Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)(=[O:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:7]2[NH:6][C:5]3[CH:21]=[CH:22][C:2]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:23](=[O:25])[CH3:24])=[CH:3][C:4]=3[N:8]=2)=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Reactant: CC(=O)c1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 90 °C
Yield: 87.2 %

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.450 g, 1.21 mmol), 2-acetylphenylboronic acid (0.298 g, 1.82 mmol), sodium carbonate (0.771 g, 7.26 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.079 g, 0.121 mmol) in DME (10 mL) and H2O (2.5 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the product as a yellow oil (0.433 g, 87%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[NH2:21][OH:22].C([O-])(=O)C.[NH4+]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[N:21][OH:22])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2cc(F)ccc2O)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)N1CCC(C(=NO)c2cc(F)ccc2O)CC1
Yield: 65.6 %

Procedure:
A mixture of 12.7 g of 1-acetyl-4-(5-fluoro-2-hydroxybenzoyl)piperidine, 6.6 g of hydroxylamine hydrochloride, 11.0 g of ammonium acetate and 200 ml of ethanol-ether was heated under reflux for 10 hrs. After cooling, most of the ethanol was removed under reduced pressure. The resultant suspension was diluted with water and extracted with dichloromethane. The dichloromethane was evaporated in vacuo to given an oil. The oil was dissolved in ethyl acetate and cyclohexane was added to precipitate a solid. The solid was recrystallized from ethyl acetate to give 8.8 g (65.4%) of product, mp, 181°-183°. The chromatogram showed 2 spots.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1.[C:16](Cl)(=O)[O:17]C(Cl)(Cl)Cl>O1CCOCC1>[F:15][C:3]1[C:2]([N:1]=[C:16]=[O:17])=[CH:14][C:6]2[N:7]([CH2:11][C:12]#[CH:13])[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: C#CCn1c(=O)sc2cc(F)c(N)cc21
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: C#CCn1c(=O)sc2cc(F)c(N=C=O)cc21
Yield: 119.5 %

Procedure:
To a solution consisting of 3.2 g of 5-amino-6-fluoro-3-propargyl-2-benzothiazolone and 50 g of dioxane were dropwise added 2.4 g of trichloromethyl chlorocarbonate at a temperature in the range of from 5° to 15° C. and the resulting mixture was heated under reflux for six hours. A residue was obtained by distilling off the low-boiling material from the mixture under reduced pressure, and it was dissolved in 150 ml of dried toluene and filtered. From the resulting filtrate toluene was distilled off to obtain 3.6 g of 6-fluoro-5-isocyanato-3-propargyl-2-benzothiazolone having a melting point in the range from 134° to 135° C.
Reaction SMILES: [C:1]1([N:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:8]([O:10][C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:24]=3[N:25]=[C:26]([NH:28][C:29](=[S:32])[NH:30][CH3:31])[N:27]=2)[C@@H:16]2[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[CH2:17]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][O:40][C:41]1[CH:62]=[CH:61][C:44]([C:45](Cl)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)=[CH:43][CH:42]=1.O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([C:45]([O:22][CH2:21][C@H:20]2[O:23][C@@H:16]([N:15]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[S:32])[NH:30][CH3:31])[N:27]=[C:11]([O:10][C:8](=[O:9])[N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:12]=4[N:13]=[CH:14]3)[CH2:17][C@@H:18]2[OH:19])([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:44]2[CH:61]=[CH:62][C:41]([O:40][CH3:39])=[CH:42][CH:43]=2)=[CH:51][CH:50]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CNC(=S)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CNC(=S)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](COC(c4ccccc4)(c4ccc(OC)cc4)c4ccc(OC)cc4)O3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
The above-obtained 6-O-diphenylcarbamoyl-2-N-methylthiocarbamoyldeoxyguanosine (400 mg, 0.744 mmol) was azeotroped with anhydrous pyridine three times and dissolved in anhydrous pyridine (8.0 mL), and 4,4′-dimethoxytrityl chloride (278 mg, 0.818 mmol) was added thereto. The mixture was stirred at room temperature for 3 hours, and then sodium bicarbonate water (3 mL) was added thereto to terminate the reaction. The reaction solution was extracted with ethyl acetate (150 mL)/sodium bicarbonate water (120 mL) once and with ethyl acetate (150 mL)/brine (100 mL) twice. Then, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (N60: spherical neutral silica gel) with methanol/3% to 4% chloroform containing 1% triethylamine to give 5′-O-(4,4′-dimethoxytrityl)-6-O-diphenylcarbamoyl-2-N-methylthiocarbamoyldeoxyguanosine (570 mg, 78%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]=[O:12])(=[O:5])=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=2)=[CH:17][CH:16]=1>>[CH3:1][N:2]([CH3:13])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=2)=[CH:17][CH:16]=1)[OH:12])(=[O:4])=[O:5]
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Reactant: CN(C)S(=O)(=O)n1ccnc1C=O
Product: CN(C)S(=O)(=O)n1ccnc1C(O)c1ccc(C2=NC(C)(C)CO2)cc1
Yield: 40.3 %

Procedure:
Similar to Production Example 164, 4.54 g of N,N-dimethyl-2-formylimidazole-1-sulfonamide was treated with 7.0 g of 2-(4-bromophenyl)-4,4-dimethyl-2-oxazoline to thereby give 3.41 g of the title compound.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].CN([CH:12]=[CH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1)=O)C>C(O)C>[NH2:7][C:6]1[N:8]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:5]=1
Reactant: CN(C)C=CC(=O)c1ccc(C(C)(C)C)cc1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2ccnc(N)n2)cc1
Reaction time: 8 h

Procedure:
Sodium metal (10.4 g) was added to absolute ethanol (40 ml). When all the sodium had dissolved, the sodium ethoxide solution so formed was added to a mixture of guanidine carbonate (1.56 g) and (1-(N,N-dimethylamino)-3-(4-(1,1-dimethylethyl) phenyl)prop-1-en-3-one (2.5 g) dissolved in absolute ethanol (40 ml) and the mixture heated under reflux with stirring overnight. The reaction was followed by tlc. On cooling the solid material formed was filtered and washed with water to remove Na2CO3 to give a white crystalline solid, m.p. 186° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:47][CH3:48])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:39][CH:38]2[N:23]([C:24](=[O:46])[C:25]([CH3:45])([CH3:44])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]3[C:35]([C:41]([OH:43])=O)([NH:36][C:37]2=[O:40])[CH2:34]3)[CH2:22]1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:90][S:91]([CH:94]6[CH2:96][CH2:95]6)(=[O:93])=[O:92])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Cl:1][C:2]1[C:3]([O:47][CH3:48])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][CH:21]1[CH2:39][CH:38]2[N:23]([C:24](=[O:46])[C:25]([CH3:45])([CH3:44])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH:32][CH:33]3[C:35]([C:41]([NH:90][S:91]([CH:94]4[CH2:96][CH2:95]4)(=[O:93])=[O:92])=[O:43])([NH:36][C:37]2=[O:40])[CH2:34]3)[CH2:22]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCC(C)(C)C(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCC(C)(C)C(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
The title compound was prepared from 18-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-14,14-dimethyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (54) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=798 (M+H)+. 1H NMR (CDCl3): 0.96 (m, 1H), 1.05-1.15 (m, 2H), 1.17 (s, 3H), 1.32 (s, 3H), 1.23-1.36 (m, 7H), 1.38 (d, J=6.8 Hz, 6H), 1.43-1.53 (m, 2H), 1.75-1.94 (m, 3H), 2.39 (m, 1H), 2.56 (m, 3H), 2.85-2.95 (m, 1H), 3.20 (m, 1H), 4.02 (s, 3H), 4.15 (dd, J=3.7 Hz, J=11.6 Hz, 1H), 4.23 (d, J=11.6 Hz, 1H), 4.73 (t, J=7.5 Hz, 1H), 4.99 (t, J=9.4 Hz, 1H), 5.52 (m, 1H), 5.80 (q, J=8.8 Hz, 1H), 7.08 (s, 1H), 7.17 (m, 2H), 7.54 (s, 1H), 7.84 (d, J=9.2 Hz, 1H), 10.3 (s, 1H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH:14]1([C@H:17]([NH2:39])[C:18]([N:20]2[CH2:24][C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])=[CH:22][C@H:21]2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:19])[CH2:16][CH2:15]1.C(N(CC)CC)C>ClCCl>[CH:14]1([C@H:17]([NH:39][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[C:18]([N:20]2[CH2:24][C:23]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])=[CH:22][C@H:21]2[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:19])[CH2:16][CH2:15]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
A solution of 4-nitrophenyl chloroformate (188 mg, 0.931 mmol, 1.10 equiv) in dichloromethane (5 mL) was added dropewise to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7, 300 mg, 0.847 mmol, 1 equiv) and triethylamine (0.354 mL, 2.54 mmol, 3.00 equiv) in dichloromethane (10 mL) at 0° C. The reaction mixture was warmed to 23° C. and stirred for 20 hours. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (75 mL). The organic layer was washed with brine, then dried over magnesium sulfate and concentrated to provide 4-nitrophenyl(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethylcarbamate (31-1) as a pale yellow solid. LRMS m/z (M+H) 520.5 found, 520.2 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([NH:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=O)=O.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[N:28]([CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[C:17](=[O:19])[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1
Reactant: CN(C)CCN
Reactant: COc1ccc(OC)c(CC(=O)Nc2ccccc2C(=O)O)c1
Solvent: Cc1ccccc1C
Product: COc1ccc(OC)c(Cc2nc3ccccc3c(=O)n2CCN(C)C)c1
Yield: 13.6 %

Procedure:
A mixture of 0.62 g (2 mmol) of N-(2,5-dimethoxyphenylacetyl) anthranilic acid and 0.36 g (3 mmol) of 2-dimethylaminoethylamine in xylene (5 ml) were heated under reflux for 24 hours. After cooling, the resulting reaction mixture was purified by silica gel column chromatography (eluent; chloroform: ethanol=98:2) to obtain 0.10 g (yield 14%) of 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-4(3H) quinazolinone as an oily substance. 0.10 g of the oily substance thus obtained was dissolved in ethanol (1 ml) and then a 7% HCl-ethanol solution (0.2 mol) was added thereto and the resulting reaction mixture was cooled overnight. The resulting colorless precipitates were collected by filtration to obtain 0.1 g of the hydrochloride which is the desired compound. This hydrochloride coincides with the compound obtained in Example 16 in melting point and infrared absorption spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[NH2:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[N:5]=[C:6]([NH:11][NH2:12])[CH:7]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1nc(Cl)cc(NN)n1
Reaction time: 72 h
Yield: 38.2 %

Procedure:
4,6-dichloro-2-methoxy-pyrimidine (1.1 g, 6.2 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran. To the resultant reaction solution hydrazine (0.19 mL, 6.2 mmol) and potassium carbonate (2.6 g, 18 mmol) were added and the reaction mixture was stirred for 3 days. The potassium carbonate was removed by filtration and the filtrate was concentrated in vacuo. Crystallization of the residue from ethyl acetate:hexanes yielded 414 mg (39%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[O:19][CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CC(O)C>CCCCCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]2[O:19][CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1cnco1
Solvent: CC(C)O
Solvent: CCCCCC
Product: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1cnco1
Yield: 47.6 %

Procedure:
Racemic compound 5.4 (1.3 g, 5 mmol) was separated on a semi-preparatory chiral CHIRALCEL OJ-H column (30×250 mm), using 20% i-PrOH in hexane as eluant. Eluant containing the peak with greater retention time was concentrated and compound 5.5 (620 mg, 2.38 mmol) was obtained as off-white solid. The absolute configuration was assigned by analogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 262.1 (M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CN2CCCC2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
Using General Procedure B: To a stirred solution of 4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (150 mg, 0.37 mmol), pyrrolidine (30 μL, 0.36 mmol) and AcOH (20 μL, 0.37 mmol) in THF (4 mL) was added NaBH(OAc)3 (235 mg, 1.11 mmol) and the mixture was stirred at room temperature for 1.5 hours. Purification of the crude white foam (205 mg) by column chromatography on silica gel (100:1:1—CH2Cl2:MeOH:NH4OH) afforded the desired product (160 mg, 96%) as a white foam.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6].O>C(O)(=O)C>[C:5]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[C:19]([N+:1]([O-:4])=[O:2])[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCC2(CC1)Cc1ccccc1O2
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCC2(CC1)Cc1cc([N+](=O)[O-])ccc1O2
Temperature: 100 °C

Procedure:
3.8 g of nitric acid (sp gr 1.42) in 30 ml of glacial acetic acid are added dropwise to a stirred solution of 4.7 g of 2,3-dihydro-1'-acetylspiro[benzofuran-2,4'-piperidine], Example 16, in 65 ml of glacial acetic acid. After total addition, the reaction mixture is slowly heated to 100° C. over a 2 hour span and then cooled and poured into 500 ml of water. The diluted mixture is extracted with chloroform and the chloroform extracts are washed sequentially with a saturated sodium bicarbonate solution, a saturated sodium chloride solution and then dried. The chloroform is removed under reduced pressure. The residue is triturated with ether, causing an orange precipitate which is collected and recrystallized first from an ethyl alcohol-ether mixture and then from ethyl alcohol to provide the product, 2,3-dihydro-1'-acetyl-5-nitrospiro[benzofuran-2,4'-piperidine], mp 149°-150° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:13]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]1[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][S:26]([CH2:25][CH2:24][N:15]2[C:14](=[O:13])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:23])(=[O:27])=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Product: CC(C)(C)OC(=O)N1CC(NS(=O)(=O)CCN2C(=O)c3ccccc3C2=O)C1

Procedure:
3-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonylamino]-azetidine-1-carboxylic acid tert-butyl ester was prepared by an analogous procedure as described for example 1 i) starting from 189 mg (1.1 mmol) 3-amino-azetidine-1-carboxylic acid tert-butyl ester and 300 mg (1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride. The product was obtained in crude form as light yellow foam. Yield: 480 mg MS (ES+): m/e=410.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.[O:20]=[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=2)[O:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Si:13]([O:12][C@@H:10]([C@@H:6]1[C@@H:5]([C@H:22]2[C:21](=[O:20])[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=3)[O:24][CH2:23]2)[NH:8][C:7]1=[O:9])[CH3:11])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCO2
Reactant: CC(=O)O[C@H]1NC(=O)[C@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)C(=O)[C@H]([C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C)CO2

Procedure:
Starting from 960 mg (3.35 mmol) of (3S, 4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one and 1.03 g (5.0 mmol) of methyl 4-oxochroman-6-yl carboxylate, 370 mg (25%) of the less polar diastereomer were obtained after chromatography (eluent: toluene/ethyl acetate=10: 1, 1.11, then 2:1) as described under step 1 in Example 14. -1H-NMR (270 MHz, CDCl3): 6 m 0.08 and 0.10 (2×1s, 2×3H, SiCH3); 0.90 (s, 9H, SiC(CH3)3); 1.28 (d, 3H, CH--CH3); 2.85-2.98 (m, 2H, O--CH2 --CH and H-3); 3.72 (dd, 1H, H-4); 3.92 (s, 3H, CO2CH3); 4.18 (mc, 1H, CH--CH3); 4.32 and 4.65 (2×mc, 2×1H, O--CH2 --CH); 6.26 (bs, 1H, NH); 7.03 (d, 1H, aromatic H); 8.18 (dd, 1H, aromatic H) 8.59 (d, 1H, aromatic H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1[C:12](=[O:17])[NH:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([I:26])C(=O)C1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1[C:12](=[O:17])[NH:13][CH:14]=[C:15]([I:26])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc[nH]c1=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: O=C(Nc1cc(I)c[nH]c1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
(2-Oxo-1,2-dihydro-pyridin-3-yl)-carbamic acid benzyl ester (410 g, 1.68 mol, 1.0 Eq.) was charged to a flask followed by DCM (6.6 L) and NIS (378 g, 1.68 mol, 1.0 Eq.). The reaction was then allowed to stir at ambient temperature overnight. Tlc analysis showed starting material was still present, therefore a further amount of NIS (25 g, 0.11 mmol, 0.07 Eq.) was added and the reaction stirred for a further 3 hours. NMR analysis of the reaction showed 87% conversion, therefore the reaction mixture was filtered and the red solid washed with DCM (2 L) and Et2O (2 L). The solid was then slurried in dilute aqueous sodium thiosulfate solution (2 g in 2 L), filtered, and then slurried twice in water (2×1.5 L). The pale pink solid was dried on the filter and then in vacuo at 50° C. overnight to give the desired product as a pale pink solid (287 g, 775 mmol, 46%)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)O1>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:36]4[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(N)cc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methylsulfonyl-piperazine-1-yl-methyl)-4-morpholin-4-yl-thieno[3,2-d}pyrimidine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in General Procedure A. Purification on silica yielded 4-[6-(4-Methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-aniline. This was then reacted with acetic anhydride in dichloromethane and triethylamine to give the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:15]1[O:16][C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)([CH3:9])[O:10][CH2:14]1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(c2ccc(O)c([N+](=O)[O-])c2)OCCO1

Procedure:
A solution of 4'-hydroxy-3'-nitroacetophenone (known compound, 12.1 g, 67.0 mmol), benzene (100 ml), ethylene glycol (5.61 ml, 100 mmol) and p-toluenesulfonic acid hydrate (catalytic amount) was refluxed overnight removing the resulting water by azeotropic distillation with benzene. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel to give the object compound (1) as an oil. Yield 14.6 g (97%).