Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]#[CH:21])[C@H:14]2[CH3:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[CH:28][C:27]=1[O:36][CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]#[C:21][C:26]3[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[CH:28][C:27]=3[O:36][CH3:37])[C@H:14]2[CH3:22])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C#CCN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: COc1cc(F)c(C(C)C)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1cc(F)c(C(C)C)cc1C#CCN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-prop-2-yn-1-yl-1,3-oxazolidin-2-one (100 mg, 0.285 mmol), 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (27.4 wt % in toluene, 233 mg, 0.259 mmol), bis(triphenylphosphine)palladium dichloride (18.2 mg, 0.0259 mmol), copper (I) iodide (4.9 mg, 0.0259 mmol), triphenylphosphine (13.6 mg, 0.0518 mmol), and diethylamine (283 mg, 406 μL, 3.88 mmol) in dry DMF (0.5 mL) was degassed and subjected to microwave irradiation (120° C., 60 min). The reaction mixture was diluted with 0.1N HCl (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-30% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)prop-2-yn-1-yl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.38 (20% EtOAc/hexanes). LCMS calc.=518.2; found=518.2 (M+1)+. 1H NMR (500 MHz, CDCl3): δ 7.89 (s, 1H); 7.78 (s, 2H); 7.26 (d, J=8.4 Hz, 1H); 6.56 (d, J=12.0 Hz, 1H); 5.76 (d, J=8.3 Hz, 1H); 4.70 (d, J=17.8 Hz, 1H); 4.53-4.47 (m, 1H); 4.08 (d, J=17.8 Hz, 1H); 3.82 (s, 3H); 3.17-3.09 (m, 1H); 1.22 (d, J=6.9 Hz, 6H); 0.90 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH:42]1([C:45]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[O:46])[CH2:44][CH2:43]1>ClCCl>[CH:42]1([C:45]([N:47]2[CH2:52][CH2:51][N:50]([C:6]([C:5]3[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=3)[CH:1]=[O:2])=[O:8])[CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:44]1
Reactant: O=C(C1CC1)N1CCNCC1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 94.3 %

Procedure:
To a stirred mixture of 3-formylbenzoic acid (450 mg, 3 mmol) in anhydrous dichloromethane (20 mL) was added triethylamine (758 mg, 7.5 mmol), 1-hydroxybenzotriazole (466 mg, 3.45 mmol), followed by 1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride (629 mg, 3.45 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C. and cyclopropyl(piperazin-1-yl)methanone hydrochloride (629 mg, 3.3 mmol) was added in portion-wise. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated citric acid (100 mL×2), followed by saturated sodium bicarbonate (100 mL×2), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzaldehyde (810 mg, yield 94%) as a light yellow oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 0.79-0.85 (m, 2H), 1.00-1.04 (m, 2H), 1.73-1.76 (m, 1H), 3.47-3.77 (m, 8H), 7.62-7.66 (t, J=7.6 Hz, 1H), 7.70-7.72 (d, J=7.6 Hz, 1H), 7.95-7.98 (m, 2H), 10.1 (s, 1H); LC-MS (ESI) m/z: 287 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:14]([OH:16])=[O:15])[C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[C:4]([CH3:17])=[N:3]1.C(OC(=O)C)(=O)C>>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]3[C:14](=[O:16])[O:15][C:11](=[O:12])[C:7]3=[CH:8][CH:9]=2)[C:4]([CH3:17])=[N:3]1
Reactant: Cc1nn(C)c2ccc(C(=O)O)c(C(=O)O)c12
Solvent: CC(=O)OC(C)=O
Product: Cc1nn(C)c2ccc3c(c12)C(=O)OC3=O
Temperature: 5 °C

Procedure:
A mixture of 1,3-dimethyl-1H-indazole-4,5-dicarboxylic acid (6.30 g, 26.9 mmol) and acetic anhydride is stirred at reflux temperature for 3 hours, cooled to 5° C. and filtered. The filter cake is air-dried to give the title product as chartreuse needles (4.80 g, 82.5%), mp 214°-215.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Agent: Cl
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=O)c1cccnc1

Procedure:
According to the general method of Example 61, 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine and nicotinoyl chloride hydrochloride were combined to provide N3-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]nicotinamide as a white crystalline solid, m.p. 84.5-86.1° C. 1H NMR (300 MHz, DMSO-d6) δ8.91 (s, 1H), 8.69 (m, 1H), 8.56 (m, 1H), 8.07 (m, 2H), 7.75-7.41 (m, 8H), 7.21 (m, 1H), 6.72 (broad s, 2H), 4.60 (m, 2H), 3.15 (t, J=6.0 Hz, 2H), 1.86 (m, 2H), 1.40 (m, 2H); MS (CI) m/e 437 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[C:7]([OH:14])[CH:6]=1)[CH3:2].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[CH2:24][CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[C:7]([O:14][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=2[Cl:16])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OCC)c(O)c1
Reactant: OCCc1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCC)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.5 g (2.38 mmol) of 4-Ethoxy-3-hydroxy-benzoic acid ethyl ester was dissolved in 10 ml of anhydrous tetrahydrofuran. To this solution was added 0.5 g (2.62 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 2.38 g (equivalent to 7.13 mmol PPh3) of triphenylphosphine derivatized polystyrene and 1.24 g (7.13 mmol) of DEAD. The solution was shaken for 16 h at RT. The polymer was filtered off and washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was taken-up in ethyl acetate and the solution was washed three times with water and twice with saturated aqueous sodium chloride. The organic phase was dried with magnesium sulphate, filtered and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/n-heptane (1/4).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N+:14]([O-])=O)[C:8]=2[N:7]=[C:6]1[C:17]1[C:22](OC)=[CH:21][CH:20]=[CH:19][C:18]=1[F:25].[C:31](O)(=[O:33])C>Cl>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([NH2:14])[C:8]=2[N:7]=[C:6]1[C:17]1[CH:22]=[CH:21][C:20]([O:33][CH3:31])=[CH:19][C:18]=1[F:25]
Reactant: CC(=O)O
Reactant: COc1cccc(F)c1-c1nc2c([N+](=O)[O-])cccc2n1Cc1c(F)cccc1F
Agent: Cl
Product: COc1ccc(-c2nc3c(N)cccc3n2Cc2c(F)cccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2-fluoro-4-methoxylphenyl)-4-nitrobenzimidazole (Example 50) (2.00 g, 4.98 mmol) dissolved in acetic acid (20 mL) was added SnCl2x2H2O (9.02 g) dissolved in concentrated HCl (8 mL). After stirring for 30 min at room temperature, the mixture was concentrated. The residue was diluted with CH2Cl2 and washed with NaHCO3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na2SO4), filtered, and evaporated. The crude product was recrystallized from methanol to give 3.26 g of white crystals, (8.78 mmol, 70% yield). M.p. 200-202° C. 1H-NMR (200 MHz, CD2Cl2) δ 7.45 (m, 1H, H4′), 7.22 (m, 1H, H4″), 7.05 (dd, J=7.8, 7.6 Hz, 1H, H6), 6.85-6.72 (m, 5H, H3″,5″), 6.50 (dd, J=7.7, 1.0 Hz, 1H, H5), 5.21 (d, J=5.4 Hz, 2H, CH2PhF2 (rotamers)), 4.34 (br, 2H, NH2), 3.72 (s, 3H, OCH3).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)=[N:6]1)[CH3:4].[C:22]([C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:22]([C:25]1[CH:29]=[C:28]([C:30]([NH:1][CH2:2][C@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23]
Reactant: C[C@H](CN)n1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)n2)[nH]n1
Yield: 73.3 %

Procedure:
The title compound was synthesized from (R)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile (381 mg, 1.3 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (200 mg, 1.3 mmol), HOBt (210 mg, 1.55 mmol), DIPEA (0.271 mL, 1.55 mmol) and EDCI (298 mg, 1.55 mmol) using DCM as solvent using the method of Example 34(d) affording 410 mg of the title compound. 1H NMR (400 MHz; d6-DMSO): δ 1.50 (d, 3H), 2.47 (s, 3H), 3.63 (m, 2H), 4.69 (m, 1H), 7.03 (d, 1H), 7.25 (bs, 1H), 7.90 (d, 1H), 8.18 (m, 2H), 8.27 (m, 1H), 14.15 (bs, 1H).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:8]2[CH2:9][C:10]3[S:14][C:13]([SH:15])=[N:12][C:11]=3[C:16]=2[CH:17]=[CH:18][CH:19]=1)C.[Br-].[C:22]1([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:15][C:13]2[S:14][C:10]3[CH2:9][C:8]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:20])=[CH:19][CH:18]=[CH:17][C:16]=4[C:11]=3[N:12]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Agent: [Br-]
Product: O=C(O)COc1cccc2c1Cc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Yield: 61 %

Procedure:
Using ethyl[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and diphenylmethane bromide, the procedure of Example 21 was otherwise repeated to synthesize the title compound. Yield 61%.
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([C:8]([NH:10][C@H:11]([C:15]([N:17]2[CH2:37][CH2:36][CH2:35][C@H:18]2[C:19]([NH:21][CH:22]([CH:32]([CH3:34])[CH3:33])[C:23](=[O:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])=[O:20])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].C(Cl)(=O)C(Cl)=O.[CH3:46][NH:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.CN1CCOCC1>CN(C=O)C>[CH3:46][N:47]([CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1)[C:1]([C:4]1[CH:39]=[CH:38][C:7]([C:8]([NH:10][C@H:11]([C:15]([N:17]2[CH2:37][CH2:36][CH2:35][C@H:18]2[C:19]([NH:21][CH:22]([CH:32]([CH3:34])[CH3:33])[C:23](=[O:31])[C:24]([F:29])([F:30])[C:25]([F:27])([F:26])[F:28])=[O:20])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])=[CH:6][CH:5]=1)=[O:2]
Reactant: CNCCN1CCOCC1
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)O)cc1)C(C)C)C(=O)C(F)(F)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)N(C)CCN2CCOCC2)cc1)C(C)C)C(=O)C(F)(F)C(F)(F)F
Yield: 56.6 %

Procedure:
The acid of Example 13 (b) (0.36 g, 0.64 mmol) was activated with oxalyl chloride (0.07 mL, 0.83 mmol) and DMF (3 drops) and coupled with 4-[2-(methylamino)ethyl]-morpholine (92 mg, 0.64 mmol) using NMM (0.14 mL, 1.28 mmol) according to the method described in Example 5 (h). Purification by flash chromatography (75:25 acetone:EtOAc) gave 0.25 g (57%) of the title compound (7:1 L-L-L:L-L-D) as an off-white foam. TLC: Rf 0.19 (3:1 acetone:EtOAc). 1H NMR (partial): δ7.88-7.82 and 7.52-7.46 (pr m, 4H, aryl), 7.42 (br d, J=7.6 Hz, 1H, NH), 6.84 (br d, J=8.8 Hz, 1H, NH), 5.02-4.96 (m, 1H, CH), 4.85 (dd, J=8.6, 7.0 Hz, 1H, CH), 4.72 (dd, J=8.0, 2.0 Hz, 1/8H, CH of Pro), 4.6 (dd, J=8.1, 2.9 Hz, 7/8H, CH of Pro), 1.14-0.82 (m, 12H, 4×CH3). 19F NMR: δ−82.12 (s, CF3, major isomer), −82.15 (s, CF3, minor isomer), −121.52 and −122.70 (AB quartet, J=294 Hz, CF2, minor isomer), −121.54 and −122.58 (AB quartet, J=294 Hz, CF2, major isomer). MS (DCI/CH4): m/z (rel intensity) 691 (26), 690 (MH+, 100), 374 (62), 317 (18), 113 (22), 100 (43), 84 (36), 83 (23). HRMS (C32H45F5N5O6) (MH+): calcd, 690.3290; obsd, 690.3274.
Reaction SMILES: CS(C)=O.[OH-].[K+].[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)([O-:9])=[O:8].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=2)[CH:13]=[CH:14]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2c(ccn2Cc2ccccc2)c1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
Dry dimethylsulphoxide (20 ml) was added to potassium hydroxide (4.2 g, 0.074 mol) (crushed pellets) and the mixture was stirred under nitrogen for 5 mins. 5-Nitroindole (commercially available) (3.0 g, 0.019 mol) was then added and the red mixture stirred for 30 min at room temperature. The mixture was then cooled to −10° C., benzyl bromide (4.4 ml, 0.037 mol) was slowly added and the mixture stirred and allowed to warm to room temperature over a period of 40 mins. Water (50 ml) was then added and the mixture was extracted with diethyl ether (2×200 ml). The extracts were washed with water (4×50 ml), dried over sodium sulphate and evaporated to leave an oily solid. The excess benzyl bromide was removed by dissolving the whole in diethyl ether (50 ml), diluting this solution with 40-60 petrol (50 ml) and then gradually removing the diethyl ether in vacuo to leave a yellow solid suspended in the petrol. The solid was filtered, washed with copious amounts of 40-60 petrol and dried to give 1-benzyl-5-nitroindole (2.4 g, 51%) as a yellow solid, m.p. 102-104° C.; δH [2H6]-DMSO 8.53 (1H, s, 4-H), 8.00 (1H, d, J 9. 6-H), 7.78 (1H, s, 2-H), 7.68 (1H, d, J 9, 7-H), 7.36-7.20 (5H, m, 2′-H, 3′-H, 4′-H, 5′-H, 6′-H), 6.81 (1H, s, 3-H), 5.52 (2H, s, CH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[S:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[S:15].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:19]1[S:13][C:14](=[S:15])[NH:16][C:17]1=[O:18]
Reactant: O=C1CSC(=S)N1
Reactant: COc1cccc(C=O)c1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(C=C2SC(=S)NC2=O)c1OC
Yield: 95.6 %

Procedure:
A mixture of 2,3-dimethoxybenzaldehyde (5.2 g, 30 mmoles), rhodanine (4.0 g, 29 mmoles), sodium acetate (8.4 g, 102 mmoles), and acetic acid (50 ml) is stirred under an inert atmosphere and heated to reflux. After 4 hours the mixture is stirred into water (250 ml) and the precipitate is filtered off, rinsed successively with water (3X), ethanol (2X), and ether (2X), and dried to afford the pure product (7.8 g), mp 268°-269° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]#[N:14])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:24])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]#[N:14])[C:10]=1[O:11][CH3:12])[C:5]([Cl:24])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(Cl)cc(C(=O)O)cc1C#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(C(=O)Cl)cc1C#N
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-chloro-5-cyano-4-methoxybenzoic acid (932 mg), toluene (9.3 mL), N,N-dimethylformamide (0.03 mL) and thionyl chloride (0.38 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (993 mg) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@@H:8]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)[C@@H:9]([OH:30])[CH2:10][C@H:11]([C:14](N1[C@H]2C3C=CC=CC=3C[C@H]2OC1(C)C)=[O:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C@@H:9]1[CH2:10][C@@H:11]([CH2:12][CH3:13])[C:14](=[O:15])[O:30]1)[CH2:31][C:32]1[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](C[C@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)C(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC[C@@H]1C[C@@H]([C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)OC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(1S,2S,4R)-[1-(3,5-Difluorobenzyl)-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazole-3-carbonyl)-2-hydroxyhexyl]-carbamic acid tert-butyl ester (VIII, 60 mg) was dissolved in 5:1 toluene/CH2C12 (3 mL), and p-toluenesulfonic acid monohydrate (23 mg) was added. This was stirred at rt for 18 h. The mixture was then filtered, and partitioned between half-saturated NaHCO3 (3 mL) and 1:1 EtOAc/hexanes (2×3 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. Flash chromatography of the residue afforded desired product as a solid: MH+370.2.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[CH2:23][CH2:22][CH2:21]2>>[CH2:23]1[C:24]2[C:20](=[CH:19][C:18]([NH:17][C:2]3[CH:16]=[CH:15][C:5]4[C:6](=[O:14])[NH:7][C:8]5[C:13]([C:4]=4[CH:3]=3)=[CH:12][CH:11]=[CH:10][N:9]=5)=[CH:26][CH:25]=2)[CH2:21][CH2:22]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: O=c1[nH]c2ncccc2c2cc(Nc3ccc4c(c3)CCC4)ccc12
Yield: 29.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (1000 mg, 0.43 mmol) and 5-aminoindan (87 mg; 0.65 mmol) to provide 247 (41 mg, 26% yield) as a brown solid. LC-MS (M+H (parent)=328, obsd.=328).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:29][N:28]=[C:27]([CH3:30])[C:26]=4[CH2:31]O)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:9])[CH3:6].C([O-])(O)=O.[Na+]>COCCOC>[CH2:5]([O:7][C:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:29][N:28]=[C:27]([CH3:30])[C:26]=4[CH2:31][Br:2])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:9])[CH3:6]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CO)cc3)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phosphorus tribromide (0.43 mL, 4.53 mmol) was added to a solution of 1-[4′-(4-hydroxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (1.14 g, 3.02 mmol) in DME (30 mL) at 0° C. The reaction was stirred overnight at room temperature, and then cooled to 0° C. and neutralized with saturated aqueous NaHCO3 to pH 7. The mixture was partitioned between CH2Cl2 and H2O, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:28][CH2:27][C@H:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:29][C@H:26]1[CH2:27][CH2:28][N:24]([C:23]2[C:6]3[C:5]4[CH:4]=[C:3]([C:1]#[N:2])[N:11]=[CH:10][C:9]=4[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=3[N:20]=[CH:21][CH:22]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(N3CC[C@H](N)C3)ccnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)pyrrolidin-3-ylcarbamate (401 mg, 0.79 mmol) in methylene chloride (9.0 mL) was added trifluoroacetic acid (9.0 mL), and the mixture was stirred at ambient temperature for 10 minutes. The solvent was evaporated in vacuo, and the resulting residue was dissolved in methylene chloride and treated with a solution of saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo to afford the title compound as a yellow foam, which was used in the next step without any further purification (268 mg, 83%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:23]([C:25]1[CH:29]=[CH:28][NH:27][N:26]=1)=[O:24]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]([C:25]2[CH:29]=[CH:28][NH:27][N:26]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1cc[nH]n1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2cc[nH]n2)cc1

Procedure:
The title compound was prepared by the reaction of 4-t-butylbenzenesulfonyl chloride with (2-Amino-5-chloro-phenyl)-(1H-pyrazol-3-yl)-methanone following the general procedure. MS: m/z 418.1 (M++1). Remove this example—same as [0676 below]