Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])O)=[CH:30][CH:29]=1>C(Cl)Cl.C(#N)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:52])([CH3:51])[CH2:35][CH:36]([I:25])[Sn:38]([CH2:47][CH2:48][CH2:49][CH3:50])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:30][CH:29]=1
Reactant: II
Reactant: CCCC[Sn](CCCC)(CCCC)C(O)CC(C)(C)c1ccc(Cl)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: CCCC[Sn](CCCC)(CCCC)C(I)CC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.4 %

Procedure:
A solution of 14.0 grams (0.053 mole) of triphenylphosphine in about 54 mL of methylene chloride was stirred, and 3.6 grams (0.053 mole) of imidazole was added. Upon completion of addition, the reaction mixture was stirred about 45 minutes until the imidazole dissolved. The reaction mixture was then cooled in an ice bath, and 13.6 grams (0.053 mole) iodine was added portionwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature, where it stirred for about 15 minutes until the iodine dissolved. After this time the reaction mixture was cooled to 0° C., and a solution of 17.4 grams (0.036 mole) of 3-(4-chlorophenyl)-3-methyl-1-tributylstannylbutanol in about 36 mL of methylene chloride was added dropwise while maintaining the reaction mixture temperature below 5° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. The reaction mixture was then taken up in about 100 mL of acetonitrile and extracted with three 150 mL portions of hexane. The combined extracts were concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using petroleum ether as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 8.7 grams of 3-(4-chlorophenyl)-3-methyl-1-iodo-1-tributylstannylbutane. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[Na]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Cl)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Yield: 65 %

Procedure:
To a solution of tert-butyl-4-oxopiperidine-1-carboxylate (1.0 g, 0.005 mmol) in tetrahydrofuran (16 mL) in a microwave reaction vessel were added 4-chloroaniline (640 mg, 0.005 mmol) and sodium triacetoxyboryhidride (3.2 g, 0.015 mmol), followed by irradiating the solution with microwaves at 80° C. for 10 min. The reaction was terminated by the addition of distilled water. The resulting reaction mixture was diluted in ethyl acetate (100 mL) and washed with distilled water (200 mL) to separate an organic solvent layer. The organic solvent layer was dried over anhydrous magnesium sulfate and evaporated at reduced pressure. Isolation and purification of the residue through silica gel chromatography produced tert-butyl-4-(4-chlorophenylamino)piperidine-1-carboxylate (yield: 65%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21]>>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:27][CH:26]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Product: O=C(CCCN1CCC(N2CCc3ccccc32)CC1)c1ccc(F)cc1
Yield: 27.6 %

Procedure:
1-(Piperidin-4-yl)indoline (1.0 g) and 4-chloro-1-(4-fluorophenyl)-1-butanone (1.1 g) were treated as in Example 2 to give the title compound (0.5 g) (yield: 27%).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3[C:12]([CH3:29])=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35]>>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:2]1[CH:9]=[C:8]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3[C:12]([CH3:29])=[CH:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: NCCCCO
Product: Cc1cn(-c2ccc(C#N)c(NCCCCO)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 35 %

Procedure:
According to Example 1(6), a crude product of 2-(4-hydroxybutylamino)-4-{3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile was prepared using compound (40f) instead of compound (1e) and using 4-amino-1-butanol instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (55) (the second stage yield: 35%) was prepared as a white solid using 2-(4-hydroxybutylamino)-4-{(3-methyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [I:1]Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:11][C:6]=2[CH2:5][CH2:4]1.C(#N)C>C(Cl)Cl>[I:1][C:8]1[C:7]2[O:3][CH2:4][CH2:5][C:6]=2[CH:11]=[C:10]([S:12]([Cl:15])(=[O:13])=[O:14])[CH:9]=1
Reactant: ClI
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Solvent: ClCCl
Solvent: CC#N
Product: O=S(=O)(Cl)c1cc(I)c2c(c1)CCO2
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A solution of ICl (7.7 g, 47 mmol) in DCM (100 mL) was added dropwise to a solution of 2,3-dihydro-benzofuran-5-sulfonyl chloride (5 g, 23 mmol; Intermediate 54) in DCM (100 mL) at reflux temperature under nitrogen atmosphere. The reaction was heated at reflux overnight. The reaction mixture was cooled at room temperature and acetonitrile (50 mL) was added. The resultant mixture was washed with a saturated solution of NaHCO3 and the organic phase was separated followed by elimination of the volatiles under vacuum to give 8 g of brown oil which was used to the next step without further purification. 1H NMR 270 MHz (CDCl3) δ ppm 3.45 (t, J=8.91 Hz, 2H) 4.82 (t, J=8.91 Hz, 2H) 7.79 (d, J=1.48 Hz, 1H) 8.16 (d, J=1.98 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:26])[CH:21](OCC)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1([CH2:31][CH2:32][N:33]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[C:36]([CH3:44])([CH3:43])[O:35][C:34]2=[O:45])[CH2:30][CH2:29]1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:26])[CH2:21][NH:27][C:28]2([CH2:31][CH2:32][N:33]3[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[C:36]([CH3:43])([CH3:44])[O:35][C:34]3=[O:45])[CH2:30][CH2:29]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)N(CCC2(N)CC2)c2ccccc21
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c2c1OCC(=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)OC(=O)N(CCC2(NCC(O)c3ccc(OCc4ccccc4)c4c3OCC(=O)N4)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
900 mg (2.5 mmol) of 5-benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 700 mg (2.7 mmol) of 1-[2-(1-aminocyclopropyl)ethyl]-4,4-dimethyl-1,4-dihydrobenzo [d][1,3]oxazin-2-one is dissolved in 20 mL of ethanol and stirred in each case for 30 minutes at 80° C. and 50° C. The reaction mixture is cooled, combined with 200 mg (5.3 mmol) sodium borohydride, and stirred for 2 hours at ambient temperature. Glacial acetic acid is added, the mixture is stirred for 10 minutes, and evaporated down. The residue is taken up in dichloromethane and washed successively with potassium hydrogen sulfate solution, 15% potassium carbonate solution, and sodium hydrogen carbonate solution. Then the organic phase is dried with sodium sulfate and freed from solvent. The residue is purified by column chromatography (silica gel; ethyl acetate/methanol/ammonia gradient). Recrystallization from diisopropylether. White solid. Yield: 690 mg (49%); mass spectroscopy: [M+H]+=558.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:27]([CH3:28])=[CH:26][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]4[CH:24]=[N:23][N:22]([CH3:25])[C:19]4=[N:20][CH:21]=3)[S:15][C:11]=2[C:10]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[OH2:36].C(#N)C>C(#N)C>[C:1]([O:5][C@@H:6]([C:9]1[C:27]([CH3:28])=[CH:26][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]4[CH:24]=[N:23][N:22]([CH3:25])[C:19]4=[N:20][CH:21]=3)[S:15][C:11]=2[C:10]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([OH:36])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(-c3cnc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: O
Solvent: CC#N
Product: Cc1cc2nc(-c3cnc4c(cnn4C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzo[d]thiazol-6-yl)ethanol from previous reaction (assume 0.024 mmol) in 25% water/acetonitrile (0.70 mL) was added sequentially, a stock solution of CrO3/H5IO6 (296 μL, 0.439 M solution) and CrO3 (3 mg, 0.030 mmol) at room temperature. The reaction was stirred for 1 h, diluted with acetonitrile, filtered and purified by reverse phase HPLC. Fractions containing product were pooled and evaporated to the desired product. LCMS-ESI+: calc'd for C27H26ClN4O3S: 521.1 (M+H+); 521.2 (M+H+); 1H NMR (400 MHz, CD3OD): δ 9.26 (d, J=1.9 Hz, 1H), 8.79 (d, J=1.9 Hz, 1H), 8.20 (s, 1H), 7.87 (s, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.61-7.59 (m, 3H), 5.26 (s, 1H), 4.15 (s, 3H), 2.61 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([CH2:9][Br:17])=[CH:7][CH:6]=[CH:5][C:4]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C)cccc1Oc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COc1c(CBr)cccc1Oc1ccccc1
Yield: 103.5 %

Procedure:
A mixture of phenyl 2-methoxy-3-methylphenyl ether (6 g), N-bromosuccinimide (5.2 g) and azobisisobutyronitrile (500 mg) in dried benzene (60 ml) was treated in a similar manner to that of Example 14-(3) to give oily phenyl 2-methoxy-3-bromomethylphenyl ether (8.5 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:41])=[C:11]([N:18]3[CH2:22][CH2:21][CH:20]([C:23]4([N:26]([CH:28]5[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]5)[CH3:27])[CH2:25][CH2:24]4)[CH2:19]3)[C:12]([F:17])=[CH:13]2)=[C:8]([CH:42]2[CH2:44][CH2:43]2)[CH:7]=1)=[O:5])C.[Li+].[OH-]>C(O)C.O>[C:37]([O:36][C:34]([N:31]1[CH2:30][CH2:29][CH:28]([N:26]([CH3:27])[C:23]2([CH:20]3[CH2:21][CH2:22][N:18]([C:11]4[C:12]([F:17])=[CH:13][N:14]5[C:9]([C:10]=4[CH3:41])=[C:8]([CH:42]4[CH2:43][CH2:44]4)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]5=[O:16])[CH2:19]3)[CH2:25][CH2:24]2)[CH2:33][CH2:32]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(N3CCC(C4(N(C)C5CCN(C(=O)OC(C)(C)C)CC5)CC4)C3)c(F)cn2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(N2CCC(C3(N(C)C4CCN(C(=O)OC(C)(C)C)CC4)CC3)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 60 °C
Yield: 100.1 %

Procedure:
To a solution of 8-(3-{1-[(1-tert-butoxycarbonyl-piperidin-4-yl)-methyl-amino]-cyclopropyl}-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (15 g, 24 mmol) in ethanol (200 mL) was added the solution of LiOH (10 g, 238 mmol) in water (100 mL) in a round bottom flask. The solution was heated at 60° C. for one hour. The resulting solution was partitioned between dichloromethane (400 mL) and saturated aqueous NH4Cl (200 mL) and well shaken. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to yield a yellow solid (14 g). This was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][CH:17]=1.[Al+3].[Cl-].[Cl-].[Cl-]>O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:17]2[CH:16]=[CH:15][C:14]([O:18][CH3:19])=[CH:13][C:12]=2[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COc1ccc(C(=O)c2ccc(Br)cc2)c(C)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
To a mixture of 4-bromobenzoyl chloride (1.12 g, 5.12 mmol) and 3-methyl anisole (1.95 mL, 15.47 mmol) at 0° C. was added AlCl3 (0.83 g, 6.20 mmol). The mixture was allowed to warm to RT over 12 h with stirring. Water was added slowly, and the mixture was extracted with CH2Cl2. The organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography on silica gel (EtOAc:hexanes) to yield 1.14 g (73%) of compound 27. 1H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H), 3.86 (s, 3H), 6.74 (dd, J=2.5 Hz, 8.6 Hz, 1H), 6.82 (d, J=2.6 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[N:23][N:24]([C:26]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=2[CH:28]=O)[CH:25]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:28]1[C:27]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:26]=1[N:24]1[CH:25]=[C:21]([Cl:20])[CH:22]=[N:23]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: COc1ccc(-n2cc(Cl)cn2)c(C=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-n2cc(Cl)cn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Yield: 27.1 %

Procedure:
A solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (180 mg, 0.70 mmol) and 2-(4-chloro-pyrazol-1-yl)-5-methoxy-benzaldehyde (270 mg, 1.14 mmol) in acetic acid (5 mL) is warmed to 100° C. for 16 hours, then cooled to room temperature and neutralized with NaHCO3 (sat.). The product is extracted into EtOAc (3×) and the combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-5% MeOH/CH2Cl2) follows by reverse phase HPLC (20-100% CH3CN/H2O, each solvent containing 0.1% TFA) affords the title compound (90 mg, 27%). LCMS (ESMS): m/z 474.20 (M++1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:19][C:20](=O)[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=[O:23])C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[NH:15][C:20](=[O:19])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1ccc(I)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 88 %

Procedure:
Prepared from (2-amino-4-iodo-phenyl)-carbamic acid tert.-butyl ester (Example G1) (900 mg, 2.7 mmol) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester (880 mg, 4.1 mmol) according to the general procedure K. Obtained as a yellow solid (1.2 g).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: O=C=Nc1ccccc1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN
Product: CCCc1nc2cnc3ccccc3c2n1CCCCNC(=O)Nc1ccccc1
Yield: 18.7 %

Procedure:
Using the general method of Example 146 Part B, 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-amine (2.50 g, 8.9 mmol) was reacted with phenyl isocyanate (1.78 mL, 16.4 mmol) to provide 0.67 g of N-[4(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-phenylurea as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[N:11][C:10]=2[CH3:18])=[CH:5][CH:4]=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>ClCCl>[C:15]([NH:14][C:12]1[S:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([S:20]([Cl:19])(=[O:22])=[O:21])[CH:7]=2)=[C:10]([CH3:18])[N:11]=1)(=[O:17])[CH3:16]
Reactant: COc1ccc(-c2sc(NC(C)=O)nc2C)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(-c2sc(NC(C)=O)nc2C)cc1S(=O)(=O)Cl
Reaction time: 2 h

Procedure:
To N-[5-(4-Methoxy-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 28a) (0.0947 g, 0.361 mmol) is added at 0° C. chlorosulfonic acid (3 ml) followed by dichloromethane (1 ml). The reaction mixture is stirred below 0° C. for 2 hours then poured into crushed ice and extracted with dichloromethane (3×5 ml). The organic layers are combined and dried over MgSO4. The solvent is removed to give 5-(2-acetylamino-4-methyl-thiazol-5-yl)-2-methoxy-benzenesulfonyl chloride, which is dissolved into dioxane (2 ml). To this solution is added N,N-dimethyl-ethylenediamine (0.0636 g, 0.72 mmol) and 2M Na2CO3 (0.5 ml). The reaction mixture is stirred at room temperature for 2 hours. The mixture is concentrated and the residue is taken into water (2 ml) and extracted with dichloromethane (3×5 ml). The combined organic layers are dried over MgSO4. After filtration the solvent is removed in vacuo to give the titled compound which is dried overnight in vacuum oven at 25° C. MH+ (ESMS): Mp 413.0° C.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([O-:12])=[CH:8][CH:7]=1.[CH2:18]([O:20][C:21](=[O:33])[CH:22]([C:28](=[O:32])[CH:29](Cl)[CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:19]>CS(C)=O>[CH2:26]([O:25][C:23](=[O:24])[CH:22]([C:28](=[O:32])[CH:29]([O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:3]=2[Cl:2])=[CH:11][CH:10]=1)[CH3:30])[C:21]([O:20][CH2:18][CH3:19])=[O:33])[CH3:27]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Cl
Reactant: [O-]c1ccc(Oc2ccc(Cl)cc2Cl)cc1
Agent: [Na]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 63.9 %

Procedure:
27.7 g of sodium-4-(2',4'-dichloro-phenoxy)-phenolate and 25.1 g of diethyl-2-chloro-propionyl-malonate are dissolved in 150 ml of dimethyl sulfoxide and the reaction mixture is stirred at 60° C. for 48 hours under stirring. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in 100 ml of benzene and washed successively with 100 ml of a saturated aqueous sodium hydrogen carbonate solution and water. The benzene solution is evaporated. Thus 30 g of the desired compound are obtained, yield 61%.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[C:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([Cl:27])[CH:19]=1)([OH:17])=[O:16]>>[Cl:27][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[C:3]1[C:2]([F:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[CH:4]=1)[C:15]([OH:17])=[O:16]
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Reactant: COc1ccc2cc(I)c(F)cc2c1
Product: COc1ccc2cc(-c3ccc(C(=O)O)cc3Cl)c(F)cc2c1
Temperature: 90 °C
Yield: 70 %

Procedure:
Followed the coupling procedure described in Step 1 of Example 20, where the starting materials were 3-fluoro-2-iodo-6-methoxynaphthalene (Intermediate 6) and 4-carboxy-2-chlorophenylboronic acid and wherein the reaction was heated to 90° C. for 3 hours. The desired product (380 mg, yield 70%) was isolated as a solid after workup.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[Cl:11][C:12]1[C:13]([OH:19])=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1>N1C=CC=CC=1>[Cl:11][C:12]1[C:13]([O:19][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Oc1cc(=O)[nH]cc1Cl)c1cccnc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 51 %

Procedure:
A 2.93 g quantity of nicotinoyl chloride hydrochloride was added to a suspension of 2.00 g of 5-chloro-4-hydroxy-2-pyridone in 100 ml of pyridine, and the mixture was stirred at room temperature for 9 hours. The reaction mixture was concentrated and the concentrate was washed with ethyl acetate and water, thereby producing 1.77 g of the title compound in a yield of 51%.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>O1CCOCC1>[CH2:13]([O:12][C:10]([NH:1][C@@H:2]([CH2:3][CH2:4][OH:5])[C:6]([OH:8])=[O:7])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H](CCO)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1COCCO1
Product: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of H-Hse-OH (3 g) in dioxane/2M NaOH (100 mL/25 mL) was added benzyl chloroformate (4 mL) dropwise over 15 min. The reaction mixture was allowed to warm to RT and was stirred overnight at RT. The solvent was evaporated off and the aq. residue was extracted with Et2O and acidified with a 2M HCl solution. The aq. phase was extracted with DCM. The DCM layers were combined, dried (Na2SO4) and evaporated off to give the desired product as a white powder (4.13 g).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1>C(O)C>[CH:8](=[C:5]1[S:1][C:2](=[O:7])[NH:3][C:4]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2ccccc2)S1
Yield: 90.2 %

Procedure:
To a solution of 20 g (171 mmol) of 2,4-thiazolidinedione and 17.4 ml (171 mmol) of benzaldehyde in 350 ml of ethanol, 1.68 ml (17.1 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 31.67 g of the desired compound (90.4% yield, pale yellow crystals).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([C:18]([O:20][CH3:21])=[O:19])[CH2:9]1)C1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][C:27]([Cl:30])([Cl:29])[Cl:28])=[O:24]>CC#N>[Cl:28][C:27]([Cl:30])([Cl:29])[CH2:26][O:25][C:23]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([C:18]([O:20][CH3:21])=[O:19])[CH2:9]1)=[O:24]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1c1ccsc1
Solvent: CC#N
Product: COC(=O)C1CN(C(=O)OCC(Cl)(Cl)Cl)CC1c1ccsc1
Yield: 84.2 %

Procedure:
A solution of 1.02 g (3.38 mmol) of 1-benzyl-3-(SR)-carbomethoxy-4-(RS)-(3-thienyl)pyrrolidine (Example 1) and 0.51 mL (3.72 mmol) of 2,2,2-trichloroethyl chloroformate in 15 mL of CH3CN was stirred at rt for 1.5 h. The reaction mixture was concentrated and the residue was purified by chomatography (silica, hexanes, ethyl acetate, 6:1) to give 1.1 g of the title compound. 1H NMR (CDCl3) δ3.21 (m, 1H), 3.58 (m, 1H), 3.716, 3.723 (s, 3H), 4.81 (m, 2H), 7.00 (m, 1H), 7.12 (s, 1H), 7.33 (m, 1H);