Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[B:6]([O:11]C)(OC)[O:7]C.Cl>O1CCCC1>[CH:1]1[C:3]2[CH:4]=[C:2]([C:3]3[CH:4]=[CH:3][C:2]([B:6]([OH:11])[OH:7])=[CH:1][CH:4]=3)[C:1]3[C:1](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:2]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2cc3ccccc3c3ccccc23)cc1
Temperature: -80 °C
Yield: 74 %

Procedure:
Into a 100 mL three-neck flask, 2.0 g (11 mmol) of PnPBr obtained in the above Step 1 was put, and the air in the flask was replaced with nitrogen. Into the flask, 35 mL of tetrahydrofuran (THF) was added, and then this solution was stirred at −80° C. Into this solution, 8.3 mL (14 mmol) of n-butyllithium (1.6 mol/L hexane solution) was dropped by a syringe. After the dropping, this solution was stirred at the same temperature for 2 hours. After the stirring, 1.3 mL (11 mmol) of trimethyl borate was added to this solution, and the solution was stirred for 18 hours while the temperature of the solution was being increased to room temperature. Into this solution, hydrochloric acid (1.0 mol/L) was added, and then the solution was stirred for one hour. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with saturated saline, and magnesium sulfate was added to the organic layer so that moisture was adsorbed. The mixture was gravity-filtered, and the obtained filtrate was concentrated to give the objective white solid. This solid was recrystallized with ethyl acetate and hexane to give the objective substance as 2.5 g of white powdered solid in a yield of 74%.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH2:36][CH2:37][CH2:38][OH:39]>>[OH:39][CH2:38][CH2:37][CH2:36][NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: NCCCO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCCCO)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and 3-amino-1-propanol, the title compound was obtained in 90% purity by HPLC. MS(ESI+): m/z=410.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[C:8]2[NH:9][CH2:10][CH2:11][S:12][CH:13]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:7]=2[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:5]1.[CH3:26][C:27]1[C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:26][C:27]1[C:32]([C:33]([N:17]2[CH2:18][CH2:19][CH:14]([CH:13]3[S:12][CH2:11][CH2:10][NH:9][C:8]4[N:4]([CH3:3])[N:5]=[C:6]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[C:7]3=4)[CH2:15][CH2:16]2)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Cn1nc(-c2ccccn2)c2c1NCCSC2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1ncccc1C(=O)N1CCC(C2SCCNc3c2c(-c2ccccn2)nn3C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A mixture of 1-methyl-4-(4-piperidyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine dihydrochloride (0.10 g, 0.25 mmol, Preparation #4), 2-methylpyridine-3-carboxylic acid (0.0341 g, 0.25 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.072 g, 0.37 mmol), 1-hydroxybenzotriazole hydrate (0.0505 g, 0.37 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.25 mmol) in DCM (50 mL) was stirred overnight at rt. Then the mixture was concentrated in vacuo and purified by column chromatography (SiO2, DCM/methanol/ammonium hydroxide 92:7.5:0.5) to give (2-methyl-3-pyridyl)-[4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]-1-piperidyl]methanone (0.080 g, 71%) as an off white solid: LC-MS (Table 1, Method a) Rt=1.50 min; m/z 449 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) 1.17-1.39 (2H, m) 1.44-1.64 (1H, m) 2.08-3.14 (10H, m) 3.22-3.55 (3H, m) 3.74-3.77 (3H, s) 4.58-4.78 (1H, br.d, J=13.0 Hz) 5.06-5.16 (1H, m) 7.05-7.20 (2H, m) 7.36-7.55 (1H, m) 7.62-7.72 (1H, m) 7.89 (1H br.t, J=9.0 Hz) 8.43-8.59 (2H, m).
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[C:41]([OH:43])=O.Cl.[NH2:45][C@@H:46]([C:48]1[S:52][C:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[CH:50][CH:49]=1)[CH3:47]>O.C(Cl)Cl>[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[C:41]([NH:45][C@@H:46]([C:48]1[S:52][C:51]([C:53]([O:55][C:56]([CH3:57])([CH3:59])[CH3:58])=[O:54])=[CH:50][CH:49]=1)[CH3:47])=[O:43]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: C[C@@H](N)c1ccc(C(=O)OC(C)(C)C)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cc2ccccc2s1)c1ccc(C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 2-dram vial was added triethylamine (0.156 mL, 1.12 mmol), HATU (0.106 g, 0.28 mmol), 1-benzothiophene-2-carboxylic acid (0.050 g, 0.28 mmol), and DCM (3 mL). The solution was stirred at rt for 30 min, then transferred to another 2-dram vial containing solid (R)-tert-butyl 5-(1-aminoethyl)thiophene-2-carboxylate hydrochloride. The mixture was stirred at rt for 16 h. To the reaction was then added DCM (3 mL) and water (1 mL). After separation, the aqueous layer was extracted with DCM (2×3 mL). The combined organic phases were evaporated to dryness to give (R)-tert-butyl 5-(1-(benzothiophene-2-carboxamido)ethyl)thiophene-2-carboxylate as a brown solid. LC-MS: (FA) ES+ 388.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](Cl)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:25]=[CH:24][C:19]2=[N:20][C:21](=[O:23])[N:22]=[C:18]2[CH:17]=1.O.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([C:12]([NH:15][C:16]2[CH:25]=[CH:24][C:19]3=[N:20][C:21](=[O:23])[N:22]=[C:18]3[CH:17]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Reactant: O=C(Cl)c1cc2ccccc2cc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1N=c2ccc(NC(=O)c3cc4ccccc4cc3O)cc2=N1
Yield: 86 %

Procedure:
CS 178560 describes the reaction of a solution of 3-hydroxy-2-naphthoyl chloride in toluene with 5-aminobenzimidazolone in the 30-fold amount of water in the presence of sodium acetate to give 3-hydroxy-N-benzimida-zolon-5-yl-2-naphthamide in 86% yield.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:13]([F:24])=[O:15])[CH:10]([CH3:12])[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with (R)-N-BOC-valine (217.1 mg, 1.00 mmol) was added 2.5 mL CH2Cl2, and pyridine (81 μL, 1.00 mmol). The solution was cooled to −15 C, and to the reaction was added cyanuric fluoride (450 μL, 5.0 mmol). The reaction remained clear, but turned yellow green. The reaction was stirred at −15° C. for 60 minutes, with the gradual formation of a precipitate and transition to pale yellow. Without warming, the crude reaction was poured over ice and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with ice-cold water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 222.2 mg of 25f as a white solid. FTIR (neat) 1844 cm−1.
Reaction SMILES: [C:1]([C:3]([C:10]#[N:11])=[C:4]([CH3:9])[CH:5]=[CH:6]OC)#[N:2].S(=O)(=O)(O)[OH:13]>O>[C:1]([C:3]1[C:10](=[O:13])[NH:11][CH:6]=[CH:5][C:4]=1[CH3:9])#[N:2]
Reactant: O=S(=O)(O)O
Reactant: COC=CC(C)=C(C#N)C#N
Solvent: O
Product: Cc1cc[nH]c(=O)c1C#N
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 81.4 %

Procedure:
The mixture of 4,4-dicyano-3-methyl-3-butenal dimethyl acetatal (1) and 1,1-dicyano-4-methoxy-2-methyl-1,3-butadiene (2) produced by the preceding step was added to a stirred solution of concentrated sulfuric acid (109.8 g, 1.12 moles) at a rate so that the reaction contents did not exceed 30° C. The reaction mixture was then heated to 50° C. and held at that temperature for 1.5 hours. The reaction mixture was cooled to ambient temperature followed by the addition of water (150 mL). The product was filtered from the reaction mixture, washed with water (20 mL) and dried in a vacuum oven at 70° C. and full vacuum for 12 hours to give 40.7 g of 3-cyano-4-methyl-2-pyridone (3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:19]=[CH:18][C:12]2[N:13]=[CH:14][N:15]=[C:16](O)[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:19]=[CH:18][C:12]2[N:13]=[CH:14][N:15]=[C:16]([Cl:22])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Oc1ncnc2cnc(OCc3ccccc3)cc12
Solvent: CN(C)C=O
Product: Clc1ncnc2cnc(OCc3ccccc3)cc12
Reaction time: 5.5 h

Procedure:
6-Benzyloxy4-hydroxy-pyrido[3,4-d]pyrimidine (1.033 g, 4.1 mmol) was suspended in thionyl chloride (10 ml) under a nitogen atmosphere. DMF (3 drops) was added and the mixture was heated to reflux with stirring for 5.5 hours to give a dark solution, and then left to stand under nitrogen overnight. The mixture was concentrated in vacuo, azeotroping twice with toluene to remove all traces of thionyl cloride and acidic by-products. The material was further dried for two hours in vacuo to give the title compound as a brown solid, used without further purification; δH [2H6]DMSO 8.77(1H,s), 8.13(1H,s), 7.30-7.52 (6H,m), 5.45 (2H,s).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C:18](=[O:20])[CH3:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.O.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[CH3:30][N:31]([CH3:33])/[CH:32]=[CH:19]/[C:18]([C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([N:1]=[CH:3][N:4]([CH3:8])[CH3:5])[C:3]2=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:20]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nc2c(N)cccn12
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C=Nc1cccn2c(C(=O)/C=C/N(C)C)c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 1-[8-amino-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]ethanone (150 mg, 0.56 mmol) in N,N-dimethylformamide dimethyl acetal (5 mL) was heated at reflux for 6 days. The mixture was cooled to room temperature, ethyl acetate and water were added. The phases were separated and the organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by silica gel chromatography (1:1 acetone:ethyl acetate) gave 130 mg (62%) of N′-[3-[(2E)-3-(dimethylamino)-2-propenoyl]-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-8-yl]-N,N-dimethylimidoformamide as a foam. 1H NMR (CDCl3): δ 9.28 (d, 1H), 8.53 (s, 1H), 7.76 (q, 2H), 7.62 (d, 1H), 7.13 (t, 2H), 6.87 (m, 2H), 5.12 (d, 1H), 2.4–3.3 (m, 12H); MS m/z 380 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[C:13](=O)[CH2:14][CH3:15])=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[C:25]1([N:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][N:12]([CH2:13][CH2:14][CH3:15])[CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[CH2:20][CH2:21]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCC(=O)N(CCc1ccc([N+](=O)[O-])cc1)CCN1CCN(c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCc1ccc(N)cc1)CCN1CCN(c2ccccc2)CC1
Reaction time: 8 h

Procedure:
N-[2-(4-nitro-phenyl)-ethyl]-N-[2-(4-phenyl-piperazin-1-yl)-ethyl]-propionamide 28a (0.33 g, 0.80 mmol) was dissolved in dry EtOH (20 mL) and 10 wt % Pd/C (0.05 g) was added. The mixture was stirred for overnight under H2 at 1 atm. Pressure. The reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure and kept under vacuum for 1 h to give the corresponding aniline. In to the solution of the crude product in 15 ml dry THF was added 1 (M) BH3/THF (7 mL, 7 mmol). The reaction mixture was refluxed for 6 h. After the solution was cooled to room temperature, methanol (5 mL) was added slowly. The solvent was removed under reduced pressure and 10% HCl/MeOH (25 mL) was added into the residue and the solution was refluxed for 1 h. Solid NaHCO3 was added and the methanol was removed in vacuo. The mixture was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and evaporated to give the crude product which was purified by chromatography (EtOAc/MeOH=9/1) to give 29a as a colorless oil: 0.23 g (78% yield). 1H NMR (CDCl3, 300 MHz): δ 0.89 (3H, t, J=7.2 Hz, CH3), 1.50 (2H, q, J=7.2 Hz, CH2), 2.48-2.57 (4H, m, CH2Ar, (CH2)N), 2.63-2.75 (10H, m, (CH2)3N, (CH2)2N), 3.20 (4H, t, J=4.8 Hz, (CH2)2NPh), 3.56 (2H, bs, NH2), 6.62 (2H, d, J=8.7 Hz, ArH), 6.85 (1H, t, J=9.6 Hz, ArH), 6.91-6.99 (4H, m, ArH), 7.25 (2H, t, J=9 Hz, ArH). Free base was converted into its hydrochloride salt, mp 262-264° C. Elemental analysis calculated for C23H38N4Cl4, 1.05 H2O: C, 51.99; H, 7.60; N, 10.54. Found C, 52.37; H, 7.89; N, 10.12.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[C:16]([C:15]([O:23][CH2:24][CH3:25])=[O:22])=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([N:2]([CH3:14])[CH3:1])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(N(C)C)cc1[N+](=O)[O-])C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.2 %

Procedure:
A mixture of 89 g (0.5 mol) of 4-dimethylamino-2-nitrobenzaldehyde [H. Baumann, et al German Pat. 2,363,458], 237 g (1.4 mol) of diethyl malonate, 3.44 g (40.4 mmol) of piperidine and 2.43 g (40.4 mmol) of acetic acid in 400 mL of toluene was refluxed for 16 hours under argon, with a Dean Stark trap attached. The solution was cooled to room temperature and washed with 200 mL of 5% aqueous KOH. The organic phase was separated, dried over sodium sulfate (Na2SO4), filtered, and the solvent evaporated. The dark red solid residue was dissolved in 40 mL of CH2Cl2 and 100 mL of hexane added. After standing for 1 hour, the solution was filtered to yield 10.4 g of orange crystals. Recrystallization from CH2Cl2 - hexane produced an analytical sample, m.p. 101°-102° C.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13](/[CH:15]=[CH:16]/[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH2:20][OH:21])=[N:12][C:11]=2[CH:25]=1.N1C=CN=C1.[Si:31](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C(OCC)(=O)C>[Si:31]([O:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17](/[CH:16]=[CH:15]/[C:13]2[S:14][C:10]3[CH:9]=[CH:8][C:7]([F:6])=[CH:25][C:11]=3[N:12]=2)[CH:18]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: OCc1cccc(/C=C/c2nc3cc(F)ccc3s2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(/C=C/c2nc3cc(F)ccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 ml of dimethylformamide containing 2.0 g of 3-(5-fluorobenzothiazol-2-yl-trans-ethenyl)benzyl alcohol and 1.19 g of imidazole was added 1.37 g of t-butyldimethylsilyl chloride and the reaction mixture stirred overnight under nitrogen at room temperature. After 48 hours of reaction time, the mixture was poured into 500 ml of ethyl acetate and washed with water (3×150 ml), a 1N hydrochloric acid solution (2×150 ml), water (1×200 ml) and a brine solution (1×200 ml) The organic layer was separated, dried over sodium sulfate and concentrated to a white solid. The residue was recrystallized from ethyl acetate--hexane, 1.57 g, m.p. 91°-93° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].CS(O[CH2:9][C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]1)(=O)=O>CN(C)C=O.O>[CH3:1][S:2][CH2:9][C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CSC)CC1
Temperature: 23 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
Sodium methanethiolate (4.36 g, 62.30 mmol) was added to a stirred solution of ethyl 1-((methylsulfonyloxy)methyl)cyclopropanecarboxylate (6.92 g, 31.10 mmol) in N,N-dimethylformamide (62.30 mL) at 23° C. The resulting brown suspension was stirred at 23° C. for 18 h. The reaction mixture was diluted with water and extracted with diethyl ether. The combined organic layers were dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the title compound as a brown oil (5.43 g, 100%): 1H NMR (300 MHz, CDCl3) δ 4.14 (q, J=7 Hz, 2H), 2.83 (s, 2H), 2.16 (s, 3H), 1.31 (dd, J=7, 4 Hz, 2H), 1.25 (t, J=7 Hz, 3H), 0.89 (dd, J=7, 4 Hz, 2H).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][OH:19])[N:17]=1)[CH2:10][CH2:11][CH3:12]>C(O)C.O>[CH2:9]([C:13]1[NH:17][C:16]([CH2:18][OH:19])=[C:15]([I:1])[N:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCCc1nc(CO)c[nH]1
Solvent: CCO
Solvent: O
Product: CCCCc1nc(I)c(CO)[nH]1
Yield: 95.5 %

Procedure:
N-Iodosuccinimide (148.75 g, 0.661 mol) was added to a stirred solution of 2-butyl-4-hydroxymethylimidazole (100.78 g, 0.652 mol) in 500 mL of absolute ethanol. After 20 minutes the solution was heated to 40°-45° C. for 45 minutes, diluted with 2.5 liters of water, and chilled. The crystalline product was collected by filtration, washed with water, and dried to give 174.5 g (95%) of crystals; mp 166°-166.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]([CH3:24])[CH2:22][NH2:23].NCCC1N=CNC=1>>[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]([CH3:24])[CH2:22][NH:23][C:13]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([Br:12])[N:4]=1)=[O:15]
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: CC(CN)c1ncc[nH]1
Agent: NCCc1c[nH]cn1
Product: CC(CNC(=O)c1nc(Br)c(C(F)(F)F)nc1N)c1ncc[nH]1

Procedure:
The title compound was prepared from 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate C) and 2-(1H-imidazol-2-yl)propan-1-amine (prepared according to the procedure of Steffens, Robert; Schunack, Walter. Histamine analogs, XXVI. Racemic histamine H1-agonists. Archiv der Pharmazie (Weinheim, Germany) (1984), 317(9), 771-6; 1H NMR (400 MHz, DMSO-d6) δ 11.8 (1H, s), 9.0 (1H, t), 8.1 (2H, s), 7.0 (1H, s), 6.8 (1H, s), 3.55 (2H, m), 3.15 (1H, m), 1.2 (3H, d). LC-MS [M+H]+ 393.0/395.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH2:14][OH:15])[CH:7]=[CH:6]2.ClC(Cl)(Cl)[C:19]([N:21]=C=O)=[O:20].CO.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH2:14][O:15][C:19](=[O:20])[NH2:21])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)CO)ccc2c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2cc([C@H](C)COC(N)=O)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To (S)-2-(6-methoxy-naphthalen-2-yl)-propan-ol (8.0 g, 37 mmol) in CH2Cl2 (200 mL) at 0° C. under N2 was added trichloroacetyl isocyanate (5.5 mL, 44 mmol). After the mixture was stirred at room temperature for 1 hr, the solvent was concentrated. The residue was treated MeOH (300 mL), water (40 mL) and potassium carbonate (21 g, 0.15 mol) and stirred at RT for 2 hrs to form white precipitate. The precipitate was collected by filtration and dissolved with CH2Cl2. The organic phase was washed with water, dried over MgSO4 and concentrated to give 5.5 g of white precipitate (57%).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=O)C.COC(=O)C(C1C=CC(F)=CC=1)C(=O)C1C=C[N:32]=CC=1.C(O)C>N1C=CC=CC=1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[NH:32][O:3][C:4](=[O:23])[C:5]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)C(C(=O)c1ccncc1)c1ccc(F)cc1
Reactant: CCOC(=O)C(C(=O)c1ccc(F)cc1)c1ccnc(SC)n1
Solvent: c1ccncc1
Solvent: CCO
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)[nH]oc2=O)n1

Procedure:
Using the procedure from Example 1k set forth above, substitute 3-(4-fluorophenyl)-3-oxo-2-(2-methylsulfanyl-pyrimidin-4-yl)-propionic acid ethyl ester for 2-(4-fluorophenyl)-3-oxo-3-pyridin-4-yl-propionic acid methyl ester and ethanol for pyridine to produce the title compound.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24]>>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][S:1][C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCCBr
Reactant: Cc1cn2c(S)cccc2n1
Solvent: CCN(CC)CC
Product: Cc1cn2c(SCCCCCl)cccc2n1

Procedure:
Using 657 mg (4.0 mmol) of 5-mercapto-2-methylimidazo-[1,2-a]pyridine, 0.70 ml (5.0 mmol) of triethylamine and 0.58 ml (5.0 mmol) of 1-bromo-4-chlorobutane, the same procedure as in Reference Example 1 was followed, to yield 838 mg (82.3%, light orange solid) of the desired product.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:7]([Cl:9])[CH:8]=1)([O-])=O.C(OC(=O)C)(=O)C.Cl.CO>C(O)(=O)C.[Fe]>[ClH:9].[NH2:1][C:4]1[S:5][C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:7]([Cl:9])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(-c2ccc(Cl)cc2)s1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(-c2ccc(Cl)cc2)s1

Procedure:
Following the procedure of Example 12, 2-nitro-4-chloro-5-(4-chlorophenyl)thiophene (2.3 g) is reacted with acetic anhydride (14 ml) and iron powder (2.3 g) in acetic acid (14 ml), followed by reacton with HCl and methanol (30 ml) to give 2-amino-4-chloro-5-(4-chlorophenyl)thiophene hydrochloric acid salt.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:17]([CH3:18])[N:6]2[C:7]3[CH:8]=[C:9]([C:14]([OH:16])=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:19])[NH:3]1.[CH:20](O)(C)[CH3:21]>CCCCCCC>[CH3:1][C@H:2]1[C@@H:17]([CH3:18])[N:6]2[C:7]3[CH:8]=[C:9]([C:14]([O:16][CH2:20][CH3:21])=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:19])[NH:3]1.[CH3:1][C@@H:2]1[C@H:17]([CH3:18])[N:6]2[C:7]3[CH:8]=[C:9]([C:14]([O:16][CH2:20][CH3:21])=[O:15])[CH:10]=[CH:11][C:12]=3[CH:13]=[C:5]2[C:4](=[O:19])[NH:3]1
Reactant: CC(C)O
Reactant: C[C@@H]1NC(=O)c2cc3ccc(C(=O)O)cc3n2[C@@H]1C
Solvent: CCCCCCC
Product: CCOC(=O)c1ccc2cc3n(c2c1)[C@@H](C)[C@@H](C)NC3=O
Product: CCOC(=O)c1ccc2cc3n(c2c1)[C@H](C)[C@H](C)NC3=O
Yield: 46 %
Yield: 45 %

Procedure:
Racemic cis-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylic acid (Intermediate F, 1.9 g, 6.7 mmol) is separated on a preparative chiral column (Chiralpak AD, 5 cm×50 cm, 20 u, Chiral Technologies, West Chester, Pa.) using Gilson preparative HPLC (Mobile Phase: 12% isopropanol in heptane; Flow rate: 100 mL/min) to afford ethyl (3S,4R)-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylate (870 mg, 46%) and ethyl (3R,4S)-3,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylate (852 mg, 45%).