Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1([NH:10][C:11]([C:13]2[N:17]3[C@@:18]([CH2:31][C:32]4[CH:37]=[CH:36][C:35](I)=[CH:34][CH:33]=4)([CH3:30])[C:19](=[O:29])[N:20]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=4)[C:16]3=[N:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].[NH:39]1[CH:43]=[N:42][CH:41]=[N:40]1.CN[C@@H]1CCCC[C@H]1NC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH2:1]([O:4][C:5]([C:7]1([NH:10][C:11]([C:13]2[N:17]3[C@:18]([CH3:30])([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([N:39]5[CH:43]=[N:42][CH:41]=[N:40]5)=[CH:34][CH:33]=4)[C:19](=[O:29])[N:20]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=4)[C:16]3=[N:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(I)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Reactant: c1nc[nH]n1
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(-n4cncn4)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
An 8-mL vial was charged with 1-{[(R)-7-(3,5-dichloro-phenyl)-5-(4-iodo-benzyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester (251 mg, 0.377 mmol), 1,2,4-triazole (39 mg, 0.57 mmol), and (1R,2R)—N,N′-dimethyl-cyclohexane-1,2-diamine (16 mg, 0.11 mmol), K3PO4 (160 mg, 0.76 mmol), and 0.5 mL of DMF. The vial was purged with N2 and sealed with a screw cap. The green reaction mixture was heated at reflux for 20 h. The reaction mixture was cooled to room temperature, diluted with 3 mL of EtOAc, and filtered through a small plug of Celite, washing with 20 mL of ethyl acetate. The filtrates were washed with 3×10 mL of water and 10 mL of brine, dried over Na2SO4, filtered, and concentrated. The crude was purified by flash chromatography on silica gel (20 g, 0-3% MeOH/CH2Cl2) to provide 109 mg (48%) of 1-{[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-1,2,4-triazol-1-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester as a pale orange foam.
Reaction SMILES: [N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:16][N:15]([CH2:17][CH2:18][C@@H:19]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH2:20][N:21]([CH3:35])[C:22](=[O:34])[C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Br:33])[CH:24]=4)[CH2:14]3)[CH2:9][CH2:8]2)=[O:6])CCC1.N1CC(N2CCC(C(N)=O)CC2)C1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[Br:33][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=1)[C:22]([N:21]([CH3:35])[CH2:20][C@H:19]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH2:18][CH2:17][N:15]1[CH2:14][CH:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:5]([NH2:1])=[O:6])[CH2:8][CH2:9]2)[CH2:16]1)=[O:34]
Reactant: CN(C[C@@H](CCN1CC(N2CCC(C(=O)N3CCC3)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: NC(=O)C1CCN(C2CNC2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CN(C[C@@H](CCN1CC(N2CCC(C(N)=O)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.5 %

Procedure:
3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see method 1; 1.00 g, 2.24 mmol) and 1-azetidin-3-ylpiperidine-4-carboxamide (see method 4; 0.49 g, 2.69 mmol) and triethylamine (1.24 mL, 9.0 mmol) were dissolved in methylene chloride (30 mL) together with methanol (5 mL). To the resultant solution was added sodium cyanoborohydride (0.21 g, 3.36 mmol) and the mixture was stirred at RT for 20 min. The solvent was removed by evaporation and the residue was partitioned between methylene chloride and saturated aqueous NaHCO3. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (ammonia saturated methanol/methylene chloride, 1-20% methanol). There was obtained 0.24 g (17%) of the title compound. 1H NMR (500 MHz, CDCl3): δ 1.4-3.8 (cm, 23H), 5.7 (b, 1H), 5.8 (b, 1H), 6.8-7.4 (cm, 6H), 7.7 (s, 1H); LCMS: m/z 614 (M+1)+.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=[O:8])=[O:4].[OH:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH:18]([N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])[C:17]1=[O:34].C(NCC)C>C(Cl)Cl>[CH2:15]([N:16]([CH2:17][CH3:18])[CH2:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=[O:8])=[O:4])[CH3:14].[OH:13][CH2:14][CH2:15][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH:18]([N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])[C:17]1=[O:34]
Reactant: CC(C)[C@H](NC(=O)CBr)C(=O)O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)CC(=O)N[C@H](C(=O)O)C(C)C

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-(2-bromoacetamido)-3-methylbutanoate (120 mg) was dissolved in DCM (8 mL). The mixture was stirred and diethylamine solution was added slowly dropwise (0.04 mL). The reaction mixture was stirred additionally for 2 hrs at room temperature. The solvent and the residual diethylamine were removed by rotary evaporation in vacuo. 101 mg of white solid were obtained after purification of the crude product by silica gel column chromatography (eluted with acetic ether:petroleum ether=3:1). 1H NMR (CDCl3, ppm) δ 7.94 (d, 1H, J=8.4 Hz), 7.87-7.91 (m, 2H), 7.76-7.79 (m, 2H), 4.97-5.08 (m, 1H), 4.38-4.43 (m, 1H), 4.05-4.30 (m, 3H), 3.25 (dd, 1H, J=4.8, 13.2 Hz), 3.05 (s, 2H), 2.95-3.05 (m, 1H), 2.80-2.95 (m, 2H), 2.45-2.58 (m, 4H), 2.10-2.20 (m, 1H), 1.90-2.10 (m, 2H), 1.00-1.20 (m, 7H), 0.95-0.98 (m, 3H), 0.87-0.91 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:12]2[C:15]3[C:4]=1[CH2:5][CH2:6][CH:7]([CH2:16][NH:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])[C:8]=3[CH:9]=[CH:10][CH:11]=2.[H-].[Na+].S(OC)(O[CH3:29])(=O)=O>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:12]2[C:15]3[C:4]=1[CH2:5][CH2:6][CH:7]([CH2:16][N:17]([CH3:29])[C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])[C:8]=3[CH:9]=[CH:10][CH:11]=2
Reactant: COc1ccc2cccc3c2c1CCC3CNC(=O)C1CC1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2cccc3c2c1CCC3CN(C)C(=O)C1CC1

Procedure:
The compound obtained in Example 3 is reacted in the presence of NaH (1.5 eq) and dimethyl sulphate (1.2 eq). The reaction is monitored using TLC. When all the starting material has disappeared, the reaction mixture is hydrolysed and then extracted. After evaporating off the solvents, the title product is isolated by flash chromatography.
Reaction SMILES: C[Cl:2].CF.C(F)F.[CH:8]([Cl:11])(F)F.[F:12][C:13]([F:20])([F:19])[C:14]([F:18])=[C:15]([F:17])[F:16].FF>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH:8]([C:15]([CH:14]([C:13]([F:20])([F:19])[F:12])[F:18])([F:17])[F:16])([Cl:11])[Cl:2]
Reactant: FC(F)Cl
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CCl
Agent: CF
Agent: FCF
Agent: FF
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: FC(C(F)(F)F)C(F)(F)C(Cl)Cl
Yield: 85 %

Procedure:
Typical compounds conforming to the above general formula are CH3Cl, CH2Cl2, CHCl3, CCl4, CH3F, CH2F2, CHF2Cl, and the like. Addition of such compounds to hexafluoropropene thermally is described in J. Fluorine Chemistry 1982, 21, 253-259. For example, CH2Cl2 addition to CF3CF═CF2 at 280° C. is reported to give 85% yield of CHCl2CF2CHFCF3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([NH2:36])[CH:34]=3)[NH:29][N:28]=2)=[CH:23][CH:22]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([NH:36][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:34]=3)[NH:29][N:28]=2)=[CH:25][CH:26]=1
Reactant: CC1=C(C(=O)O)C(c2cc(F)cc(F)c2)NC(=O)N1
Reactant: Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)C(c2cc(F)cc(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,5-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, 3-(4-Fluoro-phenyl)-1H-indazole-5-ylamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=478 [M+H]+.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:44][CH2:43][C:29]2([O:34][CH:33]([C:35](O)=[O:36])[CH2:32][N:31]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:30]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.[NH2:46][CH2:47][C:48](=[O:50])[CH3:49].CCN(CC)CC>CC1CCCO1>[CH2:47]([NH:46][C:35]([CH:33]1[O:34][C:29]2([CH2:43][CH2:44][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][CH2:28]2)[CH2:30][N:31]([CH2:38][C:39]([F:41])([F:40])[F:42])[CH2:32]1)=[O:36])[C:48]([CH3:49])=[O:50]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)(F)F)CC(C(=O)O)O2
Reactant: CC(=O)CN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: CC(=O)CNC(=O)C1CN(CC(F)(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 45 °C
Yield: 49.4 %

Procedure:
T3P (591 mg, 553 μL of 50% w/w, 0.93 mmol) was added to a mixture of 9-(tert-butoxycarbonyl)-4-(2,2,2-trifluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (142 mg, 0.37 mmol), 1-aminopropan-2-one hydrochloride salt (41 mg, 0.37 mmol) and Et3N (188 mg, 259 μL, 1.86 mmol) in 2-methyltetrahydrofuran (706 μL). The reaction mixture was then heated at 45° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc/saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to a dark foam. The crude product was purified by silica gel column chromatography using 0-50% EtOAC in DCM as eluent to afford tert-butyl 10-(acetonylcarbamoyl)-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (80 mg, 49%) as a yellow solid. ESI-MS m/z calc. 437.5. Found 438.7 (M+1)+; Retention time: 1.01 minutes (3 min run).
Reaction SMILES: C(CC([C:10]1[CH:11]=[N:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1)CC(O)=O)(O)=O.F[C:19](F)(F)[C:20]([O:22][C:23](=[O:28])[C:24](F)(F)F)=[O:21].[CH3:31]CCCCCC>C1COCC1>[CH3:17][O:16][C:13]1[N:14]=[CH:15][C:10]([CH:24]2[C:23](=[O:28])[O:22][C:20](=[O:21])[CH2:19][CH2:31]2)=[CH:11][N:12]=1
Reactant: CCCCCCC
Reactant: COc1ncc(C(CC(=O)O)CC(=O)O)cn1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ncc(C2CCC(=O)OC2=O)cn1
Temperature: 25 °C
Yield: 94 %

Procedure:
4-Carboxy-3-(2-methoxypyrimidin-5-yl)butanoic acid (11.5 kg) was treated with trifluoroacetic anhydride (12.1 kg) in THF (58 L) at 50-55° C. for several hours. Slow addition of heptane (195 L) followed by cooling to ambient temperature resulted in the crystallization of the title compound; 94% yield.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[I:22][C:23]1[N:28]=[C:27](I)[CH:26]=[CH:25][N:24]=1>>[I:22][C:23]1[N:28]=[C:27]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Ic1ccnc(I)n1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(I)n3)cnc2n1
Yield: 74.3 %

Procedure:
3-Bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (5.0 g, 13.5 mmol) and 2,4-diiodopyrimidine (prepared according to Leprete et al. in Tetrahedron, 2000, 56, 265-273) (5.6 g, 16.9 mmol) were reacted together as described in Example 39, Step 1. Purification by column chromatography on silica using 2.5% MeOH/CH2Cl2 gave 3-(2-iodopyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (4.97 g, 74%): 1H NMR (400 MHz, CDCl3) δ 9.95 (1H, d, J 7.3), 8.47 (1H, s), 8.35 (1H, d, J 5.4), 7.66 (1H, d, J 7.3), 7.59 (1H, d, J 5.4), 1.66 (6H, s), 1.00 (9H, t, J 8.0), 0.67 (6H, q, J 8.0).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1.Cl.[CH3:23][NH:24][O:25][CH3:26]>ClCCl>[CH3:26][O:25][N:24]([CH3:23])[C:19]([CH:16]1[CH2:15][CH2:14][O:13][CH2:18][CH2:17]1)=[O:21]
Reactant: O=C(O)C1CCOCC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCOCC1
Reaction time: 2 h
Yield: 114.5 %

Procedure:
Add 1,1′-carbonyldiimidazole (333.41 g, 1.2 eq) to a solution of tetrahydro-2H-pyran-4-carboxylic acid (223 g, 1.71 mol) in dichloromethane (2.23 L) portion wise over 15 minutes. Stir for two hours. Add N,O-dimethylhydroxylamine hydrochloride (183.86 g, 1.1 eq) portionwise and stir for three hours. Wash the organics with saturated aqueous ammonium chloride, then with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate and concentrate in vacuo to give N-methoxy-N-methyl-tetrahydropyran-4-carboxamide (339 g, 114%) as crude material and use as such in next reaction. 1H NMR (300 MHz, DMSO-d6) δ 4.02 (m, 2H), 3.71 (s, 3H), 3.46 (m, 2H), 3.19 (s, 3H), 2.91 (m, 1H), 1.86 (m, 2H), 1.65 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].BrC1C=NNC=1.IC(C)C.C(N1C=C([B:33]2[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]2)C=N1)C>CCOC(C)=O.CN(C=O)C>[CH:7]([N:5]1[CH:6]=[C:2]([B:33]2[O:37][C:36]([CH3:39])([CH3:38])[C:35]([CH3:41])([CH3:40])[O:34]2)[CH:3]=[N:4]1)([CH3:9])[CH3:8]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1cc(Br)cn1
Agent: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C

Procedure:
4-bromo-1-isopropyl-1H-pyrazole. A sealable vessel was charged with potassium carbonate (3.76 g, 27.2 mmol), 4-bromo-1H-pyrazole (4.00 g, 27.2 mmol), and 10 mL DMF. To this mixture, 2-iodopropane (3.27 ml, 32.7 mmol) was added and the vessel sealed. The mixture was heated at 80 C for 16 h and allowed to cool to rt. The mixture was diluted with EtOAc, extracted with water, water, sat NaHCO3, and the organic layer dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a EtOAc in CH2Cl2 gradient. The desired compound (as determined by TLC, 12 stain) was collected as a colorless liquid. b) 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The title compound was prepared in the same manner as described for 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:23][C:24]([NH:26][CH3:27])=[S:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([N:23]=[C:24]1[N:26]([CH3:27])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:25]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNC(=S)NCc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Solvent: CCOCC
Product: CN1C(=NCc2ccccc2)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 2.7 g of 1-benzyl-3-methylthiourea were reacted as prescribed in Example 23 and the reaction mixture was introduced into 200 ml of diethyl ether while stirring. The hygroscopic crystals of the 2-benzylimino-4-(4-chloro-3-sulfamoylphenyl)-3-methyl-1,3-thiazolidine-4-ol-hydrobromide were rapidly filtered off, dissolved in 70 ml of water and converted into the end product according to the prescription of Example 28. Colorless solid body: decomposition beginning at 110° C, γC=N 1610 cm-1.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([O:9]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:4][CH2:3]1.[N:29]1[N:30]=[C:31]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[C:41](O)[CH:42]=[C:43]([F:48])[CH:44]=3)[N:39]=2)[N:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=12.C(N=C(N(C)C)N(C)C)(C)(C)C>CC#N.O>[N:29]1[N:30]=[C:31]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[C:41]([O:9][C@H:8]4[C@@H:2]([F:1])[CH2:3][CH2:4][N:5]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:6][CH2:7]4)[CH:42]=[C:43]([F:48])[CH:44]=3)[N:39]=2)[N:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H](Oc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
trans-tert-Butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate (0.526 g, 1.26 mmol) and 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (0.320 g, 1.14 mmol) were slurried in CH3CN (5.5 mL). To this mixture was added 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.276 mL, 1.37 mmol) dropwise. The mixture was warmed to 40° C. and stirred overnight. The mixture was cooled to ambient temperature and diluted with water (10 mL) and stirred for 15 minutes, then filtered, and the solid was washed with water and hexanes and dried. This provided 0.460 g of the title compound (81%) as an off-white solid (>95% pure by HPLC). MS ESI (+) m/z 496.0 (M+1) detected.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:52])[N:33]([C:43]1[CH:44]=[N:45][C:46]([O:49][CH2:50][CH3:51])=[CH:47][CH:48]=1)[C:34]1[CH:39]=[CH:38][C:37]([CH:40]=[O:41])=[C:36]([F:42])[N:35]=1)([CH3:30])([CH3:29])[CH3:28].O>O1CCCC1>[C:27]([O:31][C:32](=[O:52])[N:33]([C:43]1[CH:44]=[N:45][C:46]([O:49][CH2:50][CH3:51])=[CH:47][CH:48]=1)[C:34]1[CH:39]=[CH:38][C:37]([CH:40]([OH:41])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([CH3:11])[CH:9]=3)[N:4]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:3]=2)=[C:36]([F:42])[N:35]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1cnc2c(c1)c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cn1
Temperature: -5 °C
Yield: 83.2 %

Procedure:
To a solution of 3-iodo-5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8, 0.43 g, 1.0 mmol) in 5 mL of tetrahydrofuran at −40° C. under nitrogen, isopropylmagnesium chloride (0.51 mL, 2.00 M in tetrahydrofuran, 1.0 mmol) is added slowly. The reaction is allowed to warm to −5° C. over 60 minutes, then cooled to −45° C., followed by addition of (6-ethoxy-pyridin-3-yl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (69, 0.06 g, 0.2 mmol) in 2.0 mL of tetrahydrofuran. The reaction is allowed to warm to room temperature over 2 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (70, 108.1 mg).
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].[CH:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:4]=[CH:3][C:1](=[CH2:2])[CH3:6].[CH2:1]=[CH:2][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:4]=[CH:3][C:1](=[CH2:2])[CH3:6]
Reactant: [Li]C(C)CC
Reactant: c1ccccc1
Product: C=CC(=C)C
Product: C=Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Styrene-isoprene block copolymers were synthesized by a two-stage process. In the first stage, living poly(styrene) was synthesized to initiation with sec-butyl lithium in benzene at an initiator level calculated to yield a 50,000, Mn, "living" polystyryl anion. The polymerization was carried out at 0° C. for 30 minutes after which time the reaction mixture was held at ambient temperature for 1 hour. The solution of living polymer was then split and isoprene was added to each fraction. In the first instance, an amount of isoprene sufficient to yield an isoprene block segment Mn, about 70,000, was added; in the second a larger amount of isoprene sufficient to yield an isoprene block segment of 100,000 Mn was added. In each instance the polymerization was carried out for about 2 hours at 0° C. followed by 19 hours at ambient temperature.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:15]([C:17]1[N:18]([CH2:31][C:32]#[CH:33])[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH3:16]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[IH:1].[CH2:15]([C:17]1[N:18]([CH2:31][C:32]#[C:33][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:19]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:29])[C:20]=2[N:30]=1)[CH3:16]
Reactant: C#CCn1c(CC)nc2c(N)nc3ccccc3c21
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCc1nc2c(N)nc3ccccc3c2n1CC#Cc1ccccc1
Product: I
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.6 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (62.1 mg, 0.03 eq.), 4-iodobenzene (0.45 g, 1.1 eq.), triethylamine (0.61 g, 3 eq.), and copper (1) iodide (23 mg, 0.06 eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 2.0 mmol, 1.0 eq) in DMF. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to provide crude product which was purified by column chromatography (silica gel eluting with 8/92 methanol/dichloromethane). The residue was purified by recrystallization from 1,2-dichloroethane to provide 60 mg of 2-ethyl-1-(3-phenyl-2-propynyl)-1H-imidazo[4,5-c]quinolin-4-amine hydroiodide as a brown powder, mp 200-212° C. (dec). 1H NMR (300 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.79 (br, 2H), 8.53 (dd, J=0.9, 8.5 Hz, 1H), 7.86 (dd, J=0.9, 8.3 Hz, 1H), 7.74 (ddd, J=1.2, 7.2, 8.4 Hz, 1H), 7.66 (ddd, J=1.2, 7.2, 8.3 Hz, 1H), 7.36 (m, 5H), 5.82 (s, 2H), 3.15 (q, J=7.5 Hz, 2H), 1.43 (t, J=7.5 Hz, 3H); MS (APCI) m/z 327 (M+H)+; Anal. Calcd for C21H18N4.HI: C, 55.52; H, 4.22; N, 12.33. Found: C, 55.80; H, 3.94; N, 12.46.