Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([N:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=O)[C:11]2=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CC[N:22]([CH:26]([CH3:28])C)[CH:23]([CH3:25])C.[CH3:29][N:30](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C@H:1]1([N:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH:30][C:29]3[CH:25]=[CH:23][N:22]=[CH:26][CH:28]=3)=[O:18])[C:11]2=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cccn([C@@H]2CCc3ccccc32)c1=O
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1)c1cccn([C@@H]2CCc3ccccc32)c1=O
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 7.8 g (1.0 eq.) (R)-1-(2,3-dihydro-1H-inden-1-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid in 100 ml DMF was added DIEA (10 ml, 2.5 eq.), HBTU (13.8 g, 1.2 eq.) and 4-amine-pyridin (3.45 g, 1.2 eq.). The resulting mixture was stirred at rt. overnight. The reaction was diluted with 300 ml water. The precipitate was collected by filtration, and washed with 2×50 ml water. The solid was purified on short flash column in silica gel to provide white solid 8.1 g (80%) (R)-1-(2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide. Retention time (min)=2.592, method [7], MS (ESI) 332.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 12.99 (s, 1H), 8.72 (d, 2H), 8.49 (d, 1H), 8.19 (d, 2H), 7.68 (d, 1H), 7.36 (m, 2H), 7.33 (m, 1H), 7.24 (m, 1H), 7.15 (d, 1H), 6.61 (t, 1H), 6.49-6.52 (m, 1H), 3.03-3.16 (m, 1H), 2.71-2.98 (m, 1H), 2.66-2.69 (m, 1H), 2.06-2.14 (m, 1H).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([C:19](O)=[O:20])=[CH:16][C:15]=2[CH:22]=1.S(Cl)([Cl:25])=O>>[ClH:25].[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([C:19]([Cl:25])=[O:20])=[CH:16][C:15]=2[CH:22]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Product: Cl
Product: O=C(Cl)c1cc2cc(Oc3nc4ncccc4s3)ccc2o1
Yield: 98 %

Procedure:
A mixture of 5-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-2-carboxylic acid (326 mg, 1.04 mmol) and thionyl chloride (10 mL) was heated to reflux for 2 h. The crude mixture was concentrated, re-dissolved in CH2Cl2 and concentrated again to provide the product as a yellow solid (375 mg, 98%). 1H NMR (400 MHz, DMSO-d6): 8.61-8.51 (m, 2H), 7.97 (d, J=2.5, 1H), 7.94-7.86 (m, 1H), 7.74 (s, 1H), 7.68-7.61 (m, 1H), 7.46-7.38 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH:13]=2)[CH:7]=1
Reactant: Cc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Cl)cc1
Product: Cc1ccc(Br)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 76 %

Procedure:
Following the method described in Example 26, 4-(5-bromo-2-methyl-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (76% yield). 1H NMR (DMSO-d6) δ 2.35 (s, 3H, CH3), 6.39 (s, 1H, Ar), 7.40 (d, 1H, J=8.4 Hz, Ar), 7.47 (d, 2H, J=8.5 Hz, Ar), 7.70-7.71 (m, 2H, Ar), 7.84-7.89 (m, 2H, Ar), 10.95 (br s, 1H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7]Br.[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: COc1ccccc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccccc1OCCN1CCC(NC(=O)c2ccccc2)CC1
Yield: 83.3 %

Procedure:
2-(2-Methoxyphenoxy)ethyl bromide (2.31 g.), 4-benzamidopiperidine (2.04 g.) and anhydrous potassium carbonate (1.38 g.) were well mixed and heated on a steam bath for 4 hr. The resultng mass was crushed and stirred in water (200 ml.) at 60° for 12 hr. Filtration afforded the crude base of the title compound (2.95 g.). Conversion to the hydrochloride by solution in ethanol/HCl and precipitation with ether provided 3.01 g. of the title compound, as the hydrochloride m.p. 193.4° .
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:54]=[CH:53][C:18]([CH2:19][O:20][CH2:21][C@H:22]([CH3:52])[C@H:23]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[C@@H:24]([CH3:43])[CH2:25][C@@H:26]([CH3:42])[C:27](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:28])=[CH:17][CH:16]=1>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][CH2:21][C@H:22]([CH3:52])[C@H:23]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[C@@H:24]([CH3:43])[CH2:25][C@@H:26]([CH3:42])[CH2:27][OH:28])=[CH:53][CH:54]=1
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C[C@@H](C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C[C@@H](C)CO)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
n-BuLi (2.5 M in hexane, 17.6 mL, 44 mmol) was added to a solution of diisopropylamine (6.65 mL, 47.4 mmol) in THF (48 mL) stirred at −78° C. The solution was stirred at −78° C. for 5 min and warmed to 0° C. for 15 min. Borane-ammonia complex (90%, 1.55 g, 45.2 mmol) was added and the resulting mixture was stirred at 0° C. for 15 min, warmed to room temperature for 15 min and then cooled to 0° C. A solution of amide 26 (6.62 g, 11.3 mmol) in THF (35 mL) was added dropwise and the reaction was stirred at 0° C. for 1 h and then at room temperature for 2 h. The mixture was cooled to 0° C. and quenched carefully with saturated aqueous NH4Cl. The mixture was extracted with Et2O and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (step gradient of 4:1 to 7:3 hexane/EtOAc) to afford the alcohol 27 (4.57 g, 96%) as a colorless oil: IR (film) 3410, 1612, 1513, 1249, 1067, 1038 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.26 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 4.44 (d, J=11.7 Hz, 1H), 4.39 (d, J=11.7 Hz, 1H), 3.81 (s, 3H), 3.51 (m, 2H), 3.44 (dd, J=5.6, 3.4 Hz, 1H), 3.37 (dd, J=10.6, 6.5 Hz, 1H), 3.22 (dd, J=9.0, 7.0 Hz, 1H), 2.03-1.95 (m, 1H), 1.78-1.62 (m, 2H), 1.53 (br, 1H), 1.41 (ddd, J=13.5, 7.5, 5.8 Hz, 1H), 0.95 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H), 0.88 (s, 9H), 0.87 (d, J=6.9 Hz, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.2, 130.9, 129.4, 113.9, 77.5, 72.8, 67.7, 55.4, 38.3, 38.0, 33.6, 33.2, 26.3, 18.6, 18.0, 15.6, 15.5, −3.5, −3.8; [α]20D−6.3 (c 1.7, CHCl3).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C(C)=C1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].[Si:41]([O:48][CH2:49][C@@H:50]1[C:55]([CH:56]([CH3:58])[CH3:57])=[CH:54][C@H:53](O)[CH2:52][N:51]1[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>>[CH2:1]([O:4][N:5]([C@H:53]1[CH2:52][N:51]([C:60]([O:62][C:63]([CH3:65])([CH3:64])[CH3:66])=[O:61])[C@H:50]([CH2:49][O:48][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])[C:55]([CH:56]([CH3:58])[CH3:57])=[CH:54]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: CC(C)C1=C[C@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 78 %

Procedure:
(2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-3-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (0.928 g, 78%) was prepared as described in Intermediate 80 as a pale yellow oil, using (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-3-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 90, 0.731 g, 1.90 mmol) as a starting material.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:23]5=[N:24][S:25](=[O:29])(=[O:28])[CH2:26][CH2:27][N:22]5[CH:21]=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>C1COCC1>[O:29]=[S:25]1(=[O:28])[CH2:26][CH2:27][N:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH:8]4[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]4)=[CH:17][CH:16]=3)[C:23]2=[N:24]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(OC4CCC5(CC4)OCCO5)cc3)C2=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCC(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A mixture of 9-[4-(1,4-dioxaspiro[4.5]dec-8-yloxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (130 mg), 1M hydrochloric acid (15 mL) and dehydrated THF (15 mL) was stirred at room temperature for 8 hr. The reaction mixture was neutralized with 1M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give the title compound (109 mg) as a pale-yellow solid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=O.CCCCCC>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:25][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1
Reactant: COc1cccc(CCCC=O)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cccc(CCCC=C(Br)Br)c1
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
To a solution of carbon tetrabromide (16.7 g) in methylene chloride (35 ml) was added triphenylphosphine (26.0 g) in methylene chloride (35 ml) at 0° C., and the mixture was stirred for 10 min. To the mixture was added a solution of 1-(3-formylpropyl)-3-methoxybenzene (3.00 g) in methylene chloride (20 ml) at 0° C. The mixture was stirred for 30 min at 0° C. To the mixture was added gradually n-hexane, and the mixture was filtered to remove triphenylphosphineoxide. The filtrate was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=24:1) to give the title compound (5.33 g) having the following physical data.
Reaction SMILES: [C:1]([C:4]1[NH:8][CH:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)(=[O:3])[NH2:2].[H][H].[ClH:23]>CO.O1CCOCC1.[Pd]>[ClH:23].[C:1]([C:4]1[NH:8][CH:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: NC(=O)c1[nH]cc(C(=O)O)c1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(=O)c1[nH]cc(C(=O)O)c1-c1ccc(N)cc1

Procedure:
To a suspension of 0.135 g (0.126 mmol) of 10% palladium-on-charcoal in 20 cm3 of methanol is added, at a temperature in the region of 20° C., 0.15 g (0.545 mmol) of 5-carbamoyl-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylic acid. After hydrogenating for 3 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 30° C., the reaction mixture is taken up in 5 cm3 of a 4N solution of hydrogen chloride in dioxane, and then filtered. The catalyst is rinsed with twice 2 cm3 of a 4N solution of hydrogen chloride in dioxane, and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.141 g of 5-carbamoyl-4-(4-aminophenyl)-1H-pyrrole-3-carboxylic acid hydrochloride in the form of a yellow solid; ES+: m/z=246: [M+H]+
Reaction SMILES: C(N/[C:5](=[CH:9]/[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([NH2:20])=[C:12]([Cl:21])[CH:11]=1)/[C:6]([OH:8])=[O:7])(=O)C.Cl.[OH2:23]>CN1C(=O)CCC1>[NH2:20][C:13]1[C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10](/[CH:9]=[C:5](/[OH:23])\[C:6]([OH:8])=[O:7])=[CH:11][C:12]=1[Cl:21]
Reactant: O
Reactant: CC(=O)N/C(=C/c1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)O
Agent: Cl
Solvent: CN1CCCC1=O
Product: Nc1c(Cl)cc(/C=C(/O)C(=O)O)cc1C(F)(F)F
Temperature: 130 °C
Reaction time: 3 h

Procedure:
51.0 g (158 mmol) (E)-2-acetylamino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-acrylic acid, dissolved in 408 ml NMP, were combined with 612 ml aqueous 4-molar hydrochloric acid solution and stirred for 3 hours at a bath temperature of 130° C. stirred. The reaction mixture was cooled and poured onto 2000 ml of water with stirring. The precipitate formed was suction filtered, washed with 400 ml of water, dried overnight at 60° C. and recrystallised from 1000 ml boiling toluene.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>N1CCCCC1.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.[Cu]I>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]#[C:31][CH2:30][CH2:29][OH:33])=[CH:4][N:3]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3csc4c(I)cnc(N)c34)cc2)c1
Reactant: C#CCCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3csc4c(C#CCCO)cnc(N)c34)cc2)c1
Temperature: 80 °C
Yield: 82.4 %

Procedure:
A suspension of Example 144A (0.227 g, 0.45 mmol) in piperidine (3 mL) was degassed by bubbling nitrogen through the suspension for 5 minutes, treated with 3-butyn-1-ol (0.069 mL, 0.91 mmol), Pd(PPh3)4 (26 mg, 0.023 mmol), and CuI (5 mg, 0.023 mmol), then heated to 80° C. in a sealed tube for 30 minutes. The resulting homogeneous solution was cooled to room temperature and concentrated under a stream of nitrogen. The residue was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide 164 mg (81%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.65 (t, J=6.78 Hz, 2H), 3.63 (q, J=6.73 Hz, 2H), 4.92 (t, J=5.59 Hz, 1H), 5.70 (s, 2H), 6.81 (d, J=7.46 Hz, 1H), 7.17 (t, J=7.80 Hz, 1H), 7.25–7.28 (m, 1H), 7.32 (s, 1H), 7.37 (d, J=8.48 Hz, 2H), 7.49 (s, 1H), 7.60 (d, J=8.48 Hz, 2H), 7.93 (s, 1H), 8.65 (s, 1H), 8.85 (s, 1H); MS (ESI(+)) m/e 443 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](CBr)=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].C1N2CN3CN(C2)CN1C3.[C:23](O)(=[O:25])C.Cl>O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:23]=[O:25])=[CH:7][CH:6]=1)([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: COC(=O)c1ccc(C=O)cc1
Reaction time: 2 h
Yield: 71 %

Procedure:
A mixture of 68.7 g (0.3 mole) of methyl-α-bromotoluate, 84 g (0.6 mole) of hexamethylenetetraamine, 150 ml of acetic acid and 150 ml of water were refluxed with stirring for two hr. Ninety ml of concentrated hydrochloric acid was then added and kept at room temperature for 15 min. The cooled solution was extracted with ether, washed with water, 10% NaHCO3 solution, water and dried. Evaporation of the solvent and recrystallization of the residue from petroleum ether gave 35 g of p-carbomethoxybenzaldehyde, yield 71% m.p. 61°-63° C. (lit. m.p. 61°-63° C.). The infrared spectrum showed absorption at 1720 cm-1 ##STR6## 1690 cm-1 (--CHO). NMR (CDCl3) δ3.8 (s,--COOCH3,3), 7.8-8.2 (m, aromatic, 4), and 10.2 (s,--CHO,1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]#[CH:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6].Cl[C:24]1[CH:29]=[N:28][CH:27]=[C:26]([CH3:30])[N:25]=1>C(N(CC)CC)C.C(#N)C.C(OCC)(=O)C.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.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[C:5]([NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]#[C:19][C:24]4[CH:29]=[N:28][CH:27]=[C:26]([CH3:30])[N:25]=4)([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6]
Reactant: Cc1cncc(Cl)n1
Reactant: C#CC12CC3CC(C1)CC(NC(=O)c1cccc(Cl)c1)(C3)C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cncc(C#CC23CC4CC(C2)CC(NC(=O)c2cccc(Cl)c2)(C4)C3)n1
Temperature: 70 °C
Yield: 38.9 %

Procedure:
To a stirred mixture of intermediate 8, 3-chloro-N-(3-ethynyl-adamantan-1-yl)-benzamide (60 mg, 0.19 mmol) and 2-chloro-6-methylpyrazine (60 mg, 0.47 mmol) in triethylamine (0.5 mL) and acetonitrile (2 mL) was added Pd(PPh3)4 (3 mg, 0.02 mmol), followed by an addition of CuI (3 mg, 0.016 mmol). After heated at 70° C. for three hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (50 mL) and brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by Prep HPLC to give 30 mg (38%) of the title compound, 3-chloro-N-[3-(6-methyl-pyrazin-2-ylethynyl)-adamantan-1-yl]-benzamide. 1H NMR (500 MHz, CDCl3): δ 8.57 (brs, 1H), 7.69 (t, J=2.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 5.78 (s, 1H), 2.57 (s, 3H), 2.40 (s, 2H), 2.25 (s, 2H), 2.17-2.15 (m, 2H), 2.06-1.96 (m, 6H), 1.73-1.70 (m, 2H); ESI-MS m/z: 406 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15]Br)=[CH:7][CH:6]=1)=[O:4].C(=O)(O)[O-:18].[Na+].CCOC(C)=O>CS(C)=O.CCCCCC>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:18])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc(CBr)c2ccccc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C=O)c2ccccc12
Temperature: 95 °C
Yield: 52.1 %

Procedure:
To a stirred solution of 4-bromomethyl-naphthalene-1-carboxylic acid methyl ester (Preparation 51, 10.5 g, 37.63 mmol) in DMSO (99.36 mL) was added sodium bicarbonate (6.32 g, 75.27 mmol) at room temperature. Resulting reaction mixture was heated at 95° C. for 3 hours. Progress of the reaction was monitored by TLC using 10% EtOAc in hexane. Rf of new spot and starting material was 0.7 and 0.8 respectively. After consumption of starting material, reaction mixture was quenched with water (400 mL) and extracted with EtOAc (2×300 mL). Combined organic layer was dried over sodium sulphate and evaporated off in vacuo to get brown colored thick mass. Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired product was eluted in 4.5% EtOAc in hexane to afford faint green solid (4.2 g, 52.17%). Compound the same as that from Preparation 3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[CH2:14]1[S:16][CH2:15]1>CCOCC.O>[CH3:9][S:10]([O-:13])(=[O:12])=[O:11].[SH:16][CH2:15][CH2:14][N+:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CS(=O)(=O)O
Reactant: Cc1cccc(C)n1
Reactant: C1CS1
Solvent: O
Solvent: CCOCC
Product: CS(=O)(=O)[O-]
Product: Cc1cccc(C)[n+]1CCS
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19 %

Procedure:
A mixture of 2,6-dimethylpyridine (19.2 mL, 0.165 mol) and methanesulfonic acid (3.27 mL, 0.050 mol) was stirred for 15 min, treated with ethylene sulfide (4.17 mL, 0.070 mol) and stirred at 100° C. for 42 h under a nitrogen atmosphere. After cooling to 25° C., the reaction mixture was diluted with ether (45 mL) and water (30 mL). The two layers were separated and the organic layer was extracted with water (2×5 mL). The aqueous layers were combined, filtered through a Celite pad, washed with ether (2×15 mL), pumped to remove the traces of organic solvents and poured on top of a column (3.0×12 cm) of μ-bondapak C-18. Elution with 3% acetonitrile 97% water mixture gave after lyophylization of the appropriate fractions 2.5 g of the impure title compound as a syrup. It was repurified by hplc (μ-bondapak C-18) to give 0.90 g (7%) of the title compound. ir (film) νmax : 2520 (SH), 1640 and 1625 (pyridinium), 1585, 1490, 1200 cm-1 (sulfonate), 1Hmr (DMSO-d6 +D2O) δ: 2.36 (3H, s, CH3SO3-), 4.62 (2H, m, CH2N+), 7.74 (2H, m, Hm of pyridinium), 8.24 (1H, m, Hp of pyridinium), uv (H2O) max : 272 (4080)mμ.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[C:6]1([C:12]2([CH2:17][C:18]#[N:19])[O:16][CH2:15][CH2:14][O:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[OH:1][NH:19][C:18](=[NH:4])[CH2:17][C:12]1([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:16][CH2:15][CH2:14][O:13]1
Reactant: [OH-]
Reactant: NO
Reactant: N#CCC1(c2ccccc2)OCCO1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(CC1(c2ccccc2)OCCO1)NO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.1 %

Procedure:
NaOH (3.1 g, 77 mmol) is added to hydroxylamine hydrochloride (5.2 g, 75 mmol) at 0° C. and is stirred for 15 min. A solution of (2-phenyl-1,3-dioxolan-2-yl)acetonitrile (7 g, 37 mmol) in methanol (25 mL) is added dropwise to the reaction mixture at 0° C. The reaction mixture is allowed to warm to room temperature and is heated at 90° C. for 16 h. The solvent was evaporated under reduced pressure to afford the title compound as a brown solid (7 g, 85%) which is used in the next step without purification.
Reaction SMILES: F[C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[C:19](=[S:21])=[S:20].[CH2:22](N(CC)CC)C.CI>CS(C)=O>[CH2:10]([O:9][C:7]([C:6]1[C:4](=[O:5])[C:3]2[CH:12]=[C:13]([F:18])[C:14]([F:17])=[C:15]([F:16])[C:2]=2[S:20][C:19]=1[S:21][CH3:22])=[O:8])[CH3:11]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: S=C=S
Solvent: CS(C)=O
Solvent: CI
Product: CCOC(=O)c1c(SC)sc2c(F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of 3.00 g (11.4 mmol) of ethyl 2,3,4,5-tetrafluorobenzoylacetate, 870 mg (11.4 mmol) of carbon disulfide and 9 ml of dried dimethyl sulfoxide were added 2.31 g (22.8 mmol) of triethylamine at room temperature, and the mixture was stirred for 1 hour at room temperature. Then, at room temperature, 3.24 g (22.8 mmol) of methyl iodide were added and the mixture was stirred for 2 hours, which was poured into ice-water. The crystals deposited were collected by filtration and dried to obtain 2.81 g (8.41 mmol) of title compound (yield 74%.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][NH:5][C:4](=[S:7])[NH:3]1.[CH3:9][I:10]>C(O)(C)C.CCOCC>[IH:10].[CH3:1][C:2]1([CH3:8])[CH2:6][NH:5][C:4]([S:7][CH3:9])=[N:3]1
Reactant: CC1(C)CNC(=S)N1
Reactant: CI
Solvent: CCOCC
Solvent: CC(C)O
Product: CSC1=NC(C)(C)CN1
Product: I
Temperature: 25 °C

Procedure:
A suspension of 110 g (0.83 M) of 4,4-dimethyl-2-imidazolidinethione in 700 ml isopropanol was treated with 148 g (1.04 M) methyl iodide and stirred at room temperature under reflux for 1/2 hour. When all had dissolved, heated to gentle reflux for 1 hour. Cool, dilute to 2 liters with anhydrous ether, seed, and cool in ice. Filter and wash with dry ether. Yield of 4,4-dimethyl-2-(methylthio)imidazoline hydroiodide was 221 g, 98%, mp 93.5°-95° C. Pure material melts at 94.5°-95° C.