Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[F:17][C:18]([F:42])([F:41])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]>>[F:17][C:18]([F:41])([F:42])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39][N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(C(F)(F)F)cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-trifluoromethyl-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])=[O:8])=[CH:5][CH:4]=1)#[N:2].[OH-:20].[K+].[Cl-].[Na+]>C(O)(C)(C)C>[CH3:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[NH:9][C:7]([C:6]1[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:20])=[CH:19][CH:18]=1)=[O:8]
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(C#N)cc1
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: Cc1cccc(C)c1NC(=O)c1ccc(C(N)=O)cc1
Yield: 43 %

Procedure:
Ten grams of 4-cyano-N-(2,6-dimethylphenyl)benzamide and 3 grams of finely powdered potassium hydroxide were slurried in t-butanol and heated at reflux for 50 minutes. The homogeneous mixture was poured into a saturated sodium chloride solution and extracted in chloroform. Material which was insoluable in both the organic and water phases were recovered by filtration, crystallized from methanol, and provided the title compound in 43% yield, m.p. 246°-248° C.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9]1([C:15](=O)[C:16]([C:21]#N)=[CH:17][N:18](C)C)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>>[NH2:7][C:6]1[N:8]=[C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:16]([C:17]#[N:18])=[CH:21][N:5]=1
Reactant: CN(C)C=C(C#N)C(=O)c1ccccc1
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cnc(N)nc1-c1ccccc1

Procedure:
2-Amino-5-cyano-4-phenylpyrimidine was prepared from guanidine carbonate (1.57 g, 17.5 mmol), 1-phenyl-2-cyano-3-dimethylaminopropen-1-one (3.5 g, 17.5 mmol) and sodium hydroxide (720 mg, 19.3 mmol) in a similar method to the compound of Example 1, as an off-white solid, m.p. 147°.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[C:13]([NH:15][C@H:16]([C:18]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:22](=[O:30])[C:21]5=[C:31]([CH3:34])[CH:32]=[CH:33][N:20]5[N:19]=4)[CH3:17])=[N:12][CH:11]=[N:10][C:9]=3[N:8](COCC[Si](C)(C)C)[CH:7]=2)=[N:2]1.[F:43][C:44]([F:48])([F:47])[CH2:45]I.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O.N>CN(C=O)C>[CH3:34][C:31]1[CH:32]=[CH:33][N:20]2[C:21]=1[C:22](=[O:30])[N:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]([C@@H:16]([NH:15][C:13]1[C:14]3[C:6]([C:3]4[CH:4]=[CH:5][N:1]([CH2:45][C:44]([F:48])([F:47])[F:43])[N:2]=4)=[CH:7][NH:8][C:9]=3[N:10]=[CH:11][N:12]=1)[CH3:17])=[N:19]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc[nH]n3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: FC(F)(F)CI
Agent: N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5ccn(CC(F)(F)F)n5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 80 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
(S)-2-(1-((5-(1H-Pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.07 mmol) and 1,1,1-trifluoro-2-iodoethane (36 mg, 0.17 mmol) were dissolved in DMF (2 ml) and cesium carbonate (140 mg, 0.43 mmol) was added. After stirring the mixture at 80° C. for 2 h, the solvent was evaporated under reduced pressure and the residue was suspended in water and extracted with ethyl acetate (×3). The organic phase was successively washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. The residue (54 mg) was treated with trifluoroacetic acid (1 mL, 13 mmol) and a solution of ammonia (7N in methanol, 10 ml, 70 mmol) according to the method described in Example 27 to give 4.6 mg (12% yield) of the title compound. Purity 93%.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6](=O)[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17][C:15]3=2)[CH:10]=[CH:9]1)C.O>C1COCC1>[OH:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17][C:15]3=2)[CH:10]=[CH:9]1
Reactant: CCOC(=O)Cn1ccc2ccc3c(c21)CCN(C(=O)OC(C)(C)C)CC3
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc3ccn(CCO)c3c2CC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 111.8 %

Procedure:
Under N2, a flame-dried, 100-mL, three-necked flask was charged with lithium borohydride (0.39 g, 17.0 mmol) and anhydrous THF (10 mL) and cooled to −10° C. A solution of tert-butyl 1-(2-ethoxy-2-oxoethyl)-6,7,9,10-tetrahydroazepino[4,5-g]indole-8(1H)-carboxylate (2.11 g, 5.66 mmol) in anhydrous THF (20 mL) was added and the mixture was allowed to warm to room temperature and was stirred for 2 hours. An additional equivalent of lithium borohydride (0.13 mL, 5.66 mmol) was added and the mixture was stirred at room temperature for 16 hours. Water was added slowly and the mixture was partitioned between EtOAc and water. The combined organic layers were concentrated to give 2.09 g of an oil. Column chromatography (elution with 10–30% Et2O/hexane) gave 1.70 g (91%) of the title compound as a clear oil. An analytical sample was crystallized from EtOAc hexane to give a white solid: mp 109–111° C.; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8 Hz, 1 H), 7.03 (d, J=3 Hz, 1 H), 6.90 (d, J=8 Hz, 1 H), 6.45 (d, J=3 Hz, 1 H), 4.45 (t, J=5 Hz, 2 H), 3.99–3.88 (m, 2 H), 3.72–3.54 (m, 4 H), 3.39–3.25 (m, 2 H), 3.10–2.99 (m, 2 H), 1.38 (s, 9 H); IR (diffuse reflectance) 3470, 2976, 1666, 1457, 1428, 1369, 1350, 1312, 1267, 1251, 1192, 1178, 1081, 816, 720 cm−1; MS (EI) m/z 330 (M+); Anal. Calcd for C19H26N2O3: C, 69.06; H, 7.93; N, 8.48. Found: C, 68.92; H, 7.94; N, 8.43.
Reaction SMILES: CCCCC(N([C@H](C(O)=O)C(C)C)CC1C=CC(C2C=CC=CC=2C2NN=NN=2)=CC=1)=O.Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[N:51]([C:52]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:50]=[N:49][N:48]=2)=[CH:37][CH:36]=1.[CH2:71]([O:78][C:79](=[O:85])[C@H:80]([CH:82]([CH3:84])[CH3:83])[NH2:81])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1>>[CH2:71]([O:78][C:79](=[O:85])[C@H:80]([CH:82]([CH3:83])[CH3:84])[NH:81][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[N:51]([C:52]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[N:50]=[N:49][N:48]=2)=[CH:37][CH:36]=1)[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Agent: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Product: CC(C)[C@H](NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)OCc1ccccc1

Procedure:
According to U.S. Pat. No. 5,399,578, Valsartan can also be prepared by reaction of 4-bromomethyl-2′-(1-triphenylmethyltetrazol-5-yl)biphenyl (VI) with L-valine benzyl ester to produce N-[[2′-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]-methyl]-L-valine benzyl ester (VII), followed by treatment with valeryl chloride to produce N-(1-oxopentyl)-N-[[2′-(1-triphenylmethyltetrazol-5-yl)[1,1′-biphenyl]-4-yl]-methyl]-L-valine benzyl ester (VIII). Compound (VIII) is deprotected under acidic conditions to produce N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]-methyl]-L-valine benzyl ester (IX), which is then hydrogenated in presence of Pd/C catalyst to give finally Valsartan. The process is shown in scheme II, below:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH2:28]([C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:28]([C:30]1[N:31]([C:2]2[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:13][CH:14]([CH:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[CH2:15]4)[S:8][C:6]=3[N:7]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)sc2n1
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)sc2n1
Temperature: 145 °C

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-2-[3-(tetrahydro-pyran-4-yl)azetidin-1-ylmethyl]thiazolo[5,4-d]pyrimidine (90 mg, 0.22 mmol), 2-ethylbenzimidazole (38 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol), Xphos (21 mg, 0.04 mmol) and Cs2CO3 (143 mg, 0.44 mmol) in dioxane (2.5 mL) was purged with argon then heated at 145° C. for 30 min in a microwave reactor. The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-7%). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 483 as an orange solid (82 mg, 72%). LCMS (Method I): RT 2.70 min, [M+H]+ 520.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.76-7.71 (m, 1 H); 7.30-7.24 (m, 2 H); 4.41 (m, 4 H); 4.04-3.94 (m, 4 H); 3.91-3.82 (m, 4 H); 3.61 (m, 2 H); 3.44-3.30 (m, 4 H); 3.10 (m, 2 H); 2.40-2.30 (m, 1 H); 1.70 (m, 1 H); 1.55 (m, 2 H); 1.43 (t, J=7.5 Hz, 3 H) and 1.32-1.18 (m, 2 H)
Reaction SMILES: [CH3:1][CH:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[Br-].[CH2:14]([NH3+])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[OH-].[Na+]>O>[CH3:12][C:10]1([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[C:2]1=[CH2:1]
Reactant: CC1Nc2ccccc2C1(C)C
Reactant: CCCCCCCCCCCCCCCCCC[NH3+]
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C1N(CCCCCCCCCCCCCCCCCC)c2ccccc2C1(C)C
Yield: 31.9 %

Procedure:
A mixture of 5.2 g (32 mmol) of 2,3,3-trimethylindoline and 15.8 g (48 mmol) of octadecylammonium bromide was heated with stirring followed by treating with a solution of 8 g of sodium hydroxide in 50 ml of water. After usual working-up, there were obtained 4.2 g of the title compound in a 84.1% yield.
Reaction SMILES: [S:1]([O-:5])(=[O:4])(=[O:3])[CH3:2].CS(O)(=O)=O.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][O:38][C:39]([C@@H:41]1[CH2:45][C@@H:44](O)[CH2:43][N:42]1[S:47]([C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=1)(=[O:49])=[O:48])=[O:40].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.CCOC(C)=O.CCCCCC.O>[CH3:37][O:38][C:39]([C@@H:41]1[CH2:45][C@H:44]([O:3][S:1]([CH3:2])(=[O:5])=[O:4])[CH2:43][N:42]1[S:47]([C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=1)(=[O:49])=[O:48])=[O:40]
Reactant: CS(=O)(=O)[O-]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CS(=O)(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCCCCC
Product: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 80 °C
Yield: 86 %

Procedure:
Via Mesylate: A biphasic solution of 13.9 ml (215 mmol) methanesulfonic acid, 29.8 ml (215 mmol) triethylamine and 58.7 g (224 mmol) triphenylphosphine in 150 ml toluene was added to a suspension of 60 g (179 mmol) (2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester in 300 ml toluene which was stirred mechanically. After adding 44.9 ml (233 mmol) of diisopropyl azodicaboxylate (exothermic!) the solution was heated for 2.5 h at 80° C. 300 ml water was added at room temperature and extracted with EtOAc (3×300 ml). The organic phase was washed with aqueous 10% KHSO4 (2×100 ml), 10% NaCl (2×150 ml) dried over Na2SO4 and evaporated to give 180 g of crude product. Flash chromatography (EtOAc/hexane 1:1) gave 63.7 g (86%) of (4S, 2S)-4-methanesulfonyloxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methylester.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:31])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:30])=[C:25]([C:27](O)=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:63][O:64][C:65](=[O:68])[CH2:66][NH2:67]>ClCCl>[CH2:1]([O:8][NH:9][C:10](=[O:31])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:30])=[C:25]([C:27]([NH:67][CH2:66][C:65]([O:64][CH3:63])=[O:68])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)O
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A solution 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)5-methyl-1,3-oxazole-4-carboxylic acid (Preparation 72) (230 mg, 0.53 mmol), N-methylmorpholine (61 l, 0.56 mmol), 1-hydroxybenzotriazole hydrate (68 mg, 0.53 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg, 0.56 mmol) in dichloromethane (10 ml) was treated with a solution of glycine methyl ester hydrochloride (70 mg, 0.56 mmol) and N-methylmorpholine (61 l, 0.56 mmol) in dichloromethane (2 ml) and stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and washed with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of 100:0:0 (dichloromethane:methanol:ammonia) gradually changing to 98:2:0.2 (dichloromethane:methanol:ammonia) to afford the title compound as a white solid (160 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.I[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][Si:19]([C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1)([CH3:22])[CH3:21]
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Reactant: C#Cc1ccc(C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.1 %

Procedure:
Into a 50 ml round bottom flask was placed a mixture of 0.64 g (0.0054 mole) of 4-methylphenylacetylene, 1.50 g (0.005 mole) of 4-iodophenyltrimethylsilylacetylene, 0.011 g (0.0058 mmole) of CuI, 0.103 g (0.146 mmole) of bis(triphenylphosphine)palladium(II) dichloride in 10 ml of THF and 10 ml of triethylamine. The brown solution turned to an orange-yellow suspension when solid started to form. The mixture was stirred at room temperature under nitrogen for 3 days. It was filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 25 ml of chloroform and the solution was washed two times with water (15 ml each) and then dried over anhydrous MgSO4, filtered and concentrated. 1.43 g (quantitative yield) of solid was obtained. 1HNMR indicated ˜10% of by product present. The solid product was used for the next step without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[NH3:6]>>[CH3:1][Si:2]([NH:6][Si:2]([CH3:5])([CH3:4])[CH3:1])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: N
Product: C[Si](C)(C)N[Si](C)(C)C

Procedure:
In a summary of the process shown in FIG. 1, liquid trimethylchlorosilane (TMCS) and gaseous ammonia are fed to the first of a set of two or more reactors where they combine to form "crude" HMDS and an ammonium chloride by-product slurry. As set forth below, the first stage of the set of two or more reactors is a high shear vessel in which the TMCS and ammonia mixture is subjected to continuous high shear agitation in a recirculating reactor loop. Ammonium chloride produced as a by-product is in a "prilled" form in the resultant slurry. The slurry is then optionally fed to a second high shear reactor to insure that a complete reaction of all TMCS occurs. Then, the slurry is passed to a centrifuge where the ammonium chloride crystals are removed. In the centrifuge, HMDS is removed from the solid ammonium chloride particles in the centrifuge cake by displacement of the HMDS with a non-reactive wash. Suitable washes may be hydrocarbons or a buffered saturated ammonium chloride water solution. The HMDS liquid filtrate passes on to a mix tank where solid sodium amide is added.
Reaction SMILES: [Br:1][C:2]([N+:7]([O-:9])=[O:8])([CH2:5][OH:6])[CH2:3][OH:4].[CH:10]1C=CC=C[CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)C>O>[Br:1][C:2]1([N+:7]([O-:9])=[O:8])[CH2:5][O:6][CH:10]([CH3:11])[O:4][CH2:3]1
Reactant: c1ccccc1
Reactant: O=[N+]([O-])C(Br)(CO)CO
Agent: CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC1OCC(Br)([N+](=O)[O-])CO1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Forty grams (0.2 mole) of 2-bromo-2-nitropropane-1,3-diol were suspended in 200 ml. of benzene and about 0.3 g. of p-toluene sulfonic acid was added. The mixture was cooled in an ice-water bath and a condenser attached to the reaction vessel. About 13.5 g. (0.3 mole) of acetaldehyde were slowly added through the condenser and the reaction mixture was stirred for 30 minutes. A Dean-Stark trap was connected and the mixture warmed slowly, then heated to reflux until water no longer was evolved. (About 4 ml. of water was evolved in 1.5 hours). The solution was filtered and evaporated on a rotating evaporator at about 45° C. A dark oil residue was obtained, which was vacuum distilled at 0.25 mm. Thirty-six and one-half grams (85% yield) of 5-bromo-2-methyl-5-nitro-1,3-dioxane were obtained having a boiling range at 0.25 mm. of from 72°-74° C. The NMR and IR were consistent with the structure, and an elemental analysis disclosed the following percentage composition:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:16])[CH2:3][NH:4][C:5]1[S:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([CH3:10])[N:9]=1.N[C@H](C)CNC1SC([C:27](OCC)=[O:28])=C(C)N=1>>[CH3:10][C:8]1[N:9]=[C:5]([N:4]2[CH2:3][C@@H:2]([CH3:16])[NH:1][C:27]2=[O:28])[S:6][C:7]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1sc(NC[C@@H](C)N)nc1C
Reactant: CCOC(=O)c1sc(NC[C@H](C)N)nc1C
Product: CCOC(=O)c1sc(N2C[C@@H](C)NC2=O)nc1C

Procedure:
Following the procedure as described in Preparation 4, making variations as required to replace (S)-ethyl 2-(2-aminopropylamino)-4-methylthiazole-5-carboxylate with (R)-ethyl 2-(2-aminopropylamino)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid (74%): MS (ES+) m/z 269.7 (M+1).
Reaction SMILES: [N+]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:17])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[N+:20](C1C=C(C=CC=1)C(Cl)=O)([O-:22])=[O:21]>>[N+:20]([C:19]1[CH:18]=[C:7]([CH:6]=[CH:5][CH:4]=1)[C:8]([N:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:17])=[O:9])([O-:22])=[O:21]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Product: O=C1CCCCCN1C(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Synthesized as for N-(4-nitrobenzoyl)caprolactam (Example XXIII) using 3-nitrobenzoyl chloride (Aldrich) in place of 4-nitrobenzoyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]#[N:32])=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]#[N:32])=[CH:26][CH:25]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccc(OCc2ccccc2)n1
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ccc(-c2nccc(OCc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 29.8 %

Procedure:
A mixture of 4-(benzyloxy)-2-chloropyrimidine (3.2 g, 14.5 mmol, 1.0 equiv.), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (4.2 g, 17.4 mmol, 1.2 equiv.), Pd(dippf)Cl2 (1.18 g, 1.45 mmol, 0.1 equiv.), Na2CO3 (6.1 g, 58 mmol, 4.0 equiv.), dioxane (5 ml) and water (1 ml) was added to the filtrate. The reaction mixture was heated to 100° C. for 15 h under nitrogen atmosphere. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 200:1) to afford 2-(4-(4-(benzyloxy)pyrimidin-2-yl)phenyl)acetonitrile (1.3 g, 31%) as white solid. The title compound was determination by LC-MS (LC-MS (m/z)=302.1 [M+H]+).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.Cl.O1CCOCC1>CC(O)C.O1CCOCC1>[N:5]1[C:4]2[S:8][C:9]3[CH2:14][NH:13][CH2:12][CH2:11][C:10]=3[C:3]=2[C:2]([NH:22][C:23]2[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=2)=[N:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1cccc(O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Oc1cccc(Nc2ncnc3sc4c(c23)CCNC4)c1
Temperature: 80 °C
Yield: 132.1 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (1.00 g, 3.07 mmol) was dissolved in 2-propanol (10 mL). 3-Aminophenol (352 mg, 3.22 mmol) and a 4 M solution of gaseous hydrogen chloride in dioxane (38 μL, 0.15 mmol) were added, and the mixture was heated to 80° C. for 20 h. Subsequently, further 4 M hydrogen chloride in dioxane (1.54 mL, 6.14 mmol) was added, and the mixture was heated for additional 3 h. The precipitate was collected by suction filtration to yield 1.21 g of the title compound as hydrochloride salt. An analytical amount was dissolved in 1 M aqueous sodium hydroxide solution which was then concentrated in vacuo. The precipitate was collected by suction filtration and dried to yield the product as free base.