Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:28])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Agent: [K+]
Solvent: CI
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=410.2 [M+H]+.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[N:24]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1
Reactant: C1CSCCN1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCN2CCSCC2)cc1

Procedure:
In a manner similar to that described in Example 217, 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and thiomorpholine are converted to the named compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 50 °C

Procedure:
2,6-Dichloro-9H-purine (20 g, 0.11 mol) and 4-toluenesulphonic acid monohydrate (0.2 g) were dissolved in ethyl acetate (300 ml), the mixture was heated to 50° C. and a solution of 2,3-dihydropyran (12.6 ml, 0.14 mol) in ethyl acetate (50 ml) was added slowly over 30 min. The reaction mixture was then cooled to room temperature, water (100 ml) was added and the pH of the solution was adjusted to 7 with a saturated aqueous solution of sodium hydrogen carbonate. The layers were separated and the organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was azeotroped from pentane (×2) to afford the title compound as a slightly impure white solid (30.9 g).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CCCC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Yield: 28.2 %

Procedure:
A solution of the 9-[(phenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (1.5 g, 4.5 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.12 g, 5.0 mM) in 25 mL of toluene was stirred between 80-90° C. for 6 hours. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride/ethyl acetate) to afford 420 mg (28%) of the 9-[(phenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole as a yellow solid. 1H NMR (DMSO-d6) δ 10.25 (s, 1H), 7.7 (d, 1H, J=8 Hz), 7.4 (t, 1H, J=8 Hz), 7.4-7.0 (m, 8H), 6.6 (d, 1H, J=8 Hz), 5.6 (s, 2H), and 3.8 (s, 3H). IR (CHCl3, cm−1) 1723, 1685, 1621, 1597, 1568, 1496, 1453, 1442, 1392, 1286, 1267, 1156, and 1138. MS (ES) m/e 330, 332.
Reaction SMILES: C([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1.[CH:30]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=O)=[CH:34][CH:33]=1)=[O:31].C1C=CC2N(O)N=NC=2C=1.C(N=C=NC(C)C)(C)C>CN(C=O)C.C(#N)C>[CH:30]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:38])=[CH:39][CH:40]=1)=[O:31]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=Cc1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
To the above resin bound Fmoc β-alanine was added 500 μL of a 20% solution of piperidine in DMF. After 30 min of shaking, the resin was drained and washed with 1 mL DMF containing 1-hydroxybenzotriazole (50 mg/mL) and DMF (2×1 mL). Then 200 μmol 4-formylbenzoic acid (30 mg) and 200 μmol HOBt (31 mg) dissolved in DMF (500 μL) were added to the resin followed by 200 μmol diisopropyl carbodiimide (DIC, 25.2 mg) dissolved in acetonitrile (500 μL). The mixture was shaken for 4 hours at 25° C. followed by filtration and washing of the resin with DMF (3×1 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18](O)=[O:19])=[N:10]1.[OH:21][CH2:22][C:23]1([NH2:26])[CH2:25][CH2:24]1>>[OH:21][CH2:22][C:23]1([NH:26][C:18]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:17][C@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: O=C(O)c1nn(-c2ccc(Cl)cc2Cl)c2c1C[C@H]1C[C@@H]21
Reactant: NC1(CO)CC1
Product: O=C(NC1(CO)CC1)c1nn(-c2ccc(Cl)cc2Cl)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G using (1aR,5aR)-2-(2,4-dichloro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and (1-hydroxymethyl-cyclopropyl)-amine. LCMS m/z=378.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.51 (td, J=4.6 and 3.4 Hz, 1H), 0.90-1.03 (m, 4H), 1.14-1.21 (m, 1H), 2.00-2.07 (m, 1H), 2.27-2.37 (m, 1H), 2.97 (d, J=16.6 Hz, 1H), 3.06 (dd, J=16.6 and 6.3 Hz, 1H), 3.71 (s, 2H), 7.28 (bs, 1H), 7.40 (dd, J=8.5 and 2.1 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12]CC)=[O:11])[C:8]2([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[OH-].[K+]>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:15])[CH3:16])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1C(Oc2ccc(Cl)cc2)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)C(Oc2ccc(Cl)cc2)C1C(=O)O

Procedure:
The ethyl 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylate (l.5 g) is hydrolyzed by heating under reflux with 10% potassium hydroxide in a mixture of 20% water and 80% ethyl alcohol for 1 hr and letting stand at 25° overnight. The solution is cooled and solvent is removed in vacuo. The residue is diluted with water and extracted with ether. The aqueous phase is then acidified with aqueous HCl and extracted with ether. The organic phase is washed with water and brine, dried over sodium sulfate and the solvent removed in vacuo to give 3-(4-chlorophenoxy)-2,2-dimethylcyclopropanecarboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1Br.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH3:9][C:5]1[CH:4]=[C:3]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[C:2]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[CH:7][C:6]=1[CH3:8]
Reactant: Cc1cc(Br)c(Br)cc1C
Reactant: Nc1ccc(-c2ccccc2)cc1
Product: Cc1cc(Nc2ccc(-c3ccccc3)cc2)c(Nc2ccc(-c3ccccc3)cc2)cc1C
Yield: 75.8 %

Procedure:
The synthesis is carried out in accordance with the general procedure in accordance with Example 2 from 63.3 g (240 mmol) of 1,2-dibromo-4,5-dimethylbenzene and 85.4 g (505 mmol) of 4-aminobiphenyl. The precipitated solid is recrystallised from toluene/acetonitrile (5:1), and the residue is washed with MeOH, giving 80.3 g (182 mmol) of a crystalline solid. The overall yield is 76%.
Reaction SMILES: N[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[BrH:13].N([O-])=O.[Na+]>O>[Br:13][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Br
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cc2nc(Br)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
2-Amino-5,6-dichlorobenzimidazole (3 g, 16 mmole) was suspended in 150 ml of water and brought into solution with 2 ml of HBr. Sodium nitrite (3.3 g, 55 mmole) was then added and the mixture was stirred at room temperature for 1 hr. Excess CuBr2 was then added and the mixture was heated on a steam bath for 1 hr. The aqueous solution was extracted with ethyl acetate (3×100 ml), dried with MgSO4, concentrated, and crystallized from ethyl ether to give 1.13 g (26%) of 2-bromo-5,6-dichlorobenzimidazole (7). 1H NMR (DMSO-d6)δ7.81 ppm (s, 2H), 13.62 (s, 1H). GC/MS: m/e 266, 185, 158, 150, 133, 124, 107, 97, 88, 73, 62, 52, 37.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:11][C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:7]([Br:10])=[CH:8][CH:9]=1)=O.C([O-])(=O)C.[NH4+:28].O>C(O)(=O)C>[Br:10][C:7]1[N:6]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[NH:28][C:3](=[O:2])[C:5]2=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Br)n1CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cn2c(Br)ccc12
Temperature: 130 °C
Yield: 97.4 %

Procedure:
A mixture of 5-bromo-1-[2-oxo-2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester (0.09 g, 0.23 mmol) and ammonium acetate (90 mg, 1.17 mmol) in glacial acetic acid (3 mL) were heated to 130° C. overnight. At this time, the reaction was treated with water. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to afford 6-bromo-3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (80 mg, 97%) as light brown solid. 1H NMR (chloroform-d) δ ppm 7.75-7.83 (m, 7H), 7.68-7.74 (m, 2H), 7.27 (d, J=1.5 Hz, 1H), 7.23 (s, 1H), 7.20 (s, 1H). LC-MS calcd. for C14H7BrF3N2O [(M−H)−] 356, obsd. 354.9.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:73][C:74]1[S:75][C:76]2[CH:81]=[CH:80][N:79]=[CH:78][C:77]=2[N:82]=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:73][C:74]4[S:75][C:76]5[CH:81]=[CH:80][N:79]=[CH:78][C:77]=5[N:82]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4cnccc4s3)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 79.9 %

Procedure:
Using 306 mg of p-methoxybenzyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-{(S)-1-diphenylmethoxycarbonylethoxyimino}acetamido]-3-chloromethyl-3-cephem-4-carboxylate in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 56 mg of 2-mercaptothiazolo[4,5-c]pyridine, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 276 mg of the title compound in a yield of 80%.
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1O[CH:6]=[CH:7][CH:8]=1.Cl[CH2:10][C:11]([OH:13])=[O:12].Cl>O.CO.C(O)C>[C:11]([CH2:10][C:4]1[S:3][CH:6]=[CH:7][CH:8]=1)([OH:13])=[O:12]
Reactant: O=C(O)CCl
Reactant: Sc1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1cccs1
Temperature: 25 °C
Yield: 74 %

Procedure:
Aqueous solution of sodium hydroxide 8.8 g (0.22 mol) in water of 15 ml was added drop by drop to mixture of 2-mercapto furan 20.0 g (0.20 mol), chloroacetic acid 27.0 g (0.22 mol) and ethanol 300 ml with stirring at room temperature. After 20 minutes of stirring it was heated to 50° C., and further aqueous solution of sodium hydroxide 8.8 g (0.22 mol) in 15 ml of water was added slowly drop by drop. After stirring for 3 hours at 50° C., it was cooled to room temperature, and water was added till reaction liquid became uniform. Hydrochloric acid was added for neutralization. Prepared crystal was collected by filtration and 23.5 g (0.148 mol) of 2-carboxymethylthiofuran was obtained by recrystallization in methanol. Synthesis of yield 74%.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[CH:14]1[CH:19]=[CH:18][CH:17]=CC=1.[CH2:20]([OH:22])[CH3:21].[OH-].[K+]>[Sn].C(OCCCC)(=O)C.C(O)CCC>[CH3:17][CH2:18][CH2:19][CH2:14][O:10][C:9]([CH2:8][C:3]([O:4][C:20]([CH3:21])=[O:22])([C:5]([O:7][CH2:14][CH2:19][CH2:18][CH3:17])=[O:6])[CH2:2][C:1]([O:13][CH2:1][CH2:2][CH2:3][CH3:5])=[O:12])=[O:11]
Reactant: CCO
Reactant: c1ccccc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Agent: [Sn]
Solvent: CCCCOC(C)=O
Solvent: CCCCO
Product: CCCCOC(=O)CC(CC(=O)OCCCC)(OC(C)=O)C(=O)OCCCC
Temperature: 150 °C

Procedure:
German Pat. No. 1 041 944 describes a process in which a citric acid ester is said to be prepared from a crude citric acid broth. Specifically, the authors describe a process for producing an ester of citric acid, in which a raw 30% citric acid broth is dehydrated with benzene and ethanol to a syrup. Butanol and butyl acetate, along with a tin catalyst, are added to the syrup and the mixture is heated to a temperature of 140-160° C., whereupon the reaction is halted with potassium hydroxide. The resulting reaction product is washed with sodium carbonate in water, and the crude mixture distilled. The authors report yielding acetyl tributyl citrate in the recovered material.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:14][N:15]=[C:16]=[O:17].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:14][NH:15][C:16]([NH:9][C:6]1[S:7][CH:8]=[C:4]([CH2:3][Cl:2])[N:5]=1)=[O:17]
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a suspension of 4-(chloromethyl)thiazol-2-amine hydrochloride (7.55 g, 41 mmol) in DCM (150 mL) at 0° C. was added 3,4-dichlorobenzyl isocyanate (8.27 g, 41 mmol). A solution of DIPEA in DCM (30 mL) was added over a period of 30 min and the mixture was stirred overnight at room temperature. Evaporation of the volatiles followed by purification by column chromatography (EtOAc/heptanes 1/1) afforded 1-(3,4-dichlorobenzyl)-3-(4-(chloromethyl)thiazol-2-yl)urea as an off-white solid (10.5 g, 30 mmol) in 73% yield. 1H NMR (DMSO-d6): δ 10.80 (bs, 1H); 7.60 (d, 1H); 7.55 (s, 1H); 7.11 (t, 1H); 7.05 (s, 1H); 4.63 (s, 2H); 4.30 (d, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][N:10]3[CH:19]=[CH:20][N:21]=[C:9]23)[CH2:4][CH2:3]1.[Cl:22]N1C(=O)CCC1=O>C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:22][C:19]1[N:10]2[C:9]([C:8](=[C:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11]2)=[N:21][CH:20]=1
Reactant: CN1CCC(=C2c3ccccc3CCn3ccnc32)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN1CCC(=C2c3ccccc3CCn3c(Cl)cnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
6,11-Dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine (28 g) was stirred in DCM (500 ml), until complete dissolution. Dibenzoyl peroxide (0.1 g) was added. N-chlorosuccinimide (13.4 g) was added portionwise and the resulting reaction mixture was stirred overnight at room temperature, then for 2 hours at reflux temperature. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 97/3, upgrading to 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 23.3 g (74%) of 3-chloro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo-[2,1-b][3]benzazepine (intemediate 11).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl[C:37](OC1C=CC([N+]([O-])=O)=CC=1)=[O:38].[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)=[CH:54][CH:53]=1)([O-:51])=[O:50]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:37]([N:61]2[CH2:62][CH2:63][N:58]([C:55]3[CH:54]=[CH:53][C:52]([N+:49]([O-:51])=[O:50])=[CH:57][CH:56]=3)[CH2:59][CH2:60]2)=[O:38])(=[O:22])=[O:23])=[CH:17][C:16]=1[N+:25]([O-:27])=[O:26])[CH2:6][S:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of 4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrobenzenesulfonamide (prepared according to the procedure described in commonly owned U.S. patent application Ser. No. 09/957,256, filed Sep. 20, 2001, 60 mg, 0.142 mmol) in dichloromethane (2 mL) at room temperature was treated with triethylamine (59 μL, 0.426 mmol) and p-nitrophenyl chloroformate (31 mg, 0.156 mmol), stirred for 2 hours, treated with 1-(4-nitrophenyl)-piperazine (35 mg, 0.169 mmol) and DMAP (17 mg, 0.142 mmol), stirred overnight, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% 2N NH3 in methanol/dichloromethane) to provide the desired product (40 mg, 43%). MS (ESI) m/e 658 (M+H)+; 1H NMR (500 MHz, CD3OD) δ 8.5-6.75 (12H, m), 4.16 (1H, m), 3.69 (2H, t), 3.59 (2H, br s), 3.47 (2H, br s), 3.37 (2H, br d), 3.24 (4H, m), 2.87 (6H, s), 2.35-2.15 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:14][CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:7]=[C:8]([O:10][CH2:14][CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:9]=1
Reactant: BrCCOc1cccc2ccccc12
Reactant: COC(=O)c1cc(O)cc(O)c1
Product: COC(=O)c1cc(OCCOc2cccc3ccccc23)cc(OCCOc2cccc3ccccc23)c1

Procedure:
Using this procedure, reaction of 3,5-dihydroxybenzoic acid methyl ester with 1-(2-bromoethoxy)naphthalene gave 3,5-bis[2-(1-naphthalenyloxy)ethoxy]benzoic acid methyl ester, mp 132°-137°, Anal. Calcd for C32H28O6 : C, 75.58; H, 5.55. Found: C, 75.19: H, 5.44.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([NH:10][CH2:11][C@@H:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)[O:9][C:5]=2[CH:4]=1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:22]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)=O>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([NH:10][CH2:11][C@@H:12]3[CH2:16][CH2:15][N:14]([C:23]([C:22]4[C:26]([O:30][CH3:31])=[CH:27][CH:28]=[CH:29][C:21]=4[O:20][CH3:19])=[O:24])[CH2:13]3)[O:9][C:5]=2[CH:4]=1
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: Clc1ccc2nc(NC[C@@H]3CCNC3)oc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=CO
Product: COc1cccc(OC)c1C(=O)N1CC[C@@H](CNc2nc3ccc(Cl)cc3o2)C1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 146.3 mg (0.45 mmol) (6-chloro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3-ylmethyl-amine, hydrochloride (intermediate 1), 106.7 mg (0.586 mmol) 2,6-dimethoxy-benzoic acid (commercially available) and 206.9 mg (0.64 mmol) TBTU in 4 mL DMF and 0.3 mL DIPEA was shaken at room temperature over night. The mixture was acidified with formic acid and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 72 mg (38%) of the title compound. MS (m/e): 416.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([CH:18](Br)Br)[C:15]([Cl:21])=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].S(=O)(=O)(O)[OH:24]>>[Cl:21][C:15]1[CH:14]=[C:13]([F:22])[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:10])[F:9])[N:5]([CH3:11])[N:4]=2)=[CH:17][C:16]=1[CH:18]=[O:24]
Reactant: Cn1nc(-c2cc(C(Br)Br)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: O=S(=O)(O)O
Product: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 10 °C

Procedure:
68 g (0.14 mol) of 4-chloro-3-(4-chloro-5-dibromomethyl-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole were dissolved in 200 ml of concentrated sulfuric acid, with ice-cooling, whereupon the mixture was heated at 10° C. until the evolution of gas had ceased. It was then poured into 4 l of ice-water. The mixture was subsequently extracted three times using ethyl acetate. The combined organic phases were washed with water, then dried over magnesium sulfate and finally concentrated. The crude product was purified by means of silica gel column chromatography (eluent: hexane/ethyl acetate=8:1). Yield: 35 g; m.p.: 95-98° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](SC)[N:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1>C(O)C.[Ni].O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: CSc1nc(N)nc(C(C)O)n1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CC(O)c1ncnc(N)n1
Temperature: 85 °C
Yield: 76.8 %

Procedure:
To a solution of 1-(4-amino-6-(methylthio)-1,3,5-triazin-2-yl)ethanol (398 mg) in ethanol (20 mL) was added Raney nickel 50% slurry in water (6 mL) and the reaction mixture was heated to 85° C. for 30 minutes then cooled to room temperature, filtered and evaporated to give the title compound (230 mg).