Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[NH:1][C:20]([NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: Nc1ccc(C(F)(F)F)cc1O
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccc(C(F)(F)F)cc1O
Yield: 71.2 %

Procedure:
N-[2-Hydroxy-4(trifluoromethyl) phenyl]-N'-phenyl urea was prepared from 2-amino-5-trifluoromethylphenol (150 mg, 1.09 mmol) and phenyl isocyanate(1.09 mmol) according to the procedure in General method A. The product was purified by precipitation from methylene chloride and filtering to afford the titled compound (230 mg, 87% ). mp: °C.; 1H NMR (DMSO-d6): δ 9.45 (s, 1H, NH), 8.50 (s, 1H, NH), 8.31 (d, 1H, J=10.0 Hz), 7.45 (d, 2H, J=10.0 Hz), 7.29 (t, 2H, J=6.67 Hz), 7.10 (m, 2H), 6.99 (t, 1H, J=6.67 Hz). EI-MS m/z 296 (M+). Anal. (C14H11N2O2F3)C, H, N.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=O.C(OC(N1CCC(O[C:22]2[CH:23]=[CH:24][C:25]3[C:37](=[O:38])[C:36]4[C:35]5[C:30](=[CH:31][C:32]([C:39]#[N:40])=[CH:33][CH:34]=5)[NH:29][C:28]=4[C:27]([CH3:42])([CH3:41])[C:26]=3[CH:43]=2)CC1)=O)(C)(C)C>C1COCC1>[CH3:41][C:27]1([CH3:42])[C:28]2[NH:29][C:30]3[C:35](=[CH:34][CH:33]=[C:32]([C:39]#[N:40])[CH:31]=3)[C:36]=2[C:37](=[O:38])[C:25]2[CH:24]=[CH:23][C:22]([CH:3]3[CH2:1][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:43][C:26]1=2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1(C)c2cc(C3CCNCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C

Procedure:
With the same condition as the method for synthesizing the Compound A8-1 (THF (0.5 mL) and TFA (0.5 mL) were added to 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Compound A7-1, 35 mg, 0.072 mmol), and the mixture was stirred at room temperature until Compound A7-1 disappears. The reaction solution was concentrated under reduced pressure and the residue was desalinated by using anionic exchange resin PL StratoSpheres (trademark) PL-HCO3 MP to obtain the Compound A8-1 (37 mg, 76%)), the title compound was synthesized from the Compound B3-13-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].[CH3:11]S(C)=O.CI>O>[CH3:11][O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCc1ccccn1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCc1ccccn1
Temperature: 25 °C

Procedure:
Also, 2-(methoxymethyl)pyridine is prepared by the following alternative procedure. A mixture of 10.9 g. of 2-pyridinemethanol and 2.4 g. of sodium hydride in 50 ml. of dimethylsulfoxide is warmed on a steam bath for 15 minutes, then cooled to room temperature. Methyl iodide (14.2 g.) is added and then the mixture is heated at 40°C. for 1 hour. Water (150 ml.) is then added and the mixture is extracted with ether. The extracts are dried, concentrated and distilled to give 2-(methoxymethyl)pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][CH3:36])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:21]3[C:22](=[O:24])[O:23][C:18]([CH:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][CH3:36])[CH:29]=4)[CH2:19][C:20]=3[OH:25])[N:10]=2)[CH:7]=1
Reactant: O=Cc1nc2ncc(Br)cn2n1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Product: CCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4ncc(Br)cn4n3)C(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to Example A(224) where 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was used in place of 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde and 6-cyclopentyl-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione was used in place of 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione in that example. 1H NMR (DMSO): δ 1.15 (t, J=7.54 Hz, 3H), 1.30–1.90 (brm, 8H), 2.00–2.40 (brm, 3H), 2.50 (q, J=10.74 Hz 2H), 2.75 (m, 2H); 2.90 (m, 2H), 3.50 (m, 3H), 6.64 (d, J=5.26 Hz, 1H), 6.70 (d, J=5.26 Hz, 1H), 7.00 (s, 1H), 8.75 (s, 1H), 9.19 (s, 1H). Anal. Calcd. For C26H29O4N4Br C, 57.68; H, 5.40; N, 10.35. Found: C, 57.50; H, 5.50; N, 10.30.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=2)[CH2:11][NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][CH2:11][C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:22][CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=4)[N:7]=3)[CH:21]=[CH:20][CH:19]=2)[CH:14]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Clc1nccc(-c2cccc(CNc3cccnc3)c2)n1
Product: Oc1ccc(CCNc2nccc(-c3cccc(CNc4cccnc4)c3)n2)cc1

Procedure:
Intermediate 63 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 398. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 9.2 (m, 1H), 8.3 (s, 1H), 8.2 (m, 2H), 8.1 (m, 2H), 8.0 (m, 3H), 7.7 (s, 1H), 7.5 (d, 2H), 7.1 (m, 4H), 6.6 (m, 2H), 4.2 (m, 1H), 3.2 (m, 2H), 2.7 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>>[CH2:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C@H:16]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:17]([OH:18])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH3:35])=[CH:25][CH:24]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCCCCCCCCCCCCCCBr
Reactant: O=C[C@H](Cc1ccc(OCc2ccccc2)cc1)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 20 (597 mg, 1.37 mmol) and 1-bromopentadecane (999 mg, 3.43 mmol), alcohol 74 was obtained as a colorless oil (496 mg, 56% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH:5]([OH:9])[C:6]([OH:8])=O.[NH2:14][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16]>>[F:13][C:11]1[CH:10]=[C:4]([CH:5]([OH:9])[C:6]([NH:14][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[CH3:16])=[O:8])[CH:3]=[C:2]([F:1])[CH:12]=1
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Product: COC(=O)[C@H](C)NC(=O)C(O)c1cc(F)cc(F)c1

Procedure:
Following General Procedure E and using (R/S)-3,5-difluoromandelic acid (as set forth in General Procedure H, step A) and L-alanine, methyl ester (Bachem) the title compound was synthesized.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([CH2:25][CH2:26][O:27]CC1C=CC=CC=1)[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>[OH-].[Pd+2].[OH-].O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([CH:16]([CH2:25][CH2:26][OH:27])[CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CC(CCOCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(CCO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 4.5 h
Yield: 112.9 %

Procedure:
tert-Butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-benzyloxyvalerate (500 g), ethyl acetate (750 mL) and tetrahydrofuran (1510 mL) were mixed. To the mixture was added 20 w/w % palladium hydroxide (50 g). The mixture was stirred for 4.5 hr under hydrogen atmosphere (1 atm). The palladium hydroxide was filtered off and the filtrate was concentrated in vacuo to give the title compound (455.76 g) as a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Cl[C:10]1[C:11](=[O:25])[C:12]2[C:17]([C:18](=[O:21])[C:19]=1Cl)=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=[CH:14][CH:13]=2>C(O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([C:10]3[C:11](=[O:25])[C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([N+:22]([O-:24])=[O:23])[C:17]=4[C:18](=[O:21])[C:19]=3[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CCO
Product: O=C1c2nc3ccc(Cl)cn3c2C(=O)c2cccc([N+](=O)[O-])c21
Yield: 7.2 %

Procedure:
2.50 g (19.0 mmol) of 2-amino-5-chloropyridine are added to a solution of 2.50 g (11.0 mmol) of 2,3-dichloro-1,4-dihydro-1,4-dioxo-5-nitronaphthalene in 500 mL of ethanol. This mixture is heated to reflux for 62 h and 50 min. The solution passes from yellow to claret-colored, then to orange. After cooling, the reaction mixture is filtered. The precipitate is washed with ethanol, then dried in an oven for 20 h. The precipitate obtained is recrystallized in 650 mL of ethanol. This precipitate is purified on a flash column (support: silica; eluent: dichloromethane). 0.260 g of 2-chloro-6,11-dihydro-6,11-dioxo-7-nitronaphtho[2',3':4,5]imidazo[1,2-a]-pyridine or 2-chloro-6,11-dihydro-6,11-dioxo-10-nitronaphtho[2',3':4,5]imidazo[1,2-a] pyridine is obtained in the form of orange crystals, and 0.495 g of 10-chloro-5,6-dihydro-5,6-dioxo-4-nitronaphtho[1',2':4,5] imidazo[1,2-a]pyridine is formed in the form of orange crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:3]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1cccc(-c2nc(C)cc(Cl)n2)c1
Product: COc1ccc(Nc2cc(C)nc(-c3cccc(C)c3)n2)cc1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(3-methylphenyl)pyrimidine (100 mg, 0.457 mmol) and p-anisidine (56 mg, 0.457 mmol), similar to Example 11 as a pale green solid (39 mg, 28%). 1H NMR (DMSO-d6): 8.04 (s, 1H), 8.01–7.99 (m, 1H), 7.56–7.51 (m, 4H), 7.04 (d, J=9.0 Hz, 2H), 6.73 (s, 1H), 3.79 (s, 3H), 2.44 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:43])[C:17]4[C:22]([C:23]=3[C:24]3[CH2:25][CH2:26][N:27]([C:30]([CH:32]5[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]5)=[O:31])[CH2:28][CH:29]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[F:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[C:49]([OH:51])[CH:50]=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:43])[C:17]4[C:22]([C:23]=3[C:24]3[CH2:25][CH2:26][N:27]([C:30]([CH:32]5[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]5)=[O:31])[CH2:28][CH:29]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([C:47]3[CH:48]=[C:49]([OH:51])[CH:50]=[C:45]([F:44])[CH:46]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)C2CN(C(=O)OC(C)(C)C)C2)CC1)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cc(O)cc(F)c1
Product: CC(c1oc(=O)c2ccccc2c1C1=CCN(C(=O)C2CN(C(=O)OC(C)(C)C)C2)CC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Yield: 63.1 %

Procedure:
The title compound was prepared following the procedure reported for Example 68, from tert-butyl 3-(4-(3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)azetidine-1-carboxylate (Intermediate D28, 0.251 g, 0.360 mmol), and 3-fluoro-5-hydroxyphenylboronic acid (0.112 g, 0.720 mmol) to give tert-butyl 3-(4-(3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-1,2,3,6-tetrahydropyridine-1-carbonyl)azetidine-1-carboxylate (0.155 g, 0.227 mmol, 63.2% yield).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClC(Cl)C>[NH2:15][C:16]1[C:21]([NH:22][CH:33]2[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:31][CH2:32]2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccnc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Reaction time: 5 h
Yield: 33.2 %

Procedure:
Sodium triacetoxyborohydride (14.5 g, 68.7 mmol) was added to a solution of 2,3-diaminopyridine (5.00 g, 45.8 mmol) and N-(t-butoxycarbonyl)-4-piperidone (9.58 g, 48.1 mmol) in dichloroethane (75 mL) at room temperature. After 5 h, additional sodium triacetoxyborohydride was added (1.8 g) and again after another 2.5 h. The reaction was stirred overnight, and quenched with 5% aqueous sodium hydroxide. This was extracted with methylene chloride, and washed with 5% aqueous sodium hydroxide, water and saturated sodium chloride solution. After drying over sodium sulfate, the solution was filtered and evaporated to give the crude product. This was purified by chromatorgraphy (silica gel, 3 to 5% methanol in methylene chloride gradient elution), which gave the title compound (4.44 g). MS 293 (M+1) 1H NMR (500 MHz, CD3OD) δ 7.32 (dd, J=1, 5 Hz, 1H), 6.85 (dd, J=1, 8 Hz, 1H), 6.59 (dd, J=5, 8 Hz, 1H), 4.04 (d, J=13 Hz, 2H), 3.46 (m, 1H), 2.98 (br s, 2H), 2.01 (dd, J=2, 12 Hz, 2H), 1.46 (s, 9H), 1.37 (qd, J=4, 12 Hz, 2H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[S:25][CH:23]([OH:24])[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([OH:29])(=S)[CH3:27].C1(C)C(S(O)(=O)=O)=CC=CC=1>C(Cl)Cl>[C:26]([SH:25]1[CH:23]([OH:24])[CH2:22][CH2:21][C@H:20]1[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:29])[CH3:27]
Reactant: CC(O)=S
Reactant: CC(C)(C)[Si](OC[C@@H]1CCC(O)S1)(c1ccccc1)c1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: CC(=O)[SH]1C(O)CC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 67.1 %

Procedure:
Two grams of 5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-4-thioribofuranose (prepared according to J. A. Secrist et al., J. Med. Chem., 1992,35,533) is stirred with 0.456 g of thioacetic acid in 25 ml of methylene chloride and 0.0.025 g of toluenesulfonic acid for 68 hours. On workup the reactiion is adsorbed onto magnesium silicate and then flash chromatographed on silica gel to give 1.5 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15]C)=[CH:4][CH:3]=1.B(Br)(Br)Br.CC(C)=O>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[CH:4][CH:3]=1
Reactant: COc1ccccc1Cc1ccc(Cl)nn1
Agent: BrB(Br)Br
Solvent: CC(C)=O
Solvent: ClCCl
Product: Oc1ccccc1Cc1ccc(Cl)nn1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
2-(6-Chloro-3-pyridazinylmethyl)anisole (prepared as described in Example 33(c)) (2.35 g) was dissolved in dry dichloromethane (20 ml) and cooled with stirring to -50°. Boron tribromide (3 ml) was then added dropwise, and the solution was allowed to warm to room temperature. After 0.5 hours the orange reaction mixture was poured into ice/water (200 ml) and acetone added to dissolve the precipitated solid. The mixture was extracted with dichloromethane, the organic extracts were separated, washed with water, dried, and evaporated. The residue was recrystallised from ethyl acetate and petroleum spirit to give 2-(6-chloro-3-pyridazinylmethyl)phenol (1.75 g, 80%), m.p. 132-132.5°.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:18]=1[C:19]#[N:20]>>[CH2:1]([N:8]1[C:12]([C:13]([NH:16][C:17]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[C:18]=2[C:19]#[N:20])=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Reactant: N#Cc1c(N)cccc1N1CCCCC1
Product: N#Cc1c(NC(=O)c2nnnn2Cc2ccccc2)cccc1N1CCCCC1

Procedure:
In a manner similar to Example I, 1-benzyl-1H-tetrazole5-carbonyl chloride is condensed with 2-amino-6-(1-piperidinyl)benzonitrile to give 1-benzyl-N-[2-cyano-3-(1-piperidinyl)phenyl]1H-tetrazole-5-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[N:12]2[CH:26]=[CH:27][N:28]=[C:11]2[CH:10]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH2:17][NH2:18])[N:12]2[CH:26]=[CH:27][N:28]=[C:11]2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.42 g (10.47 mmol) of tert-butyl (2-{[7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]amino}ethyl)carbamate are dissolved in 160 ml of dichloromethane, and 16 ml (209 mmol) of trifluoroacetic acid are added. The mixture is stirred at RT for 2 h and then removed from all volatile constituents in vacuo. 4.56 g (99% of theory) of product are obtained and are employed without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9](Cl)=[O:10]>>[Cl:7][CH2:8][C:9]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:10]
Reactant: C1COCCN1
Reactant: O=C(Cl)CCl
Product: O=C(CCl)N1CCOCC1

Procedure:
7-Oxo-4,7-dihydro[1,3]thiazolo[5,4-b]pyridine-6-carboxamides. Preparation of specific examples of heterocycle W20.1 follows an established literature precedent described in Chart BM (A. Haemers J. Heterocyclic Chem. 1984, 21, 401-406.). Morpholine is condensed with chloroacetyl chloride to afford 4-(chloroacetyl)-morpholine (BM.1) which is transformed to the dithiocarboxylate methyl ester (BM.2) by the reaction with sulfur, an amine base (e.g. triethylamine) and iodomethane. Condensation of BM.2 with aminoacetonitrile bisulfate in the presence of triethylamine affords the thiazole BM.3. Subsequent reduction of the carboxamide with borane provides BM.4 which is condensed with diethyl ethoxymethylenemalonate to give BM.5. Alkylation of the enamine nitrogen with an alkylhalide (e.g. iodomethane) or other suitable electrophile in the presence of an inorganic base affords BM.6. Cyclization of BM.6 by heating in a mixture of Eaton's reagent provides the thiazolopyridine BM.7. The resulting ester is then treated with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at high temperature or the ester may be saponified to afford the corresponding acid which is then coupled with a benzylamine mediated by 1,1′-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to provide amides of the general formula BM.8.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH:9]=[N:8][C:7](Cl)=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH:3]=1.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32]>C1COCC1.O>[NH2:15][CH2:14][CH2:13][CH2:12][N:4]1[C:5]2[N:6]=[C:7]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:8]=[CH:9][C:10]=2[C:2]([Br:1])=[CH:3]1
Reactant: NCCCCC(=O)O
Reactant: O=C1c2ccccc2C(=O)N1CCCn1cc(Br)c2cnc(Cl)nc21
Solvent: O
Solvent: C1CCOC1
Product: NCCCn1cc(Br)c2cnc(NCCCCC(=O)O)nc21
Temperature: 150 °C

Procedure:
A solution of the crude 2-(3-(5-bromo-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propyl)isoindoline-1,3-dione in a mixture of THF and water (10 mL, 3:2, v/v) was added 5-aminopentanoic acid (172.3 mg, 1.47 mmol). The resulting mixture was heated at 150° C. under microwave irradiation for 1 h. After the solvent was removed, the residue was dissolved in a mixture of ethanol and water (20 mL, 3:2, v/v) followed by the addition of hydrazine (1.5 mL). Then the reaction mixture was heat at 80° C. for overnight. The solvent was removed and the residue was purified on HPLC to provide 5-((7-(3-aminopropyl)-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pentanoic acid as an clear oil (MS m/z 371.10 [M+H]+).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][CH2:8][C:4]=2[CH:3]=[C:2]1[C:9]([O:11][CH3:12])=[O:10].[C:13](O)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[C:13]([N:7]1[CH2:8][C:4]2[CH:3]=[C:2]([C:9]([O:11][CH3:12])=[O:10])[S:1][C:5]=2[CH2:6]1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1cc2c(s1)CNC2
Reactant: CC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1cc2c(s1)CN(C(=O)C(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 5,6-dihydro-4H-thieno[2,3-c]pyrrole-2-carboxylate (0.023 g, 0.127 mmol) and pivalic acid (0.014 g, 0.14 mmol) in methylene chloride (0.92 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.055 g, 0.146 mmol) and N-methylmorpholine (0.035 mL, 0.32 mmol) respectively. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with additional DCM (2 mL) and washed with saturated aqueous NaHCO3 (2 mL). The aqueous layer was extracted with additional DCM (3 mL), and the combined organic layers were concentrated to afford an oily residue. LCMS (FA) ES+ 268.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([NH:20][C@@H:21]1[CH2:25][CH2:24][C@H:23]([CH2:26][OH:27])[CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[C:13]([NH:20][C@@H:21]1[CH2:25][CH2:24][C@H:23]([CH2:26][O:27][N:29]2[C:33](=[O:34])[C:32]3[C:31](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]2=[O:39])[CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CON2C(=O)c3ccccc3C2=O)C1

Procedure:
A solution of 2.94 ml (0.01755 mol) of diethyl azodicarboxylate (93%) in 10 ml of benzene is added dropwise to a mixture of 3.6 g (0.01672 mol) of cis-3-(N-BOC-amino)-cyclopentanemethanol, 2.73 g (0.01673 mol) of N-hydroxyphthalimide, 4.49 g (0.01672 mol) of triphenylphosphine and 60 ml of benzene at 20°-30° C., while stirring. After the mixture has been stirred at room temperature for 1 hour, the precipitate formed during the reaction is filtered off, the residue on the filter is suspended in benzene and the suspension is filtered again. The latter operation is repeated twice more (residue on the filter: diethyl 1,2-hydrazinedicarboxylate), and the resulting filtrates are combined and these are evaporated in vacuo. Purification of the residue is carried out by means of flash chromatography on silica gel using ethyl acetate/hexane mixtures (1:3 and 1:1). The title compound is thus obtained, m.p. 162°-163° C.