Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:9]=[CH:10][CH:11]=1>CO.O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([OH:19])[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(C(=O)CC2CCCN2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(C(O)CC2CCCN2)c1
Yield: 80 %

Procedure:
4.8 g of sodium borohydride are added portionwise with stirring to a solution of 6.5 g of 1-(3-methoxyphenyl)-2-(2-pyrrolidinyl)-ethanone hydrochloride in 25 ml of methanol and 5 ml of water. After 1 hour the bulk of the methanol is distilled off under a vacuum. The residue is taken up with 20 ml of water and 10 ml of 6 N sodium hydroxide solution. The mixture is extracted 5 times with, in each case, 20 ml of diethylether. The organic phases are collected, dried over sodium sulphate and concentrated to an oil which is distilled. 4.5 g of the title compound are obtained as mixture of diastereoisomers of b.p. 136° at 0.005 mm Hg.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:29]=[CH:28][C:11]([CH2:12][NH:13][C:14]([C:16]3[CH:21]=[C:20]([NH2:22])[C:19]([C:23]#[N:24])=[C:18]([O:25][CH2:26][CH3:27])[N:17]=3)=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=[O:32])C.OO.O>CN(C)C=O>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]([C:16]3[CH:21]=[C:20]([NH2:22])[C:19]([C:23]#[N:24])=[C:18]([O:25][CH2:26][CH3:27])[N:17]=3)=[O:15])=[CH:28][CH:29]=2)=[O:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOc1nc(C(=O)NCc2ccc(Sc3ccccc3)cc2)cc(N)c1C#N
Reactant: CC(=O)O
Agent: OO
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nc(C(=O)NCc2ccc(S(=O)c3ccccc3)cc2)cc(N)c1C#N
Yield: 70 %

Procedure:
A mixture of Example 161B (61 mg, 0.15 mmol), 2 mL of acetic acid, 0.15 mL of hydrogen peroxide (30% solution in water) in 0.5 mL of N,N-dimethylformamide was stirred at room temperature for 2 h. Water was added, the resulting precipitate was then filtered. The solid was triturated with methanol to provide the titled compound as a beige solid (44 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=7.1 Hz, 3H), 4.43-4.53 (m, 4H), 7.05 (s, 1H), 7.29 (bs, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.46-7.55 (m, 3H), 7.63-7.72 (m, 4H), 9.08 (t, J=6.4 Hz, 1H). MS (ESI+) m/e=421 (M+H)+.
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NCCCCCCCC=O)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([NH:59][C:60]([C:62]3[CH:63]=[C:64]([S:68]([C:71]4[CH:72]=[C:73]5[C:78](=[C:79]([CH3:81])[CH:80]=4)[N:77]=[CH:76][C:75]([C:82]([NH2:84])=[O:83])=[C:74]5[NH:85][C:86]4[CH:91]=[CH:90][CH:89]=[C:88]([O:92][CH3:93])[CH:87]=4)(=[O:70])=[O:69])[CH:65]=[CH:66][CH:67]=3)=[O:61])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1>>[CH:46]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:54]=[CH:55][C:56]([NH:59][C:60]([C:62]3[CH:63]=[C:64]([S:68]([C:71]4[CH:72]=[C:73]5[C:78](=[C:79]([CH3:81])[CH:80]=4)[N:77]=[CH:76][C:75]([C:82]([NH2:84])=[O:83])=[C:74]5[NH:85][C:86]4[CH:91]=[CH:90][CH:89]=[C:88]([O:92][CH3:93])[CH:87]=4)(=[O:69])=[O:70])[CH:65]=[CH:66][CH:67]=3)=[O:61])=[CH:57][CH:58]=2)=[CH:49][CH:48]=1)=[O:45]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CO)cc6)cc5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(C=O)cc6)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 112, using Intermediate 81 as a substrate. ES/MS calcd. for C38H31N4O6S+ 671.2. Found m/z=671.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:28])([C:21]([F:27])([F:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=[CH:4][CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[BH4-].[Na+]>C(O)C>[OH:1][C:2]([CH3:28])([C:21]([F:27])([F:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=[CH:4][CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[CH2:11][CH:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCCC(F)(F)C(C)(O)C=CC1CCC(=O)N1CC(=O)CCCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC(F)(F)C(C)(O)C=CC1CCC(=O)N1CC(O)CCCCC(=O)O
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a solution of 20 (24 mg, 0.059 mmol) in ethanol (2 mL) at 0° was added sodium borohydride (9 mg, 0.238 mmol). The reaction mixture was stirred at 0° for one hour before it was quenched with two drops of acetic acid. It was then diluted with saturated sodium chloride solution and extracted with chloroform three times. The combined organic layer was dried over magnesium sulfate. Purification of the crude product on TLC plates afforded 8 mg of 7-[2-(3-hydroxy-3-methyl-4,4-difluoro-1-octen-1-yl)-5-oxopyrrolidin-1-yl]-6-hydroxyheptanoic acid (21). IR (CH2Cl2): 3500-3200 (br), 1720, 1660 cm-1 ; PMR (CDCl3): δ5.95-5.60 (m, 2H), 4.40-2.80 (m, 4H), 2.60-1.20 (m, 21H), and 0.97 (t, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1)([CH3:19])[CH3:18]
Reactant: CC(C)c1ccccc1O
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)c1ccccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 77.8 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-isopropylphenol (25 μL, 0.185 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-isopropyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (28 mg, 78%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.01 (br. s., 1H), 7.93 (d, J=8.1 Hz, 2H), 7.55-7.65 (m, 3H), 7.21 (dd, J=7.5, 1.6 Hz, 1H), 7.06-7.17 (m, 1H), 7.01 (d, J=7.3 Hz, 1H), 6.84-6.96 (m, 1H), 5.18 (s, 2H), 3.22-3.39 (m, 3H, including water peak), 1.18 (d, J=7.0 Hz, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])/[CH:3]=[CH:4]/[C:5]([C:7]1[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:15])=[N:9][CH:8]=1)=[O:6].[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CO>[CH3:16][N:2]([CH3:1])/[CH:3]=[C:4](\[F:18])/[C:5]([C:7]1[N:11]([CH:12]([CH3:13])[CH3:14])[C:10]([CH3:15])=[N:9][CH:8]=1)=[O:6]
Reactant: F[B-](F)(F)F
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Product: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C(C)C
Temperature: 27.5 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (2E)-3-(dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one, (Method 24 of WO 03/076436; 5.53 g, 25 mmol) in MeOH (100 ml) at ambient temperature, was added in portions over 5 mins, Selectfluor (14.16 g, 40 mmol). The temperature was maintained at 25-30° C. by slight cooling. After stirring for 90 min the reaction mixture was cooled in ice/acetone and filtered. The filtrate was evaporated under reduced pressure and the residue was taken into DCM. It was washed with aq. ammonia, brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The title compound was isolated by MPLC on silica gel using two separate columns (10% EtOH/EtOAc, then 3.5% EtOH/DCM) as a golden viscose oil, which crystallized on standing over several weeks. Yield=2.50 g (42%). NMR (300 Mz): 1.40 (d, 6H), 2.38 (s, 3H), 3.05 (s, 6H), 4.70 (septet, 1H), 6.96 (d, 1H), 7.08 (s, 1H); 19F NMR (376 MHz): −166.7 (d); m/z 240.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH:25]=[O:26])[CH:32]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (200 mg, 0.483 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) was added (3-formylphenyl)boronic acid (317 mg, 1.93 mmol), and Cs2CO3 (315 mg, 0.97 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis(triphenylphosphosphine) palladium (0) (48 mg, 0.043 mmol). The reaction was heated in a microwave for 30 min at 160° C. The organic layer was separated and concentrated. The residue was dissolved in MeOH until solid precipitated to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[Li].[CH2:13]([C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=1)[CH2:14][CH2:15][CH3:16].Cl>C1COCC1.[Zn+2].[Br-].[Br-].[Ni+2].C1(C)C=CC=CC=1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][C:20]2[CH:21]=[CH:22][C:17]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:18][CH:19]=2)=[CH:5][CH:6]=1
Reactant: CCCCc1ccc(Br)cn1
Reactant: COc1ccc(CCBr)cc1
Agent: [Ni+2]
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(CCc2ccc(OC)cc2)cn1

Procedure:
A mixture of 21.5 g of 2-bromo-1-(4-methoxyphenyl)ethane and 100 ml of toluene has added to it, under argon, 13.2 g of ZnBr2 and 1.4 g of lithium and is treated for 1 hour with ultrasound. A mixture of 21.4 g of 2-butyl-5-bromopyridine and 50 ml of toluene is then added, followed by a solution of 0.2 g of nickel(II) acetonylacetonate in 20 ml of THF. After a further hour 100 ml of dilute hydrochloric acid are added a little at a time, and the organic phase is worked up. Separation by column chromatography (silica gel, toluene) and recrystallization gives 5-(p-methoxyphenylethyl)-2-butylpyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)CC3C=CC(OC)=CC=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH:42]([F:44])[F:43])[CH:37]([C:45]([N:47]([CH3:49])[CH3:48])=[O:46])[CH2:36]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:25]3[CH2:26][CH2:27]3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH:42]([F:43])[F:44])[CH:37]([C:45]([N:47]([CH3:49])[CH3:48])=[O:46])[CH2:36]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(CC(F)F)C(C(=O)N(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: ClCCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CCN1CC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide (37 mg, 0.054 mmol) was taken up in DCE (0.5 mL) and anisole (0.029 mL, 0.268 mmol) was added, followed by TFA (0.124 mL, 1.608 mmol). The reaction was stirred at room temperature overnight. LCMS indicates mostly SM is present. An additional 30 eq. of TFA was added and the reaction was heated at 50° C. After 4 h, an additional 30 eq. of TFA was added, and the reaction heated for 1.5 h. The solvent was removed in vacuo and the material azeotroped 2× with toluene, then triturated with Et2O to remove anisole. The material was purified by preparative HPLC to provide 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide (20.1 mg) as a yellow solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[O:32]1[CH2:37][CH2:36][CH:35]([O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:34][CH2:33]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OC1CCOCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A light suspension containing N-hydroxylphthalimide (18.4 mmol, 3.0 g), triphenylphosphine (18.4 mmol, 4.82 g), tetrahydro-4H-pyran-4-ol (18.4 mmol, 1.75 mL) and anhydrous THF (50 mL), were transferred to a flask containing di-tert-butyl azodicarboxylate (20.2 mmol, 4.66 g) under nitrogen. Over 2 hours the reaction stirred at room temperature and changed from a dark orange to yellow in appearance. The solvent was removed under vacuum and replaced with trifluoroacetic acetic acid (10 mL). The reaction was stirred for 30 minutes and the TFA was removed under vacuum. The crude residue was then dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, 5% aqueous solution of potassium carbonate, brine and dried over magnesium sulfate. The solvent was removed under vacuum and the residual triphenylphosphine oxide was crystallized and filtered using hexanes and ether. The solvent was again removed and the crude solid was purified by silica gel chromatography (2:1 hexanes/ethyl acetate) and recrystallization using methylene chloride and hexanes providing 1.69 g (37%) of a white crystal. Rf=0.3 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.84-7.82 (2H,m), 7.75-7.73(2H,m), 4.46-4.40 (1H,m), 4.08-4.02 (2H,m), 3.50-3.44 (2H,m), 2.04-1.98 (2H,m), 1.92-1.84 (2H,m).
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.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:22][O:23][CH2:24][CH2:25]OC>CN(C=O)C.O>[CH3:22][O:23][CH2:24][CH2:25][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reaction time: 1 h
Yield: 154.8 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.8 g, 4.1 mmol), cesium carbonate (2.0 g, 6.2 mmol), and 1-(chloromethoxy)-2-methoxyethane (0.59 mL, 5.2 mmol) in DMF (14 mL) was heated in a microwave at 90° C. for 1 hr. After the initial heating, additional 1-(chloromethoxy)-2-methoxyethane (0.59 mL) and cesium carbonate (2 g) was added. Heating was repeated for an additional 1 hr. The crude reaction mixtures were then diluted with water (250 mL) and extracted with ethyl acetate (3×50 mL). The title compound was purified by silica gel column using DCM/EtOAc/MeOH (8/1.5/0.5) as eluent to give 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.6 g) as a light yellow oil. ESI-MS:m/z 283.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[Li+].[BH4-]>C1COCC1>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([O:12][CH3:13])[CH:5]=1
Reactant: COC(=O)c1ccc(C#N)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1C#N
Temperature: 70 °C

Procedure:
4-Cyano-3-methoxy-benzoic acid methyl ester from step 1 (4.7 g, 25 mmol) was dissolved in THF (125 ml). LiBH4 in THF (2M, 25 ml, 50 mmol) was added. The reaction mixture was heated at 70° C. for 3 hours. The reaction mixture was quenched carefully with 3N HCl and then extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:42][CH2:41]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH:40]4[CH2:41][CH2:42]4)[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2c(C)cc(-c3cn(CC4CC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1nc2c(C)cc(-c3cn(CC4CC4)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-ethoxy-4-methyl-6-(1-cyclopropylmethyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3C(C)=NO[N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=[C:33](N2CC[C@H](OC(=O)C(F)(F)F)C2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2N=1)(C)(C)C.ClCC1N(C2CC2)N=NN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:37]([CH:35]4[CH2:33][CH2:34]4)[N:38]=[N:39][N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Agent: ClCc1nnnn1C1CC1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3nnnn3C3CC3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-1-cyclopropyl-1H-tetrazole and isolated as light yellow gum. MS (m/e): 385.3 (MH+).
Reaction SMILES: BrCC[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.CC1C=C(C=CC=1C)C(C1CCNCC1)=O.C(N(CC)CC)C>CN(C)C=O>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: Cc1ccc(C(=O)C2CCNCC2)cc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1

Procedure:
A solution of 9.6 g of 3-(2-bromoethyl)indole, 11.5 g of 4-(3,4-dimethylbenzoyl)piperidine hydrochloride and 10.1 g of triethylamine in 300 ml of dimethylformamide is treated according to the manipulative procedure described in Example 3(b) to give an indole, which is purified on a silica gel column, eluted with 5% methanol-benzene mixture and recrystallized from an ethanol-water mixture to give the solid, mp 172°-173° C., 3-{2-[4-(3,4-dimethylbenzoyl)piperidyl]ethyl}indole.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].C[C:11]1[C:16]([C:17]([O-:19])=O)=[C:15](C)[C:14]([C:21]([O-:23])=O)=[C:13](C)[C:12]=1[C:25]([O-:27])=O.Cl>CC(C)=O.O1CCCC1>[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:9])[CH2:3][C:25]([C:12]1[CH:11]=[C:16]([C:17](=[O:19])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:15]=[C:14]([C:21](=[O:23])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:13]=1)=[O:27]
Reactant: CC(=O)C(C)(C)C
Reactant: Cc1c(C(=O)[O-])c(C)c(C(=O)[O-])c(C)c1C(=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)CC(=O)c1cc(C(=O)CC(=O)C(C)(C)C)cc(C(=O)CC(=O)C(C)(C)C)c1
Reaction time: 7 h
Yield: 52.7 %

Procedure:
In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 2.29 gm (57 mmol) of 60% sodium hydride, 5.24 gm (52 mmol) of pinacolone, 4.0 gm (15.8 mmol) of trimethyl-1,3,5-benzenetricarboxylate, and 40 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and the refluxing under heat was continued for 7 hours. After cooling the reaction mixture, 30 ml of 2N aqueous hydrochloric acid was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Acetone was added to the crude product, and recrystallization afforded 3.8 gm of the target compound as yellow crystals (yield: 52%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[NH:26][CH:25]([C:27]([OH:29])=O)[CH2:24][S:23]2)[CH:17]=1.[CH2:30]([O:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>O1CCCC1.C(OCC)(=O)C>[CH2:30]([O:37][NH:38][C:27]([CH:25]1[CH2:24][S:23][CH:22]([C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[NH:26]1)=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(NOCc1ccccc1)C1CSC(c2cccnc2)N1
Reaction time: 12 h

Procedure:
A solution of 490 mg of dicyclohexylcarbodiimide in 5 ml of tetrahydrofuran was added dropwise to a mixture of 500 mg of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, mg of O-benzylhydroxylamine, 480 mg of 1-hydroxybenzotriazole, 240 mg of N-methylmorpholine and 15 ml of tetrahydrofuran with ice cooling, and the resultant mixture was stirred with ice cooling for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (eluent:ethyl acetate) gave 260 mg of N-benzyloxy-2-(3-pyridyl)thiazolidine-4-carboxamide. This compound was dissolved in ethyl acetate, and 1.5 ml of 2N hydrogen chloride solution in dioxane was added. The resultant solid was collected by filtration, washed with ethyl acetate and dried to give 240 mg of N-benzyloxy-2-(pyridin-3-yl)thiazolidine-4-carboxamide dihydrochloride. Melting point 115° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:29])[CH:11]([CH2:16][C:17]3[N:22]=[C:21](S(C)(=O)=O)[C:20]([C:27]#[N:28])=[CH:19][CH:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:30])[CH:3]=1.[CH3:31][NH2:32]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:29])[CH:11]([CH2:16][C:17]3[N:22]=[C:21]([NH:32][CH3:31])[C:20]([C:27]#[N:28])=[CH:19][CH:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:30])[CH:3]=1
Reactant: CN
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(Cc2ccc(C#N)c(S(C)(=O)=O)n2)C1
Solvent: C1CCOC1
Product: CNc1nc(CC2CC(OC)=C(c3c(C)cc(Br)cc3C)C2=O)ccc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To 6-[[3-(4-bromo-2,6-dimethyl-phenyl)-4-methoxy-2-oxo-cyclopent-3-en-1-yl]methyl]-2-methylsulfonyl-pyridine-3-carbonitrile (2.043 mmol, 1 g) was added a solution of methylamine (5.1 ml of a 2M solution in tetrahydrofuran, 10.22 mmol). The reaction was stirred at room temperature for three hours and then concentrated under reduced pressure to give a brown gum. The crude product was purified by column chromatography on SiO2 using a hexane: EtOAc gradient to yield the desired compound (890 mg, 99%) as an orange solid. 1H NMR (400 MHz, CDCl3) (diagnostic peaks) δ ppm 7.55 (d, 1H), 7.18 (d, 2H), 6.45 (d, 1H), 3.55 (s, 3H), 3.05 (d, 3H), 2.15 (s, 3H), 2.00 (s, 3H).