Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:58])[C@H:12]([CH3:57])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:56])[CH2:22][C@@H:23]([O:54][CH3:55])[C@@H:24]([N:29]([CH3:53])[C:30](=[O:52])[C@@H:31]([NH:35][C:36]([C@:38]2([CH3:51])[CH2:43][CH2:42][CH2:41][CH2:40][N:39]2C(OC(C)(C)C)=O)=[O:37])[CH:32]([CH3:34])[CH3:33])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.[ClH:59]>O1CCOCC1>[ClH:59].[CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:58])[C@H:12]([CH3:57])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:56])[CH2:22][C@@H:23]([O:54][CH3:55])[C@@H:24]([N:29]([CH3:53])[C:30](=[O:52])[C@@H:31]([NH:35][C:36]([C@:38]2([CH3:51])[CH2:43][CH2:42][CH2:41][CH2:40][NH:39]2)=[O:37])[CH:32]([CH3:34])[CH3:33])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=[CH:7]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCCN1)C(C)C
Yield: 89 %

Procedure:
According to the general procedure C, from #177 (143 mg, 0.176 mmol, 1 eq.) and 4M solution of hydrochloric acid in dioxane (2.0 mL) was synthesized the desired material as a gum (145 mg). A portion of this crude residue (25 mg) was azeotroped with a mixture of methanol/acetonitrile to afford #178 (20 mg, 89% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ 8.96-9.07 (m), 8.79-8.96 (m), 8.58 (d), 8.02-8.08 (m), 7.77-7.83 (m), 7.25-7.31 (m), 7.19-7.24 (m), 6.56-6.67 (m), 6.12-6.21 (m), 5.13-5.22 (m), 4.72-4.81 (m), 4.63-4.70 (m), 4.50-4.59 (m), 4.07-4.16 (m), 3.98-4.05 (m), 3.80-3.86 (m), 3.55-3.76 (m), 3.46-3.54 (m), 3.38-3.44 (m), 3.26-3.35 (m), 3.18-3.24 (m), 3.05-3.18 (m), 2.98-3.04 (m), 2.40-2.55 (m), 2.27-2.35 (m), 2.08-2.27 (m), 1.74-1.98 (m), 1.50-1.74 (m), 1.20-1.46 (m), 0.73-1.16 (m). LC-MS (Protocol Q1): m/z 714.6 [M+H+], retention time=0.76 minutes. HPLC (Protocol U): m/z 714.5 [M+H+] retention time=7.124 minutes (purity=91%).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:16][C:9]1[CH:8]=[C:7]2[C:12]([N:13]=[C:14]([CH3:15])[C:5]3[N:6]2[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])=[N:3][C:4]=3[CH3:17])=[CH:11][CH:10]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
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: [K+]
Product: COc1ccccc1-c1nc(C)c2c(C)nc3ccc(F)cc3n12
Yield: 89.6 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 2-methoxyphenylboronic acid (46 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (72 mg, 90% yield). EIMS 322.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12.N1C=CN=C1.CN(C=O)C.[CH3:48][C:49]([Si:52](Cl)([CH3:54])[CH3:53])([CH3:51])[CH3:50]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:37])[C:24]4[C:29]([C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([O:17][Si:52]([C:49]([CH3:51])([CH3:50])[CH3:48])([CH3:54])[CH3:53])[CH:16]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cc(F)cc(O[Si](C)(C)C(C)(C)C)c2)c2c(N)ncnc21
Reaction time: 2 h
Yield: 92 %

Procedure:
To a stirred mixture of 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (example 40, 0.20 mmol) and imidazole (40.8 mg, 0.60 mmol) in DMF (1 ml) TBDMSCl (45.2 mg, 0.30 mmol) was added at RT and the mixture was stirred for 2 hrs. Additional imidazole (16 mg) and TBDMSCl (36 mg) were added and the mixture was stirred at the same temperature for further 2 hrs. Additional imidazole (27 mg) and TBDMSCl (121 mg) were added and the stirring was continued at room temperature overnight. The reaction mixture was diluted with DCM and washed with 0.5M HCl. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by filtration on silica gel cartridge (DCM to DCM:MeOH=95:5) to afford 3-(1-(4-amino-3-(3-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate Q.1, 112 mg, 0.184 mmol, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>C1(C)C=CC=CC=1.C(O)C.C(Cl)Cl>[Br:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cccnc2)c1
Reaction time: 0.17 h
Yield: 35 %

Procedure:
Tetrakis-(triphenylphosphine)palladium (153 mG; 0.135 mM) was added to a stirred solution of 3-bromopyridine (0.434 mL; 4.5 mM) in 9 mL of toluene. The resulting solution was stirred 10 mins. under nitrogen at R.T. 2M aqueous sodium carbonate solution (5 mL; 10 mM) followed by a solution of 3-bromophenylboronic acid (1 G; 5 mM) in 2.5 mL of absolute ethanol were added. This heterogeneous reaction mixture was vigorously stirred 20 hrs. at 80° under nitrogen, cooled, diluted with 25 mL of methylene chloride, and washed with 2×5 mL of 2M aqueous sodium carbonate solution containing 0.5 mL of conc. ammonia. The organic layer was dried over anhyd. magnesium sulfate. Solvent removal followed by purification on silica gel using ether:petroleum ether (1:1) as solvent gave 3-(3'-bromophenyl)pyridine in 35% yield as a colorless liquid boiling at 140°-2°/~2 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[C:7]([C:15]([O:17]CC)=[O:16])[C:6]2=[O:20].Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:20]
Reactant: CCOC(=O)c1c[nH]c2cc(OC)c(OC)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2[nH]cc(C(=O)O)c(=O)c2cc1OC
Reaction time: 24 h
Yield: 111.7 %

Procedure:
1,4-Dihydro-6,7-dimethoxy-4-oxo-3-quinolinecarboxylic acid, ethyl ester (68.0 g, 0.245 mol) was suspended in 588 ml of 1N sodium hydroxide solution and stirred for 24 hours at 50°-60° C. To the resulting clear solution dilute hydrochloric acid was added at 0° C. The voluminous precipitate was filtered by suction and washed with water. Drying in vacuo furnished 68.2 g of the title acid, melting point 284.4° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:27])=[C:11]([CH:15](OC)[C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([CH3:27])=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(c1cccc(OCc2ccccc2)c1C)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2c[nH]c3ncccc23)cccc1OCc1ccccc1
Yield: 77.3 %

Procedure:
A mixture of 3-[(3-benzyloxy-2-methyl-phenyl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine (625, 24 mg, 0.067 mmol), trifluoroacetic acid (1 mL, 13 mmol), and triethylsilane (2 mL, 12.5 mmol) in acetonitrile (10 mL) was refluxed for 4 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After removal of solvent, the residue was washed with a mixture of ethyl ether and hexanes (1:1) to provide the compound as a yellow solid (P-1857, 17 mg, 75%). MS (ESI) [M+H+]+=329.24.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1/[CH:11]=[N:12]\[S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14].C1(C)C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:32]=1[Cl:33]>O>[Cl:26][C:27]1[CH:28]=[C:29]([C@@H:11]([C@H:2]2[CH2:3][O:4][C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[O:1]2)[NH:12][S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: CC(C)(C)[S@](=O)/N=C\[C@H]1COC2(CCCCC2)O1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(Cl)c(Cl)c1)[C@H]1COC2(CCCCC2)O1
Temperature: 0 °C
Yield: 58.7 %

Procedure:
To a solution of 248 (2.0 g, 7.3 mmol) and toluene (30 mL) cooled to −78° C. was added (3,4-dichlorophenyl)magnesium bromide (29 mL, 15 mmol) and warmed to 0° C. for 30 min. The reaction was poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a hexane/EtOAc gradient (4:1 to 1:1) to afford 1.8 g (59%) of (S)—N—((S)-(3,4-dichlorophenyl)((S)-1,4-dioxaspiro[4.5]decan-2-yl)methyl)-2-methylpropane-2-sulfinamide (250) which appears to be a ca. 10:1 mixture of diastereomers by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([OH:21])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[CH2:22]([C:24]1[S:25][CH:26]=[C:27]([CH2:29][NH2:30])[N:28]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[N:12][CH:11]=[C:10]([CH:9]=2)[C:19]([NH:30][CH2:29][C:27]2[N:28]=[C:24]([CH2:22][CH3:23])[S:25][CH:26]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: CCc1nc(CN)cs1
Product: CCc1nc(CNC(=O)c2cnc(OCC3CC3)c(-c3ccc(Cl)cc3)c2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CAS Registry No. 1018782-76-7) and 2-ethyl-4-thiazolemethanamine as starting materials, LC-MS (UV peak area/ESI) 99%, 428.119 (M+H)+.
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:13]([OH:15])=O)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C@H:2]([C:13]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1ccccc1)OCc1ccccc1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of Z-Trp-OH (2 g, 5.9 mmol) in THF (88 mL) at 5° C. were added aniline (540 μL, 5.9 mmol) and DCC (1.6 g, 7.7 mmol). The reaction was allowed to warn up to room temperature overnight. The solvent was evaporated off and the crude was triturated with ethyl acetate (50 mL). After filtration, the organic phase was successively washed with aqueous 5% KHSO4, aqueous 10% KHCO3, brine and was dried over Na2SO4. The solvent was removed in vacuo. The crude amide was purified by precipitation in methanol/pentane to give a white amorphous solid (1.7 g, 69%). 1H NMR (300 MHz, CDCl3) δ 3.25 (dd, J=14.4 Hz, J=8 Hz, 1H, CH2), 3.46 (dd, J=14.4 Hz, J=5.3 Hz, 1H, CH2), 4.67 (m, 1H, CHα), 5.12 (m, 2H, CH2 (Z)), 5.63 (broad s, 1H, NHZ), 7.06-7.72 (m, 16H, 15 aromatic H, NH amide), 8.09 (s, 1H, NH indole). 13C NMR (75 MHz, CDCl3) δ 28.6 (CH2 Trp), 56.1 (CHα), 67.2 (CH2 (Z)), 111.4, 118.8, 119.9, 120.1, 122.4, 123.4, 124.5, 127.1, 128.1, 128.3, 128.6, 128.9, 136, 136.2, 137.1 (20 aromatic C), 156 (CO carbamate), 169.7 (CO amide). Anal. Calcd. for C25H23N3O3: C, 72.62; H, 5.61; N, 10.16. Found: C, 72.75; H, 5.58; N, 9.95.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:26][C:27](=[N:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)OC1C=CC=CC=1)#[N:25]>>[C:24]([NH:26][C:27]([NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:21])=[N:35][CH2:36][CH2:37][S:38][CH2:39][C:40]1[N:41]=[C:42]([NH:45][C:46]([NH2:48])=[NH:47])[S:43][CH:44]=1)#[N:25]
Reactant: CN(CCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: CN(CCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.53 g (1.67 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil. MS (+FAB method): m/z (rel. int. [%])=598 ([M+H]+, 6), 109 (100); IR (KBr): 2163 cm-1 (C≡N); C27H36FN11S2 (597.80).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:13][S:14][C:15](SC)=[C:16]([C:21]#[N:22])[C:17]([O:19][CH3:20])=[O:18]>C1COCC1.CCCCCC>[C:21]([C:16](=[C:15]([S:14][CH3:13])[NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:17]([O:19][CH3:20])=[O:18])#[N:22]
Reactant: Nc1cccnc1
Reactant: COC(=O)C(C#N)=C(SC)SC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C(C#N)=C(Nc1cccnc1)SC
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
1.39 g (14.8 mmol) of 3-aminopyridine are dissolved in 50 ml of THF, cooled to −20° C., and 7.4 ml of a 2M solution of n-butyllithium in hexane are added. After stirring for 15 min, 2.00 g (9.84 mmol) of methyl 3,3-bis(methylthio)-2-cyanoacrylate are added. The mixture is warmed to room temperature while stirring and then hydrolyzed with ice-water. The product is extracted with dichloromethane. After drying over sodium sulfate, the solvent is removed in vacuo and the residue is purified by preparative HPLC. 0.44 g (18.1% of theory) of the desired product is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[CH:13][C:12]=3[O:19][CH3:20])=[CH:9][N:8]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:37](#[N:39])[CH3:38]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:4]4[CH:38]=[C:37]([CH:7]=[CH:2][CH:3]=4)[NH2:39])[CH:3]=3)[N:8]([S:21]([C:24]3[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=3)(=[O:22])=[O:23])[CH:9]=2)=[C:12]([O:19][CH3:20])[CH:13]=1
Reactant: COc1cc(F)c(C)cc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)cc12
Reactant: CC#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: COc1cc(F)c(C)cc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(N)c3)cc12
Temperature: 90 °C

Procedure:
A solution of 5-bromo-3-(4-fluoro-2-methoxy-5-methylphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine 135 (250 mg, 0.5122 mmol) and 23 (145.9 mg, 0.655 mmol) in acetonitrile was added cesium carbonate (336.03 mg, 1.024 mmol). The reaction was degassed and purged with nitrogen for 10 min and Pd(dppf)Cl2 (20.8 mg, 0.02561 mmol) was added to the reaction. The reaction was degassed and purged with nitrogen for another 10 min. The reaction was heated to 90° C. under sealed condition for overnight. The reaction mixture was allowed to cool to room temperature, diluted with chloroform. The organic layer was filtered through celite plug and concentrated to get the crude compound 136. The crude was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted in 5% ethyl acetate in hexane as half white solid 3-(3-(4-fluoro-2-methoxy-5-methylphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)aniline 136.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][C:11]([O:13]CC)=[O:12])[N:5]=1)([CH3:3])[CH3:2].[Li+].[OH-].Cl>O>[CH:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][C:11]([OH:13])=[O:12])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cn1nc(C(C)C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(C)C)nn1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
A mixture of ethyl (3-isopropyl-5-methyl-1H-pyrazol-1-yl)acetate (Preparation 129, 571 mg, 2.72 mmol) and LiOH (342 mg, 8.15 mmol) in IMS (5 mL) and water (4 mL) was stirred at room temperature for 30 minutes. The reaction was acidified with 2M HCl and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title compound as a cream solid (328 mg, 66%).
Reaction SMILES: BrBr.[Br:3][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([Br:24])[C:22]=1[OH:23])[CH:7]1[CH:16]([CH3:17])[C:15](=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:19])[CH:13]=2)[O:8]1.CCC(C1C=C(O)C=CC=1O)=O.BrC1C=C(C=C(Br)C=1O)C=O.N1CCCCC1.BrC1(C)C(=O)C2C(=CC=C(O)C=2)OC1C1C=C(Br)C(O)=C(Br)C=1.[OH-].[K+]>C(Cl)(Cl)Cl.O1CCOCC1.C(O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([Br:24])[C:22]=1[OH:23])[C:7]1[O:8][C:9]2[C:14]([C:15](=[O:18])[C:16]=1[CH3:17])=[CH:13][C:12]([OH:19])=[CH:11][CH:10]=2
Reactant: CC1C(=O)c2cc(O)ccc2OC1c1cc(Br)c(O)c(Br)c1
Agent: BrBr
Agent: CC1(Br)C(=O)c2cc(O)ccc2OC1c1cc(Br)c(O)c(Br)c1
Agent: CCC(=O)c1cc(O)ccc1O
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1c(-c2cc(Br)c(O)c(Br)c2)oc2ccc(O)cc2c1=O
Reaction time: 0.08 h

Procedure:
1.6 g of bromine in 6 ml of chloroform are added dropwise to a solution of 4.12 g of 3',5'-dibromo-6,4'-dihydroxy-3-methylflavanone (m.p. 200°-202°; obtainable by reaction of 2,5-dihydroxypropiophenone with 3,5-dibromo-4-hydroxybenzaldehyde in boiling ethanol in the presence of piperidine) in 55 ml of dioxane while stirring and irradiating (500 watt Agaphot lamp). The mixture is stirred for a further 30 minutes while cooling and irradiating, the usual working-up is carried out, and the resulting crude 3,3',5'-tribromo-6,4'-dihydroxy-3-methylflavanone is dissolved in 100 ml of ethanol. 15 ml of 10% aqueous potassium hydroxide solution are added, and the mixture is boiled for 5 minutes, cooled, poured on to ice and the usual working-up is carried out. 3',5'-Dibrom-6,4'-dihydroxy-3-methylflavone ("D") is obtained, m.p. 264°-265°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(-c2ccccc2)oc1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccccc2)oc1CBr
Yield: 34.9 %

Procedure:
A solution of ethyl 5-methyl-2-phenyloxazole-4-carboxylate (11.0 g, 48 mmol), NBS (8.5 g, 48 mmol), and BPO (100 mg) in CCl4 (200 ml) was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography to give ethyl 5-(bromomethyl)-2-phenyloxazole-4-carboxylate as a tan solid (5.2 g, 35% yield).
Reaction SMILES: [CH2:1]([OH:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11](I)[CH3:12]>>[CH2:1]([O:10][CH2:11][CH3:12])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC=Cc1ccccc1
Reactant: CCI
Product: CCOCC=Cc1ccccc1

Procedure:
Reaction of cinnamyl alcohol with ethyl iodide was carried out in the same manner as described in Example I. The analytical data supported the assigned structure and GC analysis indicated a purity of 99+%: λmaxCCl4 6.66, 6.87, 7.25, 8.75-9.1, 10.35 and 14.45 μ.
Reaction SMILES: [NH2:1][C:2]([CH:8]([OH:27])[CH:9]([OH:26])[CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH2:6][OH:7])[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][C:2]([CH:8]([OH:27])[CH:9]([OH:26])[CH2:10][CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH2:3][OH:4])[CH2:6][OH:7]
Reactant: CCCCCCCCCCCCCC=CCC(O)C(O)C(N)(CO)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC=CCC(O)C(O)C(N)(CO)CO

Procedure:
A lactone compound (978 mg) of 2-amino-3-hydroxy-2-(1,2-dihydroxy-4-octadecenyl)propionic acid and 403 mg of lithium aluminum hydride were reacted in 33 ml of dry tetrahydrofuran according to the method of Example 274 to give 222 mg of the subject compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: C1CCNCC1
Product: Clc1ccc(-c2nsc3cc(C#CCCCN4CCCCC4)ccc23)cc1

Procedure:
According to the method in example 18, Methanesulfonic acid 5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and Piperidine were converted to yield 3-(4-Chloro-phenyl)-6-(5-piperidin-1-yl-pent-1-ynyl)-benzo[d]isothiazole, MS: 395 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[OH:12][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][NH2:15]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:15][CH2:14][CH:13]([OH:12])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: NCC(O)c1ccccc1
Reactant: CC(=O)Cc1ccc(C)cc1
Solvent: c1ccccc1
Product: Cc1ccc(CC(C)NCC(O)c2ccccc2)cc1
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A mixture of 4-methylphenylacetone (2.7 g) and 2-hydroxy-2-phenylethanamine (2.5 g) was refluxed in benzene (70 ml) under Dean & Stark conditions for 4h. The solvent was removed under reduced pressure, replaced with methanol (100 ml) and cooled in ice during the portionwise addition of sodium borohydride (3.0 g). The solution was stirred for 2 h, the solvent was evaporated under reduced pressure and the residue was partitioned between water (100 ml) and chloroform (100 ml). The organic extract was dried (MgSO4), the solvent was evaporated and the residual oil was crystallised from hexane to give the title compound (2.1 g) as a 44:56 mixture of diastereoisomers, mp 74°-94°.