C33H39F2N2O4: 565.28. found: 565.4.
Reaction SMILES: [CH:1]1([CH:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]=[C:13]([CH3:15])[CH3:14]>>[CH:1]1([CH:7]([CH3:11])[C:8]([O:10][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C(=O)O)C1CCCCC1
Reactant: C=C(C)C
Product: CC(C(=O)OC(C)(C)C)C1CCCCC1

Procedure:
2-Cyclohexylpropionic acid is reacted with isobutene in the presence of an acid catalyst according to the following reaction scheme to obtain tert-butyl 2-cyclohexylpropionate. ##STR7##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:50][CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][CH:56]([OH:59])[CH2:55][CH2:54]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:59][CH:56]1[CH2:57][CH2:58][N:53]([CH2:52][CH2:51][NH:50][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:54][CH2:55]1
Reactant: NCCN1CCC(O)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), DIPEA (115 mg, 5 eq.) and 1-(2-amino-ethyl)-piperidin-4-ol TFA salt (88 mg, 1.2 eq.) in 2 mL) was stirred at rt for 45 mins. To the mixture was added HATU (83 mg, 1.1 eq.). After stirring for 18 hours, the reaction was concentrated and purified on a silica gel column to give the titled compound as a yellow solid.
Reaction SMILES: CN(C=O)C.O[C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]2[N:15]=[C:16]([S:18][CH3:19])[S:17][C:8]=12.O=S(Cl)[Cl:22]>O>[Cl:22][C:7]1[C:12]([C:13]#[N:14])=[CH:11][N:10]=[C:9]2[N:15]=[C:16]([S:18][CH3:19])[S:17][C:8]=12
Reactant: O=S(Cl)Cl
Reactant: CSc1nc2ncc(C#N)c(O)c2s1
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ncc(C#N)c(Cl)c2s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of Compound 1f (34.6 g, 120 mmol), DMF-dimethyl acetal (34.0 mL, 240 mmol, 94% purity) and DMF (200 mL) were combined and heated to 80° C. for 90 minutes. The conversion to the cyclized intermediate, 7-hydroxy-2-methylsulfanyl-thiazolo[4,5-b]pyridine-6-carbonitrile was confirmed by LCMS (MS 298, MH+). The mixture was then cooled to 0° C. and SOCl2 was added dropwise (44 mL, 600 mmol). The reaction mixture was stirred for 2 hrs at ambient temperature. The mixture was then cooled back down to 0° C. and water (approximately 300 mL) was added dropwise. The resulting brown solid was collected by filtration and subsequently washed with water and MeOH to provide 7-chloro-2-methylsulfanyl-thiazolo[4,5-b]pyridine-6-carbonitrile Compound 1g (16.1 g) as a tan solid. 1H NMR (CDCl3) δ 8.82 (s, 1H), 2.91 (s, 3H). MS 242, 244 (MH+), 264, 266 (MNa+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:9]=[C:10]([N+:14]([O-])=O)[CH:11]=[CH:12][CH:13]=1)[CH2:5][CH2:6][Cl:7].O.O.[Sn](Cl)Cl.N.Cl.O1CCOCC1>Cl.O>[ClH:1].[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[NH2:14])[CH2:5][CH2:6][Cl:7]
Reactant: O=[N+]([O-])c1cccc(N(CCCl)CCCl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc(N(CCCl)CCCl)c1
Temperature: 25 °C
Yield: 192.1 %

Procedure:
3-[N,N-Bis(2-chloroethyl)amino]nitrobenzene (2.0 g; 7.6 mmol) was dissolved in 35 ml of concentrated hydrochloric acid, followed by the addition of 6.9 g (30.6 mmol; 4.0 equivalents) of tin(II) chloride dihydrate. The resultant mixture was stirred under heat for 1 hour over an oil bath controlled at 100° C. The reaction mixture was allowed to cool down to room temperature, followed by dilution with water. The diluted solution was basified with concentrated aqueous ammonia and then extracted twice with ethyl acetate. The extract was dried over sodium sulfate and then concentrated under reduced pressure. The residue so obtained was added with 4N hydrochloric acid/dioxane and concentrated. The concentrate was then crystallized from a small amount of methanol/ether, whereby 1.97 g (7.3 mmol) of the title compound were obtained as yellow crystals (yield: 96.1%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[N:4]([CH2:13][CH2:14][CH3:15])[C:3]1=[O:16].[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1/[CH:22]=[CH:12]/[C:5]1[N:4]([CH2:13][CH2:14][CH3:15])[C:3](=[O:16])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=1[N+:9]([O-:11])=[O:10])[CH3:18]
Reactant: CCCn1c(C)c([N+](=O)[O-])c(=O)n(C)c1=O
Reactant: CCOc1ccccc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCn1c(/C=C/c2ccccc2OCC)c([N+](=O)[O-])c(=O)n(C)c1=O
Yield: 75.1 %

Procedure:
A mixture of 3,6-dimethyl-5-nitro-1-propyl-1H-pyrimidine-2,4-dione (6.25 g, 27.5 mmol), 2-ethoxybenzaldehyde (4.24 mL, 30.3 mmol), piperidine (2.83 mL, 28.6 mmol) and 3 Å molecular sieves (8.75 g) in ethanol (125 mL) was refluxed for 5 hours. The resulting suspension was filtered and the filtrate was evaporated under reduced pressure. The residue was triturated with isopropyl ether and the precipitate collected by filtration and dried under vacuum to yield 6-[(E)-2-(2-ethoxyphenyl)vinyl]-3-methyl-5-nitro-1-propyl-1H-pyrimidine-2,4-dione (7.42 g, 75%) as a yellow solid.
Reaction SMILES: [C:1]1([C:6]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]2=[O:18])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21]>C(#N)C>[Cl:19][S:20]([NH:23][C:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:8]([C:6](=[O:7])[C:1]2[S:5][CH:4]=[CH:3][CH:2]=2)[C:9]1=[O:18])=[O:25])(=[O:22])=[O:21]
Reactant: O=C1Nc2ccc(Cl)cc2C1C(=O)c1cccs1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Product: O=C(c1cccs1)C1C(=O)N(C(=O)NS(=O)(=O)Cl)c2ccc(Cl)cc21

Procedure:
To a stirred slurry of 1.5 g. (5.4 mmole) of 3-(2-thenoyl)-5-chloro-2-oxindole in 15 ml. of dry acetonitrile was added 0.52 ml. (5.9 mmole) of chlorosulfonyl isocyanate, and the reaction mixture was stirred at room temperature for 2 hours. A small sample was removed, filtered and evaporated in vacuo to give a small sample of N-chlorosulfonyl-3-(2-thenoyl)-5-chloro-2-oxindole-1-carboxamide, mp 166°-169° C. To the remainder of the reaction mixture, 30 ml. of water was added slowly with stirring and stirring was continued for 1 hour. The reaction mixture was then poured into 50 ml. of 1N hydrochloric acid containing ice chips, and the resulting mixture was stirred for 20 minutes. The yellow solid was recovered by filtration, washed with water and diisopropyl ether and recrystallized from glacial acetic acid to give 200 mg. of a first crop of the title compound, mp 213°-215° C. The mother liquors from which the first crop had been recovered deposited a further yellow solid. The latter solid was recovered by filtration to give 470 mg. of a second crop of the title compound. The second crop was recrystallized from glacial acetic acid and combined with the first crop and recrystallized from glacial acetic acid. This gave 280 mg. of the title compound, mp 232°-234° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:63]=[CH:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH:55]=3)[OH:53])[CH:46]([O:64][CH3:65])[CH2:45]2)[CH:7]([CH3:67])[CH:6]([O:68][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:76])[CH3:2]>N1C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:63]=[CH:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH:55]=3)[OH:53])[CH:46]([O:64][CH3:65])[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:76])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccc5ccccc5c4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: c1ccncc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccc5ccccc5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC

Procedure:
The product from Step A was deprotected with HF/pyridine as described in Step B from above to afford 190 mg of the title compound as a colorless solid (1H NMR was consistent with the desired structure).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].CCOC(/N=N/C(OCC)=O)=O.[Br:20][C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][C:22]=1[CH3:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[CH:23][C:22]=1[CH3:28]
Reactant: Cc1cc(O)ccc1Br
Reactant: CN(C)CCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCCN(C)C)ccc1Br
Reaction time: 2 h
Yield: 60.4 %

Procedure:
3-Dimethylamino-propan-1-ol (251 μL, 2.14 mmol) and DEAD (973 μL, 2.14 mmol) were added to a solution of 4-bromo-3-methyl-phenol (200 mg, 1.07 mmol) and PPh3 (561 mg, 2.14 mmol) in THF (10 mL) at 0° C. The mixture was stirred for two hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give [3-(4-bromo-3-methyl-phenoxy)-propyl]-dimethyl-amine (176 mg, 61%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH3:4].[C:5]([OH:9])(=[O:8])[CH:6]=[CH2:7].COC1C=CC(O)=CC=1>>[C:5]([O:9][CH:2]([CH2:3][CH3:4])[CH3:1])(=[O:8])[CH:6]=[CH2:7]
Reactant: C=CCC
Reactant: C=CC(=O)O
Agent: COc1ccc(O)cc1
Product: C=CC(=O)OC(C)CC
Temperature: 100 °C
Reaction time: 4 h

Procedure:
0.9 mol (51 g) of liquid 1-butene, one mole (72 g) of acrylic acid, 11 g (8.5 % by weight/charge) of ZrSA15 and 0.018 g (250 ppm relative to the acrylic acid) of hydroquinone methyl ether, which serves as a stabilizing agent, are charged at room temperature into a stainless steel reactor with a capacity of 200 ml, fitted with a thermometer and a manometer. The reactor is closed and is immersed in an oil bath at 150° C. The reaction medium is maintained at 100° C. with stirring for four hours. The pressure falls from 10 bar at the start of the reaction to 4 bar at the end of the reaction. At the end of the reaction, the reaction mixture is cooled to room temperature. The reactor is then opened so as to degas the unreacted butene.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](F)[C:3]=1[C:13]([CH3:15])=[CH2:14].[CH3:16][S-:17].[Na+].CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:17][CH3:16])[C:3]=1[C:13]([CH3:15])=[CH2:14]
Reactant: C[S-]
Reactant: C=C(C)c1c(Cl)ccc(C(=O)OC)c1F
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(C)c1c(Cl)ccc(C(=O)OC)c1SC
Temperature: 50 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
A mixture of methyl 4-chloro-2-fluoro-3-isopropenylbenzoate (8.6 g) and sodium thiomethoxide (3.15 g) in dimethyl formamide was heated at 50° C. for 3 hours and stirred at room temperature overnight. Ether was added and the mixture was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography eluted with a mixture of ethyl acetate and hexane to give methyl 4-chloro-3-isopropenyl-2-(methylsulphenyl)benzoate (5.95 g) as a clear oil NMR (CDCl3) 2.1(s,3H), 2.35(s,3H), 3.95(s,3H), 4.9(s,1H), 5.4(s,1H), 7.45(s,2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:5]=[C:4](O)[CH:3]=1.N1C=CC=CC=1C.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:4]1[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(O)nc(SCc2ccccc2F)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccn1
Product: Nc1cc(Cl)nc(SCc2ccccc2F)n1

Procedure:
The product of example 4, step (a) (34 g) was added to a solution of 2-picoline (20 ml) in POCl3 (150 ml) and the mixture refluxed for 24 hr. The reaction mixture was concentrated in vacuo to half its original volume and poured onto ice and then neutralized with ammonia, forming a brown gum. The aqueous phase was decanted off, and the organic residues dissolved in ethyl acetate. This solution was recombined with the aqueous phase, and refluxed for 1 hr. The organic phase was separated, evaporated, and the residue purified by silica gel chromatography, eluting with dichloromethane to afford the subtitled compound as a pale yellow solid (15.6 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])=[C:13]([O:27]C)[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])=[C:13]([OH:27])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NS(=O)(=O)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NS(=O)(=O)c3ccccc3)c(O)c1)cn2C1CCCC1

Procedure:
In a similar manner to Example 33, N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]benzenesulphonamide was reacted with boron tribromide in dichloromethane at -10° C. to give N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-hydroxyphenyl]benzenesulphonamide, m.p. 265-267° C. The structure was confirmed by 1H nmr and mass spectra.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:16]P(OCC)(OCC)=O)=[N:11][C:12]=2[CH:13]=[CH:14][CH:15]=1)=[O:5])C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:33]2[N:37]3[N:38]=[CH:39][CH:40]=[C:41]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[C:36]3=[N:35][C:34]=2[CH:48]=O)[CH:30]=[CH:31][CH:32]=1>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:33]2[N:37]3[N:38]=[CH:39][CH:40]=[C:41]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[C:36]3=[N:35][C:34]=2/[CH:48]=[CH:16]/[C:10]2[CH:9]=[CH:8][C:7]3[C:6]([C:4]([OH:3])=[O:5])=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: COc1cccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)c1
Reactant: CCOC(=O)c1cccc2nc(CP(=O)(OCC)OCC)ccc12
Product: COc1cccc(-c2c(/C=C/c3ccc4c(C(=O)O)cccc4n3)nc3c(N4CCOCC4)ccnn23)c1

Procedure:
Compound 73d (53 mg, 0.15 mmol) was reacted under Horner-Emmons coupling conditions with compound 77a (51 mg, 0.15 mmol) using the procedures described in Example 20, Step A to afford compound 77b. Mass spectrum (LCMS, ESI pos.) Calcd. For C29H25N5O4 508.2 (M+H). found 508.2.
Reaction SMILES: [CH2:1]([C@:8]12[C:21]3[C:16](=[CH:17][C:18](Br)=[CH:19][CH:20]=3)[CH2:15][CH:14]=[C:13]1[CH:12]=[C:11]([O:23][CH2:24][CH3:25])[CH2:10][CH2:9]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH2:1]([C@@:8]12[CH2:9][CH2:10][C:11]([O:23][CH2:24][CH3:25])=[CH:12][C:13]1=[CH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:26]#[N:27])[CH:19]=[CH:20][C:21]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC1=CC2=CCc3cc(Br)ccc3[C@]2(Cc2ccccc2)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC1=CC2=CCc3cc(C#N)ccc3[C@]2(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 96 %

Procedure:
Zinc cyanide (13.4 g, 114 mmol) was added to a solution of 4a(S)-Benzyl-7-bromo-2-ethoxy-3,4,4a,9-tetrahydro-phenanthrene (30 grams, 75.9 mmol) in DMF (200 mL) followed by tetrakis(triphenylphosphine)palladium(0), (10.5 g, 9.11 mmol) in a flask outfitted with a bleach scrubbing system. Additional dimethyl formamide (400 mL) was used to wash the sides of the flask and funnel. The suspension was heated to 80° C. After 7 hours HPLC showed no starting material and the reaction was cooled to room temperature. The suspension was diluted with EtOAc (300 mL) and filtered through a pad of Celite. The filtrate was washed with 2N NH4OH (2 times 500 mL), brine (500 mL) and water (500 mL). Upon addition of water solids began to precipitate out so additional EtOAc (200 mL) was added. The organic layer was concentrated to ½ volume and diluted with ethanol (250 mL) and water (250 mL). The resulting solids were allowed to granulate for 1 hour and then filtered. The mother liquor was concentrated slightly and a second crop was collected. After the combined crops air dried overnight a white solid was collected: 24.9 grams (72.9 mmol), 96% yield; mp 164-165° C., IR (film) ν 2227, 1657, 1631 cm−1; [α]25D+160.06; 1H NMR (acetone-d6) δ 7.62-7.56 (m, 2H), 7.29 (s, 1H), 7.09-7.06 (m, 1H), 7.01-6.95 (m, 2H), 6.51 (d, 2H, J=7.1 Hz), 5.54 (dd, 1H, J=5.4, 2.0 Hz), 5.49 (d, 1, J=1.6 Hz), 3.91 (q, 2, J=7.1 Hz), 3.07 (d, 1, J=12.5 Hz), 2.99 (dd, 1, J=21.6, 5.8 Hz), 2.81-2.72 (m, 1H), 2.73 (d, 1H, J=12.5 Hz), 2.65 (dd, 1H, J=13.7, 6.6 Hz), 2.29 (dd, 1H, J=17.8, 5.4 Hz), 2.15 (d, 1H, J=21.6 Hz), 1.83 (ddd, 1H, J=12.8, 12.8, 6.2 Hz), 1.33 (t, 3H, J=7.1 Hz); 13C NMR (acetone-d6) δ 155.3, 147.4, 138.9, 137.4, 136.0, 131.0, 130.7, 129.5, 127.2, 127.0, 126.2, 119.0, 118.4, 109.5, 98.8, 62.5, 44.2, 42.5, 32.1, 29.9, 25.5, 14.3. Anal. Calcd for C24H23NO: C, 84.42; H, 6.79; N, 4.10. Found: C, 83.82; H, 6.87; N, 4.04. The structure and absolute configuration were confirmed by single crystal X-ray analysis.
Reaction SMILES: C1(CC(O)=O)C=CC=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:23]=[N:22][C:21]([NH:24][NH:25][C:26](=[O:34])[CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:20][C:19]=1[C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:23]=[N:22][C:21]([NH:24][NH:25][C:26](=[O:34])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:20][C:19]=1[C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1
Reactant: O=C(CC1CCCCC1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Agent: O=C(O)Cc1ccccc1
Product: O=C(Cc1ccccc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Yield: 47 %

Procedure:
The title compound (42 mg, 47%) as a white foam was prepared from 2-phenylacetic acid (41 mg, 0.3 mmol) and 1-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3)hydrazine (66 mg, 0.2 mmol) according to the procedures described for N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)-2-cyclohexylacetohydrazide (Example 7A). HPLC/MS (method A): retention time =3.30 min, (M+H)+=449.2.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:22][N:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:32](=[O:48])[C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)=[CH:25][C:24]1=[O:49].C([O-])([O-])=O.[Na+].[Na+]>O.O1CCOCC1.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([NH:31][CH2:30][CH2:29][C:26]4[CH:27]=[CH:28][N:23]([CH3:22])[C:24](=[O:49])[CH:25]=4)=[O:48])=[CH:34][CH:35]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Reactant: Cn1ccc(CCNC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1=O
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: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(-c3ccc(C(=O)NCCc4ccn(C)c(=O)c4)cc3)nc3scnc23)cc1OC
Yield: 11.8 %

Procedure:
Under N2 atmosphere, 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (150 mg, 0.47 mmol), N-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (220 mg, crude), Pd(PPh3)4 (40 mg, 0.035 mmol) and Na2CO3 (100 mg, 0.94 mmol) in 3 mL of water was added in 30 mL of 1,4-dioxane. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography, eluting with DCM/MeOH (20/1, v/v) to give 4-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide (30 mg, 12%) as a yellow sold. 1H NMR (300 MHz, CD3OD): δ 9.13 (s, 1H), 8.52-8.50 (m, 2H), 7.89-7.80 (m, 3H), 7.58 (d, 1H, J=6.9 Hz), 7.40 (dd, 1H, J1=8.4 Hz, J2=2.4 Hz), 7.03 (d, 1H, J=8.7 Hz), 6.46 (s, 1H), 6.38 (dd, 1H, J1=6.6 Hz, J2=1.8 Hz), 3.94 (s, 3H), 3.88 (s, 3H), 3.66 (t, 2H, J=7.0 Hz), 3.54 (s, 3H), 2.84 (t, 2H, J=7.0 Hz). LC-MS: 543 [M+H]+, 541 [M−H]−, tR=1.37 min. HPLC: 100% at 214 nm, 100% at 254 nm, tR=5.36 min.