Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:27])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:7]2[N:8]([N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[N:12]=2)[CH:9]=1)(=[O:3])[CH3:2].CO[CH:30](OC)[N:31]([CH3:33])[CH3:32].CCOC(C)=O>C1(C)C=CC=CC=1>[CH3:30][N:31]([CH3:33])[CH:32]=[CH:2][C:1]([C:4]1[C:5]([CH3:27])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:7]2[N:8]([N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[N:12]=2)[CH:9]=1)=[O:3]
Reactant: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(C)=O)cn2n1
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)C=CN(C)C)cn2n1
Temperature: 100 °C

Procedure:
A suspension of N-[6-acetyl-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 24, 732 mg, 1.947 mmol) and dimethylformamide dimethylacetal (4 mL) in toluene (10 mL) was heated at 100° C. for 2 hrs. The reaction mixture was cooled then EtOAc (50 mL) was added and the resultant precipitate was collected by filtration to afford the title compound as a white solid (508 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]1[CH:10]=[C:11]([C:32]2O[CH:34]=[CH:35][CH:36]=2)[C:12]([O:30][CH3:31])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:20][CH2:21]3)=[CH:17][CH:16]=2)[CH:14]=1.[S:37]1C=CC=C1B(O)O>>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]1[CH:10]=[C:11]([C:32]2[S:37][CH:34]=[CH:35][CH:36]=2)[C:12]([O:30][CH3:31])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:20][CH2:21]3)=[CH:17][CH:16]=2)[CH:14]=1
Reactant: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccco1
Reactant: OB(O)c1cccs1
Product: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1cccs1
Yield: 32 %

Procedure:
The product from Example 63, Part A (26.5 mg, 0.051 mmol) was reacted with thiophen-2-yl boronic acid (8.3 mg, 0.065 mmol) as described in Example 63, Part B to give the title compound as an off-white solid (8.6 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1H) 7.86 (d, J=7.72 Hz, 2H) 7.55-7.78 (m, 5H) 7.50 (t, J=6.25 Hz, 1H) 7.38 (d, J=2.57 Hz, 1H) 7.16-7.21 (m, 1H) 6.58 (s, 1H) 5.69 (d, J=7.72 Hz, 1H) 4.19 (d, J=4.78 Hz, 2H) 3.48 (s, 2H) 3.30 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:16])[C:7]2[N:8]([CH:15]=1)[C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[N:12]=2.[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>CC(CC)=O.O.[Cu]>[Cl:3][C:4]1[CH:5]=[C:6]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]2[N:8]([CH:15]=1)[C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[N:12]=2
Reactant: Cc1cc(=O)n2cc(Cl)cc(O)c2n1
Reactant: CC(C)CBr
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1cc(=O)n2cc(Cl)cc(OCC(C)C)c2n1
Reaction time: 1 h

Procedure:
To a stirred suspension of 1.6 g of powdered sodium hydroxide in 100 ml of pure ethyl methyl ketone is added 21. g of 7-chloro-9-hydroxy-2-methyl-4H-pyrido[1,2-a] pyrimidin-4-one. The mixture is stirred for about 1 hour and 1.5 g of isobutyl bromide dissolved in 10 ml of pure ethyl methyl ketone is added dropwise. Subsequently, 0.2 g of copper bronze is added and the mixture stirred and heated under reflux for 2 hours. The mixture is cooled, diluted with 20 ml of water, filtered, and the organic phase in the filtrate separated, washed with saturated aqueous sodium chloride, dried, and concentrated to give 7-chloro-9-(isobutoxy)-2-methyl-4H-pyrido[ 1,2-a] pyrimidin-4-one.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:5][CH:6]=1.C(N(CC)CC)C.C(NC1C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[N+:33](=[C:7]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-:34]
Reactant: CCOC(=O)Cc1nc(C)cs1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])c1nc(C)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A solution of ethyl (4-methyl-1,3-thiazol-2-yl)acetate (ENAMINE, 300 mg, 1.619 mmol) in acetonitrile (ACN) (12 mL) was treated with triethylamine (FLUKA, 0.339 mL, 2.429 mmol) at 0° C. After 20 minutes 4-acetamidobenzenesulfonyl azide (ALDRICH, 389 mg, 1.619 mmol) was added and the mixture was allowed to reach room temperature overnight. Then, 4-acetamidobenzenesulfonyl azide (ALDRICH, 94 mg, 0.391 mmol) was added and continued stirring at room temperature for 2 h. Reaction mixture was concentrated and residue was triturated with a mixture 1:1 Et2O-hexane and filtered. Solid was washed several times with the same mixture. The filtrate was concentrated to give 310 mg of crude. It was purified on a 10 g silica cartridge and eluted manually with linear gradient 0-50% hexane-ethyl acetate to yield the title compound (200 mg, 0.947 mmol, 58.5% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 7.49 (d, 1H), 4.34 (q, 2H), 2.60 (s, 3H), 1.32 (t, 3H). [ES+MS] m/z 212 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8](Br)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].Cl.[CH3:22][NH:23][CH3:24].CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:23]([CH3:24])[CH3:22])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]
Reactant: CNC
Reactant: COC(=O)c1nc2c(s1)C(Br)COc1ccc(Br)cc1-2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1nc2c(s1)C(N(C)C)COc1ccc(Br)cc1-2
Temperature: 60 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (200 mg, 0.477 mmol) in THF (6 mL) were added Dimethylamine Hydrochloride (77.8 mg, 0.954 mmol), DIPEA (308 mg, 2.38 mmol). The reaction mixture was stirred in autoclave at 60° C. overnight. Then the mixture was cooled to room temperature and partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 9-Bromo-4-dimethylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (120 mg, 65%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][N:16](CC3C=CC=CC=3)[CH2:17][CH2:18][C:11]=2[NH:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][NH:16][CH2:17][CH2:18][C:11]=2[NH:10][C:9]1=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=c1[nH]c2c(c(=O)n1Cc1ccccc1)CN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CC(=O)O
Product: O=c1[nH]c2c(c(=O)n1Cc1ccccc1)CNCC2
Yield: 88.7 %

Procedure:
A solution of 70 g of 3,6-dibenzyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione in 1.5 1 of glacial acetic acid was debenzylated in the 6-position by hydrogenolysis on 10 g of 10% palladium/activated charcoal at 70° C. and a hydrogen pressure of 3.5 bar. After the catalyst had been filtered off, the filtrate was concentrated under reduced pressure, the residual oil was taken up with 500 ml of water and the pH was adjusted to 8 with conc. sodium carbonate solution, with stirring, to give 46 g of a white precipitate of 3-benzyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:9]=3)[CH2:4]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(N)C2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(C)cc1)C2
Reaction time: 20 h

Procedure:
6.0 g (21.1 mmol) of methyl 4-(2-amino-indan-5-yl)-4-oxobutyrate hydrochloride are suspended in 60 ml of chloroform and 5.0 g (25.3 mmol) of p-toluenesulphonyl chloride are added. 5.1 g (50 mmol) of triethylamine are added, with vigorous stirring, a clear solution being formed. After 20 hours at room temperature, the mixture is washed with water, the chloroform solution is evaporated and the residue is recrystallised from methanol.
Reaction SMILES: II.S(=O)(=O)(O)O.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I:16]([O-])(=O)=O.[Na+]>O.C(O)(=O)C>[I:16][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:15])=[CH:10][CH:11]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: OCc1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: OCc1ccc(I)cc1
Reaction time: 1 h

Procedure:
A solution of glacial acetic acid (1350 ml.) and iodine (250 g.) was heated to 100° and then concentrated sulfuric acid (140 ml. of 95-97%) added, followed by benzyl alcohol (216 g.). Sodium iodate (92 g.) in water (500 ml.) was then introduced dropwise with stirring over a period of 1 hour. The temperature was maintained at 100°-110° for an additional 30 min. before the reaction mixture was poured onto 1 Kg. of crushed ice. The mixture was extracted with chloroform, the combined chloroform solution washed with water, dried, and concentrated. The remaining oil was distilled at reduced pressure to give p-iodobenzyl alcohol. A mass spectrum (70 ev) parent ion was measured at m/e 233.9545; calculated for C7H7IO, 233.9544. The ir and nmr spectrum were in agreement with the proposed structure. The use of a mass spectrum for identification of compounds is shown, for example, in R. Venkataraghaven, R. D. Board, R. Klimowsky, J. W. Amy, and F. W. McLafferty, Adv. Mass Spec., 4, 65 (1967) and R. Venkataraghaven, R. J. Klimowksy, F. W. McLafferty, Acc. Chem. Res., 3, 158 (1970).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:43])[CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:28][CH:27]=1)([CH2:15][O:16][Si](C(C)(C)C)(C)C)[CH2:6][O:7][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:1]([NH:4][C:5]([CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](=[O:43])[CH2:33][CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:30][CH:31]=1)([CH2:15][OH:16])[CH2:6][OH:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCc1ccc(C(=O)CCCCc2ccccc2)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NC(CO)(CO)CCc1ccc(C(=O)CCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-acetamido-1,3-bis(tert-butyldimethylsilyloxy)-2-(2-(4-(1-oxo-5-phenylpentyl)phenyl)ethyl)propane (0.9 g) in tetrahydrofuran (10 ml) was added a solution of tetra-n-butylammonium fluoride (1.2 g) in tetrahydrofuran (5 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure to give 2-acetamido-2-(2-(4-(1-oxo-5-phenylpentyl)phenyl)ethyl)propane-1,3-diol as a residue. The obtained residue was dissolved in water (5 ml)—methanol (5 ml)—tetrahydrofuran (3 ml), and lithium hydroxide monohydrate (0.3 g) was added thereto. The mixture was refluxed under heating for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure to give a white solid. The obtained white solid was recrystallized from ethanol-ethyl acetate-hexane to give the title compound (220 mg) as white crystals, melting point 126-127° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[S:12][C:13](Br)=[N:14][N:15]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O1CCOCC1>[Br:10][C:11]1[S:12][C:13]([N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)=[N:14][N:15]=1
Reactant: Brc1nnc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nnc(Br)s2)CC1
Temperature: 120 °C
Yield: 77.1 %

Procedure:
DIPEA (430 μL, 2.460 mmol) was added to a stirred solution of 2,5-dibromo-1,3,4-thiadiazole (300 mg, 1.230 mmol) and tert-butyl piperazine-1-carboxylate (275 mg, 1.476 mmol) in dioxane (4 mL). The reaction mixture was heated at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered under vacuum, rinsed with dioxane, and the filtrate was concentrated in vacuo to afford the crude product as an orange oily residue. The crude material was purified by preparative HPLC under neutral conditions (ammonium formate modified) to afford the title compound as a yellow solid (331 mg, 77% yield). LC-MS: Rt 1.18 min; MS m/z 351.1 [M+2]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.38-3.55 (m, 8H), 1.41 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([OH:15])(=O)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Na].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([Cl:18])(=[O:15])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CS(=O)(=O)c1ccc(CS(=O)(=O)O)cc1
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(CS(=O)(=O)Cl)cc1
Reaction time: 48 h

Procedure:
To the title A compound, (4-methanesulfonyl-phenyl)-methanesulfonic acid, sodium salt is added PCl5 (10 g) in 200 mL of chloroform and the mixture is stirred for 48 h. The solids are filtered off, the chloroform is removed by evaporation, and the residue is triturated with hexanes, and the solids are collected by filtration to afford (4-methanesulfonyl-phenyl)-methanesulfonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:13][CH2:14]1)=[O:21])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCCO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.75 g (5.84 mmol) trans-[4-(5-Hydroxy pentyl)-cyclohexyl)-methyl-carbamic acid tert-butyl ester and 0.5 ml (6.42 mmol) of methanesulfonyl chloride in 20 ml CH2Cl2 was added, under cooling with an ice bath, 1.56 ml (11.7 mmol) of Et3N. The mixture was stirred for 3 h at RT. The reaction-mixture was then partitioned between ether/1N HCl and water. The ether-solution was concentrated in vacuo to yield 2.12 g (96%) of clean trans-Methansulfonic acid 5[-4-(tert-butoxy carbonyl-methyl-amino)-cyclohexyl)-pentylester.
Reaction SMILES: [CH2:1]([C:4]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH:16]([C:21]([O:23]CC)=[O:22])[CH2:15][CH2:14]2)[CH2:2][CH3:3].I[CH3:38]>>[CH2:1]([C:4]1[CH:29]=[C:28]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16]([CH3:38])([C:21]([OH:23])=[O:22])[CH2:15][CH2:14]2)[CH2:2][CH3:3]
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc2c(c1)CCC(C(=O)OCC)O2
Reactant: CI
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc2c(c1)CCC(C)(C(=O)O)O2

Procedure:
The title compound was prepared from ethyl 6-(3-(2-propyl-4-phenoxyphenoxy)propoxy)-chromane-2-carboxylate (Example 13) following the procedures described in Example 2, Step A, employing iodomethane instead of iodopropane, and subsequently hydrolyzed following the procedure in Example 1, Step C.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1)[C:4]([OH:6])=[O:5].Cl>CC(O)(C)C>[C:3]([S:1][CH2:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[CH:9]=1)[C:4]([OH:6])=[O:5])([CH3:7])([CH3:4])[CH3:2]
Reactant: O=C(O)C(CS)Cc1cccc(Br)c1
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(C)(C)SCC(Cc1cccc(Br)c1)C(=O)O
Temperature: 25 °C

Procedure:
To the reaction mixture of step 5, under N2 atmosphere, was injected a mixture of t-BuOH (3 ml) and 37% HCl (2.5 ml). The reaction mixture was heated to reflux for 4 hours, then cooled to room temperature and partitioned between water and CH2Cl2. The combined CH2Cl2 phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with 0 to 5% EtOH in CH2Cl2 to give 2-(S-t-butylsulfanylmethyl)-3-(3-bromophenyl)propionic acid as a colorless, viscous oil, 0.133 g, 51%: HPLC purity: 94.5%, MS (ES−) [M−H+]: 329, 331.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:16](SC)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18]>O1CCCC1.[Ni]>[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([N:19]([CH3:20])[CH3:21])=[O:18]
Reactant: CSC(C(=O)N(C)C)c1cccc(C(=O)c2ccccc2)c1N
Agent: [Ni]
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1cccc(C(=O)c2ccccc2)c1N
Yield: 96.3 %

Procedure:
A solution of 33.0 g (0.1 mol) of 2-amino-3-benzoyl-α-(methylthio)-N,N-dimethylphenylacetamide in 500 ml of tetrahydrofuran was treated with 240 g of wet Raney nickel (washed 3 times with water and 3 times with trtrahydrofuran) for 10 minutes. The mixture was filtered and the filtrate was concentrated. The residue was crystallized from isopropyl alcohol to give 27.2 g (96%) of yellow needles, m.p. 123°-124° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.Cl.[F:13][C:14]1([F:18])[CH2:17][NH:16][CH2:15]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:13][C:14]1([F:18])[CH2:17][N:16]([CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:15]1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc([N+](=O)[O-])cc1CN1CC(F)(F)C1
Temperature: 65 °C

Procedure:
A sealed tube with a magnetic stirrer was charged with DMF (5 mL), 5-(Bromomethyl)-1-methyl-3-nitro-1H-pyrazole 156d (0.39 g, 1.78 mmol), 3,3-difluoroazetidine hydrochloride (276 mg, 2.13 mmol) and DIPEA (0.8 mL, 4.45 mmol). The reaction mixture was heated at 65° C. for 3-5 h. After this time the reaction was concentrated to dryness under reduced pressure, and the resulting residue was diluted with a mixture of Ethyl Acetate (15 mL) and water (15 mL). The aqueous layer was separated and extracted with Ethyl Acetate (2×15 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford a quantitative yield of 156e as yellow oil, which was used without further purification for the next step. MS (ESI+) m/z 233.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][N:6]=1.[NH4+:11].[OH-]>CCN(CC)CC>[Cl:1][C:2]1[S:3][C:4]([S:7]([NH2:11])(=[O:9])=[O:8])=[CH:5][N:6]=1
Reactant: O=S(=O)(Cl)c1cnc(Cl)s1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cnc(Cl)s1
Yield: 61.4 %

Procedure:
Prepared by general procedure III from 2-Chloro-thiazole-5-sulfonyl chloride (1.1 g, 5 mmol) and NH4OH (0.42 mL, 6 mmol) with Et3N (0.77 mL, 6 mmol to give the title compound as a light-brown solid (610 mg, 61%). MS (ISN) 197 [(M−H)−].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25]1>>[S:24]1[CH:28]=[CH:27][C:26]([C:29]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:30])=[CH:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccsc1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1ccsc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.062 mMol) 3-thiophenecarbonyl chloride, the title compound was prepared.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-n2ccnc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-imidazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 199 (M+H)+.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Zn+])=[CH:5][CH:4]=1.[CH3:11][O:12][C:13](=[O:39])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2I)[C:22](=[O:31])[C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:15]=1>>[CH3:11][O:12][C:13](=[O:39])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)/[C:23](=[C:24](/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)\[CH2:7][C:6]3[CH:9]=[CH:10][C:3]([Cl:2])=[CH:4][CH:5]=3)/[C:22]2=[O:31])[CH:15]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2I)c1
Reactant: Clc1ccc(C[Zn+])cc1
Agent: [Br-]
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/Cc3ccc(Cl)cc3)c3ccccc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 77 starting from 4-chloro-benzylzinc bromide (commercially available) and 3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.92 (s, 3H), 4.73 (s, 2H), 5.07 (s, 2H), 5.99 (d, 1H), 6.58-6.65 (m, 2H), 7.08-7.20 (m, 7H), 7.37-7.43 (m, 4H), 7.52 (d, 1H), 7.93 (d, 1H), 8.06 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[F:15][C:16]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[N:31][C:32]=3[NH2:34])[N:27]([CH2:35][C@H:36]3[CH2:40][CH2:39][CH2:38][NH:37]3)[N:26]=2)=[CH:21][CH:20]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:58]([CH2:60][C:61](O)=[O:62])#[N:59]>ClCCl>[NH2:34][C:32]1[N:31]=[CH:30][N:29]=[C:28]2[N:27]([CH2:35][C@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3[C:61](=[O:62])[CH2:60][C:58]#[N:59])[N:26]=[C:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][C:17]4[CH:41]=[CH:42][CH:43]=[C:44]([F:45])[C:16]=4[F:15])=[CH:24][CH:23]=3)[C:33]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1)nn2C[C@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.8 %

Procedure:
Into a 100 mL, round-bottom flask, was placed a solution of 3-[4-(2,3-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis(trifluoroacetic acid) salt (200 mg, 0.31 mmol, 1.00 equiv) in dichloromethane (10 mL), CDI (324 mg, 2.00 mmol, 6.50 equiv), and 2-cyanoacetic acid (170 mg, 2.00 mmol, 6.50 equiv). The resulting solution was stirred for 12 h at 25° C. and the resulting mixture was washed with water and brine. The organics were dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (20/1) to give 109 mg (72%) of 3-[(2R)-2-([4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a white solid.