Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[CH:31][N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[CH:31][N:17]2[N:16]=1)[CH2:13][CH3:14])[C:38](=[O:39])[C:37]1[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
{3-[1-(3-Benzyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propylamino]-propyl}-carbamic acid tert-butyl ester (Example 47, 25 mg, 0.0569 mmol) in CHCl3 (10 mL) at 25° C. was treated with 4-chloro-benzoylchloride (31.5 μL, 0.248 mmol) and triethylamine (23.0 μL, 0.166 mmol). The resulting mixture was stirred at 25° C. for 18 h, then concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (17.2 mg, 52.3%) as a colorless film: LC/MS 86% at 3.74 min (ESI+) 578 (M++H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])[OH:4].ClCCl.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:44](O)(=[O:46])[CH3:45]>CN(C)C=O>[C:44]([O:4][CH:3]([CH2:2][Cl:1])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])(=[O:46])[CH3:45]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(O)CCl
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(S(N)(=O)=O)cc1C(CCl)OC(C)=O

Procedure:
2.64 g (9.9 mmol) of α-chloromethyl-2-methoxy-5-sulphamoylbenzenemethanol and 100 ml of dichloromethane are introduced into a 250-ml round-bottomed flask. 10 ml of dimethylformamide are then added with stirring, followed by 852 μl of acetic acid, 2.56 g of dicyclohexylcarbodiimide and 121 mg of dimethylaminopyridine. The mixture is allowed to react for 1 hour at room temperature, and is then filtered and rinsed with 50 ml of 5% sodium hydrogen carbonate solution and then with 50 ml of water. The rinsing liquors are extracted with 2 times 20 ml of acetic acid, and the organic phases are then combined, dried and concentrated. On chromatographing the residue on a silica column with a 25:75 mixture of ethyl acetate and cyclohexane, 1.9 g of product are obtained.
Reaction SMILES: [C:1]1([C:7]#[C:8]/[CH:9]=[CH:10]/[CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS([Cl:24])(=O)=O>ClCCl>[Cl:24][CH2:11]/[CH:10]=[CH:9]/[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC/C=C/C#Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClC/C=C/C#Cc1ccccc1
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a mixture of (E)-5-phenyl-pent-2-en-4-yn-1-ol (Method 1b) (4.9 g, 31.0 mmol) and triethylamine (3.8 g, 38.0 mmol) in dry dichloromethane (200 mL) was added methanesulfonyl chloride (3.8 g, 33 mmol) dropwise. Stirring was continued at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue washed with heptane/dichloromethane (×2) to give 4.5 g (82%) crude (E)-(5-chloro-pent-3-en-1-ynyl)-benzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:49]([CH3:50])=[CH:48][C:39]([O:40][CH:41]2[CH2:45][CH2:44][C:43]([CH3:47])([OH:46])[CH2:42]2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:37]([CH3:51])=[CH:38][C:39]([O:40][CH:41]3[CH2:45][CH2:44][C:43]([OH:46])([CH3:47])[CH2:42]3)=[CH:48][C:49]=2[CH3:50])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: Cc1cc(OC2CCC(C)(O)C2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC6CCC(C)(O)C6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 3-(4-bromo-3,5-dimethylphenoxy)-1-methylcyclopentanol (enantiomer 2) following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.81 min.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 32.3 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) in DMF (3 mL) was added N-methyl piperazine (0.122 mL, 1.104 mmol) followed by diisopropyl ethylamine (0.192 mL, 1.104 mmol) and tetrabutyl ammonium iodide (136.2 mg, 0.368 mmol). The reaction mixture was heated at 60° C. for 24 h. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea (72 mg, 32%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.00 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s, 1H), 4.25 (m, 2H), 3.88 (s, 3H), 2.50-2.25 (m, 10H), 2.15 (s, 3H), 1.95 (m, 2H), 1.23 (s, 9H); LC-MS (ESI) m/z 606 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17](Cl)(=[O:19])=[O:18])[CH2:4]1)[CH3:2].[NH2:21][C:22]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]2[C:25]([C@H:26]3[CH2:36][C@H:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:21][C:22]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]3[C:25]([C@H:26]4[CH2:36][C@H:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:19])=[O:18])[CH2:4]1)[CH3:2]
Reactant: CCN1CCCC(Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Reactant: COC(=O)c1c(N)ccc2c1OC[C@@H]1C[C@H]21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1CCCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OC[C@@H]2C[C@H]32)C1
Yield: 21.5 %

Procedure:
2-(1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 222, 0.21 g) was added to a solution of methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42A 0.290 g) in DCM (10 mL) and pyridine (2 mL) and the resultant mixture was stirred at room temperature for 4 hours. The mixture was evaporated to dryness and the residue was partitioned between DCM and water. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a mixture of 2M ammonia in methanol and DCM with a gradient of 0-15% to give methyl (1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.071 g).
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:4]=[C:5]([S+:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]3[CH:33]=[CH:34][CH:35]=[CH:36][C:25]2=3)[CH:6]=[C:7]([CH3:23])[C:8]=1[O:9][CH2:10][C:11](=[O:22])[O:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])[CH3:14].[OH:37][C:38]12[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH2:39]1)[CH2:45]2.[Na].[C:49]([O:52][CH:53]([CH3:64])[C:54]([F:63])([F:62])[C:55]([F:61])([F:60])[S:56]([O-:59])(=[O:58])=[O:57])(=[O:51])[CH3:50].O>ClCCl>[OH:37][C:38]12[CH2:39][CH:40]3[CH2:46][CH:44]([CH2:43][C:42]([CH2:50][C:49]([O:52][CH:53]([CH3:64])[C:54]([F:63])([F:62])[C:55]([F:61])([F:60])[S:56]([O-:59])(=[O:58])=[O:57])=[O:51])([CH2:41]3)[CH2:47]1)[CH2:45]2.[CH3:23][C:7]1[CH:6]=[C:5]([S+:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]3[CH:33]=[CH:34][CH:35]=[CH:36][C:25]2=3)[CH:4]=[C:3]([CH3:2])[C:8]=1[O:9][CH2:10][C:11](=[O:22])[O:12][C:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:15])[CH3:14]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)OC(C)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Agent: Cc1cc(-[s+]2c3ccccc3c3ccccc32)cc(C)c1OCC(=O)OC(C)(C)c1ccccc1
Agent: [Br-]
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: CC(OC(=O)CC12CC3CC(CC(O)(C3)C1)C2)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Yield: 84.6 %

Procedure:
5-(3,5-dimethyl-4-(2-oxo-2-(2-phenylpropan-2-yloxy)ethoxy)phenyl)-5H-dibenzo[b,d]thiophenium bromide (1.8 g, 3.21 mmol) and sodium 3-hydroxyadamantane-acetoxy-1,1,2,2-tetrafluorobutane-1-sulfonate (1.44 g, 3.37 mmol) were dissolved in dichloromethane (100 mL) and water (100 mL) and stirred at r.t. overnight. The dichloromethane layer was separated and the aqueous phase washed with dichloromethane (3×100 mL). The combined organic layers were washed with water (6×200 mL) and concentrated in vacuo to afford the title compound (2.44 g, 86%) as a white solid. 1H NMR (500 MHz, ((CD3)2SO) δ: 8.53 (d, J=8 Hz, 2H), 8.35 (d, J=8 Hz, 2H), 8.03 (t, J=7 Hz, 2H), 7.83 (d, J=8 Hz, 2H), 7.51 (s, 2H), 7.40 (d, J=8 Hz, 2H), 7.31 (dt, J=8, 0.5 Hz, 2H), 7.24 (dt, J=7.5, 1 Hz, 1H), 4.65 (s, 2H), 4.31 (t, J=6.5 Hz, 2H), 2.80-2.82 (m, 2H), 2.65 (tt, J=14, 6.5 Hz, 2H), 2.29 (s, 6H), 1.72-1.81 (m, 10H), 1.65-1.67 (m, 4H), 1.56-1.59 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:7]([CH2:12][S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]2[CH3:11])=[CH:4][C:3]=1[OH:25].[CH3:26][N:27]([CH2:29]N(C)C)[CH3:28]>O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:7]([CH2:12][S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]2[CH3:11])=[C:4]([CH2:26][N:27]([CH3:29])[CH3:28])[C:3]=1[OH:25]
Reactant: CN(C)CN(C)C
Reactant: CCOC(=O)c1c(CSc2ccccc2)n(C)c2cc(Br)c(O)cc12
Solvent: O
Product: CCOC(=O)c1c(CSc2ccccc2)n(C)c2cc(Br)c(O)c(CN(C)C)c12
Yield: 69.9 %

Procedure:
To a solution containing ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate (76.4 g, 0.18 mole) in 470 ml of diowane was added bis-dimethylaminomethane (50 ml, 0.36 mole). The reaction mixture was refluxed for 3 hours, cooled, diluted with a 3-4-fold amount of water. The precipitated crystalls were removed, washed with water and dried to give 60.1 g (70%) of ethyl 6-bromo-5-hydroxy-4-dimethylaminomethyl-1-methyl-2-phenylthiomethylindole-3-carboxilate; m.p. 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:26]=[O:27])[CH:20]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=Nc1cccc(Cl)c1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1cccc(Cl)c1

Procedure:
Example 13 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-chloro-3-isocyanatobenzene (16.6 μl) to give the title compound (0.0247 g). LC-MS (System A): Rt 2.46 mins, Mass Spectrum m/z 428 [MH+].
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH2:5](Cl)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)C>[CH2:5]([NH:3][CH2:2][CH2:1][NH2:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCCN
Reactant: CCCCCCCCCl
Solvent: CCO
Product: CCCCCCCCNCCN

Procedure:
50 g (0.83 mol) of anhydrous ethylenediamine, 31.2 g (0.21 mol) of octyl chloride and 400 ml of ethanol were mixed and refluxed 6 hours under heating. After evaporation of ethanol under reduced pressure, the lower layer was removed and 200 ml of benzene and 100 ml of water were added to the upper layer for full rinsing. The benzene fraction was dried over anhydrous sodium sulfate, concentrated and then cooled to precipitate crystals. After filtering, crystals were redissolved into 200 ml of benzene and the solution was fully rinsed with water. After being dried over anhydrous sodium sulfate, the benzene solution was concentrated and cooled to precipitate crystals. After filtration, crystals were washed with a small volume of methanol.
Reaction SMILES: [OH:1]O.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH2:12][C:9]=3[CH:10]=2)[C:5](=[O:15])C1=O.Cl>[OH-].[Na+]>[NH2:3][C:11]1[CH:10]=[C:9]2[C:8]([CH2:14][CH2:13][CH2:12]2)=[CH:7][C:6]=1[C:5]([OH:15])=[O:1]
Reactant: O=C1Nc2cc3c(cc2C1=O)CCC3
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2c(cc1C(=O)O)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30% Aqueous hydrogen peroxide solution (5.4 mL) was added to a solution of a mixture of 1,5,6,7-tetrahydrocyclopenta[f]indole-2,3-dione and 1,5,6,7-tetrahydrocyclopenta[e]indole-2,3-dione (3.9 g, 20.8 mmol) in 2 N sodium hydroxide (41 mL) over a period of 5 min. The mixture was then stirred at room temperature for 3 h. 1N HCl was added to adjust the pH to 5. The resulting mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford 6-aminoindane-5-carboxylic acid. The solid was dissolved in EtOAc (4 mL) and ethanol (4 mL). To the solution above was added (trimethylsily)diazomethane (2 M in hexane) (18 mL, 36 mmol) at room temperature and The mixture was stirred for 16 h. The solvent was removed in vacuo. Flash chromatography of the residue (Si, hexanes/EtOAc) afforded methyl 6-aminoindane-5-carboxylate which contained about 10% methyl 5-aminoindane-4-carboxylate. LCMS calc.=192.1; found=192.2 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.71 (s, 1H); 6.60 (s, 1H); 3.87 (s, 3H); 2.85-2.79 (m, 4H); 2.08-2.02 (m, 2H).
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[C:6]([NH2:14])(=[S:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C>CC#N>[C:7]1([C:6]2[S:13][S:4][C:2](=[O:3])[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=S)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=c1nc(-c2ccccc2)ss1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
All the glassware were dried in the preheated oven prior to the reaction for two hours at 200° C. A 500 ml three neck round bottom flask was equipped with magnetic bar, thermometer, pressure equalizing funnel and a positive inflow of argon. The assembly was placed on to the magnetic stirrer having ice bath. Chlorocarbonyl sulfenyl chloride (9.55 grams, 72.87 mmol) was transferred to the reaction flask. 100 ml of CH3CN was also added to the flask. The mixture was cooled down to 10° C. Thiobenzamide (10 grams, 72.87 mmol) was dissolved in a separate flask using 80 ml of CH3CN and diisopropylethylamine (18.84 gm, 145.76 mmol). This solution was transferred to the pressure equalizing funnel. The thiobenzamide solution was added slowly to the reaction flask. The temperature of the flask raised to 12-15° C. The mixture was stirred for 30 min. at 5-10° C. The disappearance of the starting material and formation of two isomeric nonpolar spots was observed on TLC. The reaction mixture was filtered through a sintered funnel. The filtrate was rotaevaporated to dryness and left on high vacuum for two hours. The solid was crystallized with a mixture of hexanes and ethyl acetate in a ratio of 95:5, respectively. The upper nonpolar spot on the TLC was left behind in the mother liquor and characterized as 3,5-diphenyl-1,2,4-thiadiazole. The crystals of 3-phenyl-1,2,4-dithiazoline-5-one were light yellow in color and the recovery was 9.25 gm (65%). The yield of the crude mix was 75%. The structure of 3-phenyl-1,2,4-dithiazoline-5-one was confirmed by 1H-NMR (FIG. 1), 13C-NMR (FIG. 2), mass spectrometry (FIG. 3) and elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([Li])(C)(C)C.[Br:26]Br>C1COCC1.CCCCC>[Br:26][C:8]1[C:7]([O:9][CH3:10])=[CH:6][N:5]=[C:4]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(C#Cc2ncc(OC)cc2OC)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ncc(OC)c(Br)c2OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
To a solution of 3,5-dimethoxy-2-(4-methoxyphenylethynyl)pyridine M (120 mg, 0.446 mmol) in dry THF (2.5 ml) at −78° C. was added t-butyllithium (0.49 mmol, 0.30 ml of a 1.6M solution in pentane) and the reaction stirred for 10 minutes. After this time bromine (25 μL, 0.50 mmol) was added neat and the reaction was allowed to warm to room temperature and quenched by the addition of water (10 ml) and ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica-gel, eluted with hexanes:EtOAc, 3:1) to afford the product as a white solid (45 mg, 29%). 1HNMR (300 MHz, CDCl3) δ 7.99 (s, 1H), 7.52 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.05 (s, 3H), 4.01 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:19][C:20]([C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])=[CH:21][N:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:28]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:28][C:21]1[N:22]=[C:18]([CH:7]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:19][C:20]=1[C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2ncc(C(=O)C3CC3)[nH]2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2nc(Br)c(C(=O)C3CC3)[nH]2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
To a solution (5 mL) of (2-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-1H-imidazol-5-yl)(cyclopropyl)methanone (0.038 g) in N,N-dimethylformamide was added N-bromosuccinimide (0.024 g) and the mixture was stirred at 50° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50, volume ratio) and recrystallized from diisopropyl ether-hexane to give the title compound (0.026 g, yield 56%) as colorless crystals. melting point 160-161° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:24]([CH3:23])(=[O:26])=[O:25])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CS(=O)(=O)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(C)(=O)=O

Procedure:
Using the general method of Example 242, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with methanesulfonyl chloride to provide 800 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide as light yellow needles, m.p. 193-194° C. Analysis: Calculated for C17H23N5O3S: %C, 54.09; %H, 6.14; %N, 18.55; Found: %C, 54.09; %H, 5.93; %N, 18.49.
Reaction SMILES: O=[CH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[O:12])[CH2:6][CH2:5]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][C:36]=1[Cl:37])[O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][C:36]=1[Cl:37])[O:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[O:12])[CH2:6][CH2:5]2)[CH2:30][CH2:29]1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Reactant: O=CC[C@H]1CC[C@H](NC(=O)c2ccnc3ccccc23)CC1
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound was prepared analogously to example 71 using quinoline-4-carboxylic acid trans-[4-(2-oxo-ethyl)-cyclohexyl]-amide and 4-(3,4-dichloro-phenoxy)-piperidine as starting materials.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][C:10]1=[O:16]>C(O)C.O>[C:1]1([NH:7][NH:8][C:12]2[CH2:13][CH2:14][NH:9][C:10](=[O:16])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCNC(=O)C1
Reactant: NNc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C1C=C(NNc2ccccc2)CCN1

Procedure:
Phenylhydrazine (17.4 ml) was added over 15 min to a stirred suspension of 2,4-piperidinedione (20 g) in ethanol (200 ml) at ca. 20°. The resulting suspension was diluted with ethanol (80 ml) and water (300 ml) and the solid was filtered off to give the title compound (23.31 g), m.p. 165°-168°.