Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Cl)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH:24]([NH2:26])[CH3:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CO>O1CCCC1>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:26][CH:24]([CH3:25])[CH3:23])[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc(Cl)c3nnc(C)n32)n1Cc1ccccc1
Reactant: CC(C)N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(cc(NC(C)C)c3nnc(C)n32)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a suspension of 6-benzyl-4-chloro-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20.0 mg, 0.0644 mmol, from Example 228, Step 7), 2-propanamine (51 μL, 0.60 mmol, Aldrich) and tBuXPhos Pd G1 (7.1 mg, 0.0096 mmol, Aldrich) in tetrahydrofuran (0.3 mL) was added 1.0 M LHMDS in THF (0.19 mL, 0.19 mmol, Aldrich). The reaction was stirred for 3 days, after which time additional amounts of tBuXPhos Pd G1 (6 mg, 0.008 mmol), 2-propanamine (51 uL, 0.60 mmol), THF (0.3 mL) and 1.0 M LHMDS in THF (0.2 mL, 0.2 mmol) were added and the mixture was heated at 100° C. for 2.5 hours. After cooling to room temperature, MeOH was added, and the mixture was filtered. The product was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (0.2 mg, 1%).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C1C=C[C:30]([C:31]#[N:32])=CC=1.N[C@H](C(O)=O)CS>>[CH3:25][O:24][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23])[C:12]([C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][C:4]([CH2:30][C:31]#[N:32])=[CH:3][CH:2]=2)[S:8][CH:9]=1)=[O:13]
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Reactant: N#Cc1ccc(C#N)cc1
Agent: N[C@@H](CS)C(=O)O
Product: COc1cc(C(=O)c2csc(-c3ccc(CC#N)cc3)n2)cc(OC)c1OC

Procedure:
2-(4-(4-(3,4,5-Trimethoxybenzoyl)thiazol-2-yl)phenyl)acetonitrile (2n) was prepared using the same method as used of compound 1h from terephthalonitrile and cysteine. 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 8.04 (d, 2H), 7.76 (s, 2H), 7.46 (d, 2H), 3.97 (s, 3H), 3.95 (s, 6H), 3.83 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:12]([C:14]1[N:19]2[N:20]=[CH:21][N:22]=[C:18]2[N:17]=[CH:16][CH:15]=1)[CH3:13]>COCCOC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([C:14]2[N:19]3[N:20]=[CH:21][N:22]=[C:18]3[N:17]=[CH:16][CH:15]=2)[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(Br)c1ccnc2ncnn12
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(Br)cc1)c1ccnc2ncnn12
Reaction time: 0.5 h

Procedure:
A solution of 4-bromophenol (1.73 g) in dry 1,2-dimethoxyethane was added slowly to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6 below) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The reaction mixture was stirred for 1 hour 30 minutes at room temperature. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the mixture and the residue was dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of ethyl acetate and petroleum ether (in the ratio 4:6 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-[1-(4-bromophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 2.28 g, (m.p. 121°-124° C.).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C(O)(C)C>[C:1]([O:6][CH2:7][CH:8]([OH:10])[CH2:9][NH:15][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(C)(C)N
Reactant: C=C(C)C(=O)OCC1CO1
Solvent: CC(C)O
Product: C=C(C)C(=O)OCC(O)CNC(C)(C)C
Reaction time: 3.5 h

Procedure:
There were charged to a glass pressure reactor having a volume of 250 ml, 30 ml of isopropyl alcohol, 20 grams of 90 percent pure glycidyl methacrylate and 9.92 grams of t-butylamine. The reactor was then placed in a water bath at 60° C. for 3.5 hours. Thereafter the solution was cooled in an ice bath, and a white, crystalline precipitate formed, which weighed 17.7 grams after drying. The filtrate was partially concentrated and a second filtration gave an additional 1.3 grams of the same white, crystalline solid product. This yield equalled about 70 percent based on the amount of glycidyl methacrylate charged. The melting point of this solid product was 66°-67° C. The structure of the 2-hydroxy-3-t-butylamino-1-propyl methacrylate produced was further confirmed by nuclear magnetic resonance, infrared analysis and mass spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]4[N:14]=3)[C@@:11]([CH2:26][OH:27])([CH3:25])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]3[CH:18]=[CH:17][N:16]4[N:19]=[CH:20][C:21]([C:22]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:23])=[C:15]4[N:14]=3)[C@@:11]([CH2:26][OH:27])([CH3:25])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)N
Reactant: C[C@@]1(CO)CC[C@H](c2cncc(F)c2)N1c1ccn2ncc(C(=O)O)c2n1
Product: CC(C)NC(=O)c1cnn2ccc(N3[C@@H](c4cncc(F)c4)CC[C@@]3(C)CO)nc12

Procedure:
Prepared according to the method of Example 212, Step F, using 5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and isopropyl amine. The title compound was obtained as a white solid (7.2 mg, 46% yield). MS (apci) m/z=413.1 (M+H).
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38](O)=[O:39])=[CH:32]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.[O:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH:63]1[O:68][NH2:69]>CN(C=O)C>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([NH:69][O:68][CH:63]3[CH2:64][CH2:65][CH2:66][CH2:67][O:62]3)=[O:39])=[CH:32]2)(=[O:29])=[O:30])=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NOC3CCCCO3)c2)cc1
Reaction time: 1.5 h

Procedure:
(E)-3-{1-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-benzenesulfonyl]-1H-pyrrol-3-yl}-acrylic acid (compound C15) (1.15 g, 1.16 mmol), HOBtH2O (171 mg, 1.16 mmol) and triethylamine (2 ml) is dissolved in DMF (100 ml) at room temperature. After addition of EDC HCl (786 mg, 3.48 mmol) the mixture is stirred for 1.5 hours. Then it is added O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine (136 mg, 1.16 mmol) and stirred for 17 hours. After evaporation and addition of 200 ml water the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate. Then it is filtrated and evaporated. The crude product is purified by a silica gel flash chromatography using dichloromethane-methanol eluent.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([OH:3])=O.S(Cl)([Cl:17])=O.[CH2:19]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22].Cl.C(O)C.Cl>C(Cl)Cl.N1C=CC=CC=1>[ClH:17].[CH2:19]([N:29]1[CH2:30][CH2:31][N:32]([C:1]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3)=[O:3])[CH2:33][CH2:34]1)/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])\[CH3:22]
Reactant: O=S(Cl)Cl
Reactant: CC(C)=CCC/C(C)=C/CN1CCNCC1
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)=CCC/C(C)=C/CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.9 Grams of 6-carboxy-3,4-dihydrocarbostyril was suspended in 200 ml of methylene chloride, then 2 ml of pyridine was added thereto. The mixture was kept at 0°-20° C., under stirring condition, 1.4 g of thionyl chloride was added dropwise. After the dropwise addition was finished, the whole reaction mixture was stirred for 1 hour at the same temperature, and 10 ml of methylene chloride containing 2.19 g of geranylpiperazine was added dropwise. After the dropwise addition was finished, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was thoroughly washed with an aqueous solution of potassium carbonate, then further washed with water and diluted hydrochloric acid, then dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue thus obtained was converted into hydrochloride by adding ethanol-hydrochloric acid, and recrystallized from ethanol-water to obtain 343 mg of 6-(4-geranyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril hydrochloride.monohydrate. Colorless needle-like crystals. Melting point: 265°-266° C. (dec.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8](Br)[C:9]([OH:11])=[O:10].[CH2:13]([N:15]1[C:19]([C:20]([C:22]2[CH:27]=[C:26]([OH:28])[C:25]([OH:29])=[C:24]([Cl:30])[C:23]=2[Cl:31])=[O:21])=[CH:18][CH:17]=[N:16]1)[CH3:14].Cl>CN(C)C=O.O>[Cl:30][C:24]1[C:25]2[O:29][CH:8]([C:9]([OH:11])=[O:10])[O:28][C:26]=2[CH:27]=[C:22]([C:20]([C:19]2[N:15]([CH2:13][CH3:14])[N:16]=[CH:17][CH:18]=2)=[O:21])[C:23]=1[Cl:31]
Reactant: CCn1nccc1C(=O)c1cc(O)c(O)c(Cl)c1Cl
Reactant: O=C(O)C(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nccc1C(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)O2
Temperature: 80 °C
Reaction time: 5 h
Yield: 38.1 %

Procedure:
6.9 g of potassium carbonate and 2.83 g of dibromoacetic acid are added to a solution of 3.01 g of (1-ethylpyrazol-5-yl)-(2,3-dichloro-4,5-dihydroxyphenyl)-methanone in 30 ml of dimethylformamide and the mixture is stirred at 80° C. for 5 hours. After cooling the reaction mixture, water is added thereto and the mixture is adjusted to pH 1 by addition of 6N hydrochloric acid. The resultant crystals are collected by filtration, washed with water and recrystallized from dimethylformamide-water to give 1.36 g of 4,5-dichloro-6-(1-ethyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH:13]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C@@H:13]3[CH2:14][CH2:15][C@H:16]([NH:19][C:28](=[O:29])[CH2:27][C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: NC1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)N[C@H]1CC[C@@H](Nc2ccnc3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(7-chloroquinolin-4-yl)-cyclohexane-1,4-diamine (20 mg, 0.07 mmol) in dichloromethane (1.0 mL) and triethylamine (0.01 mL) at 20° C. was treated with (4-fluoro-phenyl)-acetyl chloride (12 mg, 0.07 mmol). The reaction was shaken at room temperature for 18 hours then concentrated. The crude compound was purified by reverse phase HPLC to provide the desired compound. MS (ESI (+)) m/e 412 (M+H)+; 1H NMR (500 MHz, DMSO) δ ppm 8.87 (d, 1 H), 8.74 (d, 1 H), 8.54 (d, 1 H), 8.01 (d, 1 H), 7.95 (m, 1 H), 7.80 (dd, 1 H), 7.31 (m, 2 H), 7.12 (m, 2 H), 6.97 (d, 1 H), 3.91 (br.s, 1 H), 3.80 (br.s, 1 H), 3.47 (s, 2 H), 1.57-1.98 (m, 8 H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:7]=1[CH3:21])=[O:4].[CH3:22][C:23]1([CH3:33])[N:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:26]2[C:25](=[O:32])[NH:24]1.C(N(CC)CC)C>CN(C)C=O>[CH3:21][C:7]1[CH:8]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:30]1[CH2:29][CH2:28][N:27]2[C:23]([CH3:33])([CH3:22])[NH:24][C:25](=[O:32])[CH:26]2[CH2:31]1
Reactant: CC1(C)NC(=O)C2CNCCN21
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CN1CCN2C(C1)C(=O)NC2(C)C
Temperature: 70 °C
Reaction time: 20 h
Yield: 66.8 %

Procedure:
A mixture of 13.36 parts of 2-chloro-N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]acetamide, 6.76 parts of hexahydro-3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one, 7.8 parts of N,N-diethylethanamine and 180 parts of N,N-dimethylformamide was stirred for 20 hours at 70° C. The reaction mixture was evaporated. The residue was taken up in water and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 11.66 parts (66.8%) of N-[2,6-dimethyl-4-(phenylmethoxy)phenyl]hexahydro-3,3-dimethyl-1-oxoimidazo-[1,5-a]pyrazine-7(8H)-acetamide; mp. 223.8° C. (int. 1).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=3[F:24])=[N:13][C:12]=2[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][C:27]1([C:31]([O:33][CH3:34])=[O:32])[CH2:30][NH:29][CH2:28]1>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:29]4[CH2:30][C:27]([OH:26])([C:31]([O:33][CH3:34])=[O:32])[CH2:28]4)=[CH:18][C:17]=3[F:24])=[N:13][C:12]=2[CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1(O)CNC1
Reactant: O=Cc1ccc(-c2nc3cc(Cc4ccccc4)ccc3s2)c(F)c1
Product: COC(=O)C1(O)CN(Cc2ccc(-c3nc4cc(Cc5ccccc5)ccc4s3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B1 and general procedure I from 4-(5-benzylbenzo[d]thiazol-2-yl)-3-fluorobenzaldehyde (0.057 g, 0.16 mmol) and methyl 3-hydroxyazetidine-3-carboxylate (0.031 g, 0.16 mmol) to give methyl 1-((4-(5-benzylbenzo[d]thiazol-2-yl)-3-fluorophenyl)methyl)-3-hydroxyazetidine-3-carboxylate. 1H NMR (300 MHz, CDCl3) δ ppm 8.37 (t, J=7.7 Hz, 1H), 7.93 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.21-7.35 (m, 8H), 4.15 (s, 2H), 3.93-4.07 (m, 7H), 3.52-3.67 (m, 2H). MS (ESI) m/z: Calculated: 462.1 Observed: 463.1 (M++1).
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4](Br)([CH2:5]3)[CH2:3]1)[CH2:9]2.[Br-:13].[Al+3].[Br-:15].[Br-].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1.Br>>[Br:17][C:18]1[CH:23]=[C:22]([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][C:4]([C:2]5[CH:11]=[C:6]([Br:13])[CH:5]=[C:4]([Br:15])[CH:3]=5)([CH2:5]4)[CH2:3]2)[CH2:9]3)[CH:21]=[C:20]([Br:24])[CH:19]=1
Reactant: Brc1cccc(Br)c1
Reactant: [Br-]
Reactant: BrC12CC3CC(C1)CC(Br)(C3)C2
Agent: Br
Agent: [Al+3]
Product: Brc1cc(Br)cc(C23CC4CC(C2)CC(c2cc(Br)cc(Br)c2)(C4)C3)c1
Temperature: 0 °C
Yield: 194.3 %

Procedure:
After the air inside a 1 litter flask equipped with a thermometer and stirrer was replaced by nitrogen, 43 g of 1,3-dibromoadamantane and 10 g of anhydrous aluminum bromide were placed therein, and then the inside of the flask was cooled to 0° C. Thereto was added 190 g of 1,3-dibromobenzene that was cooled to 5° C. in advance, and the resulting material was agitated and reacted at an inside temperature of 0 to 10° C. for 7 hours. The reaction was carried out while the hydrogen bromide gas that was generated during the reaction was absorbed into an aqueous alkaline solution for the removal of its toxicity. After the completion of the reaction, 130 g of 4% by weight hydrochloric acid was slowly dropped and then the solution was stirred until the orange color of the reaction solution faded away. The agitation was stopped and the resulting solution was allowed to stand and then separated by funnel. The resulting organic phase was washed with water three times. 190 grams of toluene was added to the organic phase after the washing, which was then warmed to remove water under reflux. Then, the organic solution was cooled and the crystal deposited was collected by filtration. The resulting crystal was subjected to washing with toluene, methanol and water, followed by drying under reduced pressure to obtain 44 g of 1,3-bis(3,5-dibromophenyl)adamantane.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]=[O:9].[ClH:10]>>[Cl:10][CH2:8][O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=O
Reactant: Cl
Reactant: CCCCCCO
Product: CCCCCCOCCl
Temperature: 25 °C
Yield: 55 %

Procedure:
102 g of n-hexanol (1 mol) are combined with an aqueous solution of 36 g of formaldehyde gas (1.2 mol). The mixture is slowly agitated, cooled to 1°-5° C and saturated with hydrogen chloride gas. The cold mixture is slowly raised to room temperature. After about 15 hours the mixture is separated and the aqueous portion is discarded. The organic portion is diluted with 50 ml of an inert solvent such as ether, hexane or toluene. The solution is washed twice with 100 ml of ice water. The solvent is removed by distillation under vacuum. The desired chloromethyl-n-hexyl ether is obtained by fractional distillation at a convenient vacuum (between 5-10 mm). The yield is about 55-65% of the theoretical.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)C)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH3:22].[CH3:23]O>>[CH3:21][O:20][C:17]1[N:16]=[CH:15][C:14]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:22][CH3:23])[N:11]=2)=[CH:19][CH:18]=1
Reactant: CO
Reactant: N
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Product: CNc1nc(Nc2ccc(OC)nc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methylamine (10 mg, 0.030 mmol) and 7 M ammonia in methanol (1 mL) by a procedure similar to Example 10 (3 mg, 30%). 1H NMR (CDCl3): 8.04 (dd, J=2.9, 0.6 Hz, 1H), 7.49-7.43 (m, 2H), 7.39 (dd, J=5.7 and 2.7 Hz, 1H), 6.92 (brd, J=8.4 Hz, 1H), 6.85-6.78 (m, 2H), 5.65 (s, 2H), 3.96 (s, 3H), 3.54 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH2:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[C:11]([NH:19][C@H](C(O)=O)CCC(O)=O)(=[O:18])C1C=CC=CC=1>>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11]([NH2:19])=[O:18])[CH2:7][CH2:8][CH2:9][C:2]1=2
Reactant: O=C(O)CC[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: NC1CCCc2sccc21
Product: NC(=O)NC1CCCc2sccc21

Procedure:
Similarly, the salt of (+)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine and (S)-(-)-N-benzoyl glutamic acid is treated in the above manner to afford (+)-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, melting point 218° C. to 220° C.; [α]589 25 +60° , [α]436 +149.8° , [α]365 +272.5°.
Reaction SMILES: [ClH:1].O1CCOC[CH2:3]1.[NH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[NH2:9]>CO>[Cl-:1].[CH3:3][O:15][C:14]([C:13]1[CH:12]=[CH:11][C:10]([NH:8][NH3+:9])=[CH:18][CH:17]=1)=[O:16]
Reactant: C1COCCO1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: Cl
Solvent: CO
Product: COC(=O)c1ccc(N[NH3+])cc1
Product: [Cl-]
Temperature: 90 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
Hydrogen chloride 4M in Dioxan (100 mL, 399.60 mmol) was added to 4-Hydrazinobenzoic acid (15.2 g, 99.90 mmol) in MeOH (200 mL). The resulting suspension was stirred at 90° C. for 5 hours. After cooling to 20° C. the precipitate was collected by filtration, washed with Et2O (100 mL) and dried under vacuum to afford 2-(4-(methoxycarbonyl)phenyl)hydrazinium chloride (16.50 g, 82%) as a cream crystalline solid.
Reaction SMILES: [NH:1]([C:3]1[NH:8][C:7](=[O:9])[N:6]([CH3:10])[C:5](=[O:11])[CH:4]=1)[NH2:2].[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:22]=O.[CH3:24][N:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O>>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:22][N:2]1[C:30]([C:26]2[N:25]([CH3:24])[CH:29]=[CH:28][N:27]=2)=[C:4]2[C:3]([NH:8][C:7](=[O:9])[N:6]([CH3:10])[C:5]2=[O:11])=[N:1]1
Reactant: Cn1ccnc1C=O
Reactant: Cn1c(=O)cc(NN)[nH]c1=O
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Product: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-chloro-1H-indole-3-carbaldehyde, followed by 1-methyl-1H-imidazole-2-carbaldehyde
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[C:14](OCCCC)(=O)[C:15]1C=CC(C([O-])=O)=C[CH:16]=1.[K+].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([C:2]1[CH:10]=[C:9]([C:11]([Cl:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOC(=O)c1ccc(C(=O)[O-])cc1
Reactant: Cc1cc(C(=O)Cl)ccc1C(=O)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCc1cc(C(=O)Cl)ccc1C(=O)Cl

Procedure:
This compound was prepared by the procedure described for monomethyl terephthaloyl chloride. Typical reagent levels were as follows: potassium monobutyl terephthalate (10.0 g, 0.0384 mole), thionyl chloride (4.57, 0.0384 mole) and 40 ml of toluene. The yield of product was 8.5 g (92%). This material was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Brc1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccc(Br)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.6 g), triethylamine (2.8 cc) and 4-(4-bromophenyl)piperazine (4.8 g) in toluene (60 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure re (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (40 cc), 2-{3-[4-(4-bromophenyl)-1-piperazinyl]propyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (4.3 g) is obtained, m.p. 149° C.