Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH:5]([CH3:21])[N:6]3[CH3:20].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(#N)C>[F:12][C:11]1[C:2]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:3]2[C:8]3=[C:9]([C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[N:6]([CH3:20])[CH:5]([CH3:21])[CH2:4]2)[CH:10]=1
Reactant: CC1Cc2c(F)c(F)cc3c(=O)c(C(=O)O)cn(c23)N1C
Reactant: C1CCNC1
Solvent: CC#N
Product: CC1Cc2c(N3CCCC3)c(F)cc3c(=O)c(C(=O)O)cn(c23)N1C
Yield: 59.6 %

Procedure:
100 mg (0.34 mmol) of the compound (157) obtained in Example 35 and 88 mg (1.24 mmol) of pyrrolidine were added to 1 ml of acetonitrile, and the solution was heated at reflux for 3 hours. Then, the solvent was removed by distillation, and the residue was extracted with 20 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was solidified with ether and the solids were filtered off to obtain 70 mg of the subject compound (160) in a 60% yield.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[N:15]1[C:24]2[C:19](=[C:20]([N:25]3[C:29]([NH2:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[N:26]3)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:30][C:29]2[N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:19]=3[CH:18]=[CH:17][CH:16]=[N:15]4)[N:26]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:28]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Nc1cc(C(F)(F)F)nn1-c1cccc2ncccc12
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 47 %

Procedure:
To a mixture of 4-isopropoxybenzenesulfonyl chloride (0.080 g, 0.35 mmol) and 1-(quinolin-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (prepared from Example 21 step a, 0.032 g, 0.11 mmol) in pyridine (0.5 mL) was heated at 80° C. for 4 h with stirring. After cooling to room temperature, the reaction mixture was concentrated in vacuo and the crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.025 g, 0.052 mmol, 47%). 1H NMR (400 MHz, DMSO-d6) δ 8.94 (dd, J=1.6, 4.0 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.82 (t, J=8.4 Hz, 1H), 7.50-7.46 (m, 2H), 7.40 (s, 1H), 7.38 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.64 (s, 1H), 4.63 (pent, J=6.0 Hz, 1H), 1.28 (d, J=6.0 Hz, 6H); MS: (ES) m/z calculated for C22H20F3N4O2S [M+H]+ 477.2. found 477.3.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[C:10]1=[O:30].Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].Cl.Cl.[O:46]=[C:47]1[NH:55][C:50]2=[N:51][CH:52]=[CH:53][CH:54]=[C:49]2[N:48]1[CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[C:10](=[O:30])[C@H:9]([NH:8][C:32]([N:59]2[CH2:60][CH2:61][CH:56]([N:48]3[C:49]4[C:50](=[N:51][CH:52]=[CH:53][CH:54]=4)[NH:55][C:47]3=[O:46])[CH2:57][CH2:58]2)=[O:33])[CH2:15][CH2:14]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(c2ccncc2)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(c2ccncc2)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
Triethylamine (0.018 mL, 0.132 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-pyridin-4-ylazepan-2-one (42 mg, 0.132 mmol) and 4-nitrophenyl chloroformate (27 mg, 0.132 mmol) in tetrahydrofaran (2 mL) at 0° C. After 1 h, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (38 mg, 0.132 mmol) and triethylamine (0.054 mL, 0.396 mmol) were added and the mixture allowed to warm to ambient temperature. After 18 h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/methanol (10% ammonium hydroxide/methanol)] gave the title compound (53 mg). QQThe title compound was converted to the HCl salt with 2M HCl in ether. MS 562.2 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.76 (d, J=7.6 Hz, 2H), 8.11 (d, J=7.3 Hz, 2H), 8.00 (d, J=6.4 Hz, 2H), 7.30 (t, J=7.0 Hz, 1H), 7.27-7.21 (m, 3H), 5.11 (d, J=11.5 Hz, 1H), 4.72-4.65 (m, 1H), 4.60-4.55 (m, 1H), 4.35-4.33 (m, 2H), 4.14 (d, J=16.1 Hz, 1H), 3.42-3.39 (m, 1H), 3.09-3.02 (m, 2H), 2.47-2.44 (m, 1H), 2.37-2.30 (m, 2H), 2.24-2.18 (m, 2H), 2.06-2.03 (m, 1H), 1.91 (br. s, 2H).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH2:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:35][CH2:31][CH2:32][CH2:33][CH3:34])=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: CCCCN
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: CCCCNC(=O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 149) and 17.1 mg (0.23 mmol) of n-butylamine are reacted together by general method E. 15.2 mg (26.2% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.[Cl:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH:9]([S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]#[N:11]
Reactant: N#CCSc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(Cl)Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
Into a 500 ml four-necked round bottom flask equipped with a stirrer, a thermometer, and a condenser, are placed 300 ml of carbon tetrachloride and 55 g (0.3 mole) of p-chlorophenylthioacetonitrile. To this mixture is added 40 g (0.3 mole) of N-chlorosuccinimide in small portions. The reaction mixture is stirred at room temperature overnight. The white solid which forms is filtered and the filtrate is concentrated under vacuum to give 6.95 g of desired product.
Reaction SMILES: [Cl:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]2[N:6]=[C:7](SC)[O:8][C:4]=2[CH:3]=1.[NH2:16][C:17]1[CH:22]=[C:21]([N+:23]([O-])=O)[C:20](Cl)=[CH:19]C=1O.Cl.[C:29](OCC)(=O)[CH3:30]>>[Cl:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]2[N:6]=[C:7]([N:23]3[CH:21]4[CH2:22][CH2:17][N:16]([CH2:19][CH2:20]4)[CH2:30][CH2:29]3)[O:8][C:4]=2[CH:3]=1
Reactant: CCOC(C)=O
Reactant: CSc1nc2cc([N+](=O)[O-])c(Cl)cc2o1
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1O
Agent: Cl
Product: O=[N+]([O-])c1cc2nc(N3CCN4CCC3CC4)oc2cc1Cl
Yield: 74 %

Procedure:
The title compound was prepared from 6-chloro-2-methylsulfanyl-5-nitro-benzooxazole (prepared from 2-amino-5-chloro-4-nitrophenol by the methods described in Example 5 and Example 7) by the procedure described in Example 9 in 74% yield: 1H NMR (CDCl3, 400 MHz) δ 8.02 (d, 1H, J=2.1 Hz), 7.95 (d, 1H, J=2.1 Hz), 4.56-4.54 (m, 1H), 3.97 (t, 2H, J=5.8 Hz), 3.23-3.12 (m, 4H), 3.08-3.01 (m, 2H), 2.20-2.14 (m, 2H), 1.91-1.83 (m, 2H); MS (Cl) m/z 323.1 (M+1). The hydrochloride salt was prepared by diluting in ethyl acetate and adding a 2.5 N HCl solution in ethyl acetate: mp=242.3° C.
Reaction SMILES: [OH:1]O.[CH2:3]([NH:5]/[C:6](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:7]1\[C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[S:11]\1)[CH3:4]>CO.O.[Cl-].[Ti+3].[Cl-].[Cl-]>[CH2:3]([NH:5]/[C:6](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:7]1\[C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[S:11]\1=[O:1])[CH3:4]
Reactant: CCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Reactant: OO
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CCN/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1

Procedure:
3.2 ml (0.031 mol) of aqueous 30% hydrogen peroxide, dissolved in 15 ml of methanol, was added dropwise, while vigorously stirring, to a solution of 1.97 gm (0.007 mol) of (E)-2-[(ethylamino)phenylmethylene]-benzo[b]thiophen-3(2H)-one and 10 ml of an aqueous 16% solution of titanium (III) chloride in 100 ml of methanol and 20 ml of water. The course of the reaction was monitored by thin-layer chromatography. After the reaction had ended, the mixture was diluted with 300 ml of water, and the precipitate thus obtained was suction-filtered off and then recrystallized twice from ethanol. 1.75 gm (84% of theory) of pale yellow crystals, m.p. 183°-185° C., were obtained.
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]2[C:11](=[N:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[C:24]3C=CN[C:25]3=[N:26][CH:27]=2)O1.N1C2C(=CC=CC=2)C=N1>>[N:26]1[CH:27]=[CH:22][CH:23]=[C:24]([C:5]2[CH:6]=[C:7]3[CH:8]=[CH:9][NH:10][C:11]3=[N:12][CH:13]=2)[CH:25]=1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Brc1cnc2[nH]ccc2c1
Agent: OBO
Agent: c1ccc2[nH]ncc2c1
Product: c1cncc(-c2cnc3[nH]ccc3c2)c1

Procedure:
Additional compounds were prepared following the protocol of Scheme 32, either by substituting pyridine-3-boronic acid with an appropriate boronic acid or by substituting the 5-bromo-7-azaindole with 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine and reacting with a suitable aryl or heteroaryl halide (i.e. coupling with the boronic acid ester on the azaindole, and the halide on the group to be coupled to the 5-position of the azaindole). The following compounds were prepared by this procedure:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[C:46]1(B(O)O)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2ccccc2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using compound 19 (90.0 mg, 0.132 mmol), phenylboronic acid (80.5 mg, 0.660 mmol), Pd(PPh)3Cl2 (4.60 mg, 0.0065 mmol), 2 M Na2CO3 (aq., 0.198 mL, 0.396 mmol), EtOH (0.6 mL) and DME (2.4 mL). Purification by RP-LC-MS (40 min gradient of 10-100% CH3CN in 0.05% aqueous formic acid) afforded the product (33.7 mg, 38%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[N:19]2[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.O>C1COCC1.[Ni]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[N:19]2[CH2:20][CH2:21][CH:22]([CH3:25])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)Nc2ccc(Br)cc2)CC1
Agent: [Ni]
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Solvent: C1CCOC1
Solvent: O
Product: CC1CCN(c2ccc(N)cc2C(=O)Nc2ccc(Br)cc2)CC1

Procedure:
Prepared analogously to Example 4b from N-(4-bromophenyl)-2-(4-methyl-piperidin-1-yl)-5-nitro-benzoic acid amide and Ra-Ni in THF. Yield: (quantitative). MS [M+H]+=388 (Br-isotope pattern); Rt=1.36 min (Method MC-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:14][CH2:13][O:12][C:11]=12)[C:6]([OH:8])=O.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[N:30]1[CH2:36][CH2:35][CH2:34][N:33]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:32][CH2:31]1)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:14][CH2:13][O:12][C:11]=12)[C:6]([N:41]1[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:33]2[CH2:34][CH2:35][CH2:36][N:30]([C:22]3[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:31][CH2:32]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:8]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1cc(C(=O)O)cc2c1OCO2
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c5c(c4)OCO5)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 3-methoxy-4,5-methylenedioxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1([CH3:29])[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH:19]2[O:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[O:21][CH2:20]2)[CH2:13]1)=O)C.O>C1COCC1>[O:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[O:21][CH2:20][CH:19]1[CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][C:12]([CH2:10][OH:9])([CH3:29])[CH2:13]1
Reactant: CCOC(=O)C1(C)CCCN(CC2COc3ccccc3O2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(CO)CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a suspension of LiAlH4 (0.59 g, 15.54 mmol) in dry THF (45 ml), was added 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylic acid ethyl ester (1.0 g, 3.13 mmol) in dry THF (5 ml). The reaction mixture was refluxed for 1 h. Water was slowly added and the reaction mixture was extracted with EtOAc (3×20 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give the desired product which, was purified by column chromatography (EtOAc/heptane, 50:50).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].C(N(CC)CC)C.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH:8]([C:26](=[O:27])[NH:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]#[N:10]
Reactant: O=C=Nc1ccccc1
Reactant: Cn1cccc1C(=O)CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1

Procedure:
To the suspension of 1,135 g of 1-methyl-β-oxo-2-pyrrolpropionitrile in 17,000 ml of dry toluene, 913 g of anhydrous triethylamine are added, followed by 913 g of phenylisocyanate while stirring under nitrogen. The dark brown solution formed is stirred at room temperature overnight and evaporated at 60°-70°/10 mm Hg. The residue is taken up in 1,400 ml of methanol and the solution treated with 1,400 ml of 6 N hydrochloric acid in 4,200 ml of water. The suspension is cooled to 15°-20° for 20 minutes, filtered and the residue washed twice with 1,800 ml of water, twice with 1,000 ml of isopropanol and 13 times with 1,000 ml of diethyl ether. This crude residue is dried at 60° and 5 mm Hg to constant weight and 1,960 g thereof are dissolved in 44,400 ml of methylene chloride at room temperature. The solution is treated with 400 g of activated charcoal, filtered and the filtrate evaporated. The residue is triturated with 12,000 ml of anhydrous ethanol, the suspension filtered at 20°, washed 4 times with 1,000 ml of anhydrous ethanol and dried at 60° and 5 mm Hg, to yield the 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 172°-174°, it is identical with that of Examples 1, 6 or 9.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][CH3:17])(=[O:15])[CH3:14].[F:18][CH:19]([F:35])[O:20][C:21]1[CH:34]=[CH:33][C:24](/[CH:25]=[N:26]/[S@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[F:35][CH:19]([F:18])[O:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:25]([NH:26][S@:27]([C:29]([CH3:31])([CH3:30])[CH3:32])=[O:28])[CH2:14][C:13]([O:16][CH3:17])=[O:15])=[CH:33][CH:34]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccc(OC(F)F)cc1
Reactant: COC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(OC(F)F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 42.7 %

Procedure:
To a stirred solution of diisopropylamine (16.70 mL, 119.1 mmol) in THF (80 mL) at 0° C. was added dropwise 2.5M n-butyllithium (48.82 mL, 122.0 mmol) and stirring was continued for 15 min. The solution was cooled to −78° C. and methyl acetate (9.219 mL, 116.2 mmol) was added dropwise and stirring continued for 30 min. A solution of Ti(O-iPr)3Cl (58.30 mL, 244.1 mmol) in THF (20 mL) was introduced dropwise at −78° C. and stirring was continued for 45 min. A solution of 378 (16 g, 58.12 mmol) in THF (20 mL) was then added dropwise and stirring was continued for 3 h. The reaction was quenched at −78° C. by dropwise addition of satd. aq. NH4Cl and warmed to RT. The mixture was thrice extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (20 to 60% EtOAc) to afford 8.67 g (43%) of (R)-methyl 3-(4-(difluoromethoxy)phenyl)-3-((S)-1,1-dimethylethylsulfinamido)propanoate (380) as a low melting white solid along with 9.67 g impure material.
Reaction SMILES: CC1CCP(=O)(C2C=CC=CC=2)C=1.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([N:26]=[C:27]=O)([CH3:25])[CH3:24])[CH:18]=1)=[CH2:16].[C:29]1([N:35]=C=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(N=C=NC2C=CC=CC=2)C=CC=CC=1>>[C:29]1([N:35]=[C:27]=[N:26][C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:15]([CH3:14])=[CH2:16])[CH:18]=2)([CH3:25])[CH3:24])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Reactant: O=C=Nc1ccccc1
Agent: C(=Nc1ccccc1)=Nc1ccccc1
Agent: CC1=CP(=O)(c2ccccc2)CC1
Product: C=C(C)c1cccc(C(C)(C)N=C=Nc2ccccc2)c1

Procedure:
We combined 0.3182 g 3-methyl-l-phenyl-2-phospholene-1-oxide (MPPO), m-TMI [2-(3-isopropenylphenyl)-2-propylisocyanate], and 19.31 g phenyl isocyanate. After heating at 140°-150° C. for 14 hours, IR showed nearly complete conversion of isocyanates to carbodiimides. GC-MS integrated ionization current shows a response of 265944 units for the title mixed product, 3558 units for the diphenyl carbodiimide, and 3602 units for the ditertiarycarbodiimide. Assuming that the detector sensitivity for the mixed product is the same, the selectivity for the mixed product is the average of the two other products, the reaction selectivity for the mixed product is 265944/(265944+3602+3558) or 97%, so the maximum yield of either mixed product is 3%.
Reaction SMILES: FC1C=[C:4](C=CC=1F)[CH2:5][N:6]1C=CN=C1S.[CH3:16][O:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[SH:28])=[CH:20][CH:19]=1>>[NH2:6][CH2:5][CH2:4][S:28][C:24]1[N:23]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:30][CH:29]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Fc1ccc(Cn2ccnc2S)cc1F
Reactant: COc1ccc(Cn2ccnc2S)cc1
Product: COc1ccc(Cn2ccnc2SCCN)cc1

Procedure:
The Example 1 process wherein 1-(3,4-difluorobenzyl)-2-mercaptoimidazole is replaced by 1-(4-methoxybenzyl)-2-mercaptoimidazole yields 2-(2-aminoethylthio)-1-(4-methoxybenzyl)imidazole. Treatment of this compound in methylene chloride with boron tribromide yields 2-(2-aminoethylthio)-1-(4-hydroxybenzyl)imidazole.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[N:13]1([CH2:18][CH2:19][CH2:20][Cl:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[ClH:21].[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[O:1][CH2:20][CH2:19][CH2:18][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1OCCCN1CCCC1
Product: Cl
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzoic acid (8.4 g, 50 mmol), 3-(pyrrolidin-1-yl)propyl chloride (14.75 g, 0.1 mol), (prepared according to J. Am. Chem. Soc. 1955, 77. 2272), potassium carbonate (13.8 g, 0.1 mol) and potassium iodide (1.66 g, 10 mmol) in DMF (150 ml) was stirred and heated at 100° C. for 3 hours. The mixture was allowed to cool and the insolubles were removed by filtration and the volatiles were removed from the filtrate by evaporation. The residue was dissolved in ethanol (75ml), 2M aqueous sodium hydroxide (75 ml) was added and the mixture was heated at 90° C. for 2 hours. The mixture was concentrated by evaporation, acidified with concentrated hydrochloric acid, washed with ether and then subjected to purification on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with water and then with a gradient of methanol (0 to 25%) in dilute hydrochloric acid (pH2.2). The methanol was removed by evaporation and the aqueous residue was freeze dried to give 3-methoxy-4-(3-(pyrrolidin-1-yl)propoxy)benzoic acid hydrochloride (12.2 g, 77%).
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:35]2[C:36]([CH2:41]CC(F)(F)F)=[N:37]OC=2C)=NC=1>>[CH:36]([NH:37][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:41])[CH3:35]
Reactant: COC(=O)c1ccc(OCc2c(CCC(F)(F)F)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(N3CCCC3)noc2C)nc1
Product: Cc1onc(N2CCCC2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 55 %

Procedure:
As described for example 1e, 6-(5-methyl-3-pyrrolidin-1-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.28 mmol), instead of 6-[5-methyl-3-(3,3,3-trifluoro-propyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted, to the title compound (30 mg, 55%) which was obtained as a white solid after purification by chromatography (silica, 30 to 60% ethyl acetate in heptane). MS: m/e=345.2 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13])([O-:5])=[O:4]>CO.O1CCOCC1.C(OCC)(=O)C>[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([OH:14])[CH3:13])([O-:5])=[O:4]
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CC(O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH4 (3.24 g, 85.60 mmol) was slowly added to a solution of 2′-nitroacetophenone NAP (3.74 g, 22.65 mmol) in a mixture of methanol (34 mL) and dioxane (22 mL). The reaction mixture was stirred at room temperature for one hour and then diluted with ethyl acetate (100 mL) and washed with water (25 mL). The organic layer was dried with Na2SO4, filtered, and concentrated in vacuo to yield 1-(2-nitrophenyl)ethanol dC.13a (3.49 g, 92%) as a white powder.