Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[CH2:29]([C:36]1[O:37][C:38]([CH3:42])=[C:39]([CH3:41])[CH:40]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C=O>[CH2:29]([C:36]1[O:37][C:38]([CH3:42])=[C:39]([CH3:41])[C:40]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cc(Cc2ccccc2)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
At ambient temperature, to a stirred suspension containing 3,5-diisopropyl-p-anisic acid (1.95 g, 8.23 mmol, RN-117439-59-5) and oxalyl chloride (0.8 mL, 9.20 mmol) in CH2Cl2 (22.5 mL) was added N,N-dimethylformamide (2 drops). After 2 h, the reaction was cooled to −78° C. To the reaction was added tin (IV) chloride (1.05 mL) followed by a solution of 2-benzyl-4,5-dimethylfuran (1.8 g, 9.68 mmol) in CH2Cl2 (10.0 mL). After the additions were complete, the reaction was allowed to warm to ambient temperature and stirred for 24 h. The reaction was quenched into crushed ice (100 g), diluted with sat. aq. KH2PO4 (100 mL) and extracted with ether. The combined ethereal extracts were washed with sat aq. NaHCO3 (2×60 mL), with brine (1×60 mL), dried (Na2SO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 1% EtOAc/pet. ether to give 2.07 g, (62%) of the title compound as an oil; 1H NMR (DMSO-d6) δ 1.17 (d, 12H), 1.81 (s, 3H), 2.19 (s, 3H), 3.29 (septet, 2H), 3.74 (s, 3H), 3.84 (s, 2H), 7.01-7.03 (m, 2H), 7.16-7.25 (m, 3H), 7.47 (s, 2H). mass spectrum (EI), m/z 404 (M+). Anal. Calcd. for C27H32O3.0.6H2O: C, 78.07; H, 8.06; N, 0.00. Found: C, 78.04; H, 7.93; N, −0.02.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[N+:13]([C:16]1[C:28]([OH:29])=[CH:27][C:26]2[C@@H:25]3[C@@H:20]([NH:21][CH2:22][CH2:23][CH2:24]3)[CH2:19][C:18]=2[CH:17]=1)([O-:15])=[O:14]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:21]3[CH2:22][CH2:23][CH2:24][C@@H:25]4[C:26]5[CH:27]=[C:28]([OH:29])[C:16]([N+:13]([O-:15])=[O:14])=[CH:17][C:18]=5[CH2:19][C@H:20]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: O=[N+]([O-])c1cc2c(cc1O)[C@H]1CCCN[C@H]1C2
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cc(O)c([N+](=O)[O-])cc3C[C@@H]21
Yield: 32 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-7-nitro-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-ol following a procedure analogous to that described in Example 1. Yield: 32% of theory; LC (method 1): tR=2.43 min; Mass spectrum (ESI+): m/z=379 [M+H]+.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OC(=O)C[N:14]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=2)[C:15]1=[O:34])C>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([N:14]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:32])([F:33])[F:31])[CH:23]=2)[C:15]1=[O:34])[CH3:8])[CH3:7]
Reactant: CCOC(=O)C(C)Br
Reactant: CCOC(=O)CN1CC(C)(C)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O
Product: CCOC(=O)C(C)N1CC(C)(C)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O

Procedure:
The reaction was carried out as previously described in Step 1 of examples 111-127 using ethyl 2-bromopropionate in place of bromoacetic acid ethyl ester. The diastereomeric mixture of products (3) were separated by column chromatography to afford the diastereomers as either the RS or SR compound or the RR or SS compound. The RS or SR compound was used in the next reaction.
Reaction SMILES: [OH-].[Na+].CO.[C:5]1(/[C:11](/[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12]\[C:13]([O:15]CC)=[O:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O>[C:5]1(/[C:11](/[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12]\[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)/C=C(\c1ccccc1)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C(\c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
20 ml of a 10% w/v aqueous solution of sodium hydroxide were added to 35 ml of a methanol solution containing 3,41 g of ethyl (E)-3-phenyl-3-(4-pyridyl)-acrylate (prepared as described in Preparation 2), and the mixture was stirred for 1 hour an room temperature. At the end of this time, the reaction solution was poured into 50 ml of water and washed with methylene chloride. Sufficient hydrochloric acid was added to the aqueous phase to adjust the pH to a value of 2.8. The resulting precipitate was collected, giving 2.131 g of the title compound, as a white powder, melting at 239°-241° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][CH:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7][CH2:6]1.[Br:20]N1C(=O)CCC1=O>C(Cl)Cl.C(O)(=O)C>[Br:20][C:12]1[CH:13]=[C:14]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[CH2:4][C:3]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:2]=1[F:1]
Reactant: Fc1ccc(F)c(CC2CCNc3ncccc32)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1ccc(F)c(CC2CCNc3ncc(Br)cc32)c1

Procedure:
To a solution of 4-(2,5-difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (23 mg) in CH2Cl2/acetic acid (5.5 mL, 10:1, v/v) was added N-bromosuccinimide (18.8 mg, 1.2 eq). The reaction was stirred at room temperature for one (1) hour, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-60% ethyl acetate/hexane as the eluting solvent to give the title compound as a clear, colorless oil (30% yield). LCMS: m/z=339 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.66-1.75 (m, 1H), 1.75-1.86 (m, 1H), 2.73 (dd, J=9.6 and 13.4 Hz, 1H), 2.95 (dd, J=6.0 and 13.4 Hz, 1H), 2.99-3.08 (m, 1H), 3.34-3.43 (m, 1H), 3.45-3.55 (m, 1H), 5.22 (bs, 1H), 6.80-6.86 (m, 1H), 6.88-6.96 (m, 1H), 6.98-7.05 (m, 1H), 7.16 (d, J=1.9 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[C:60]([O:64][C:65]([NH:67][C@@H:68]([CH2:75][CH2:76][CH2:77][CH2:78][NH:79][C:80](=[O:97])[C@@H:81]([NH:89][C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])[CH2:82][S:83][S:84][C:85]([CH3:88])([CH3:87])[CH3:86])[C:69](OCC#N)=[O:70])=[O:66])([CH3:63])([CH3:62])[CH3:61]>O.O1CCCC1>[C:60]([O:64][C:65]([NH:67][C@H:68]([CH2:75][CH2:76][CH2:77][CH2:78][NH:79][C:80](=[O:97])[C@@H:81]([NH:89][C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])[CH2:82][S:83][S:84][C:85]([CH3:86])([CH3:87])[CH3:88])[C:69]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:70])=[O:66])([CH3:61])([CH3:62])[CH3:63]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (37.9 mg, 0.060 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-6-((R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoate (Compound 53) (103 mg, 0.179 mmol) in tetrahydrofuran (0.3 mL) were added to buffer A (11 mL), and the mixture was stirred at room temperature for 2 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-((tert-butoxycarbonyl)amino)-6-((R)-2-((tert-butoxycarbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoate (Compound 55) (12 mg, 17%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 60 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (57 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (83 mg, 0.108 mmol, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.35 (s, 1H), 8.44 (s, 1H), 8.19 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.20 Hz, 1H), 7.76 (dd, J=8.52, 2.11 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.33-7.44 (m, 3H), 7.27 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.93 (t, J=6.87 Hz, 1H), 6.67 (d, J=2.38 Hz, 1H), 6.51 (d, J=5.31 Hz, 1H), 6.48 (dd, J=8.79, 2.56 Hz, 1H), 3.97 (s, 3H), 3.79 (s, 3H), 3.30-3.35 (m, 2H), 3.11-3.20 (m, 4H), 3.03 (s, 3H), 2.74 (t, J=6.78 Hz, 2H), 2.52-2.62 (m, 4H). MS (ESI): 769 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([C:11]([F:13])([F:14])[F:12])=[CH:6][C:5]=1[NH:15][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(I)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (42.0 g, 122 mmol) in toluene (400 mL) was treated with acetic anhydride (12.8 mL, 135 mmol) and the mixture was heated to reflux for 16 h under nitrogen. It was then allowed to cool to r.t. and diluted with water. The mixture was rendered neutral by adding small portions of sodium hydrogencarbonate, and the organic layer was separated. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was recrystallized in hexanes to give 2-acetylamino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (43.4 g, 112 mmol, 92%) as a white powder, m.p. 96-98° C., ESI-MS: m/z 388 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Br:10])[CH:5]=O.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>ClCCl>[CH2:14]([O:13][C:11](=[O:12])[CH:16]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([Br:10])=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: O=Cc1ccc(Br)c(Br)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(Br)c(Br)c1
Yield: 84.6 %

Procedure:
The above aldehyde (2.25 g) was dissolved in dichloromethane (25 ml) and carboethoxymethylenetriphenylphosphorane (2.96 g) was added. After 18 hours at 25° the solution was concentrated in vacuo and the residue washed with hexane. Combined hexane washings were concentrated in vacuo to give ethyl-3-(3,4-dibromophenyl)propenoate (2.4 g). NMR 1H 7.7(2H,m), 7.50(1H,d), 7.15(1H,dd), 6.32(1H,d), 4.26(2H,q), 1.33(3H,t).
Reaction SMILES: [OH:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH2:26]([O:25][C:23]([CH2:22][O:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4])=[O:24])[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: COc1ccccc1OC(c1ccccc1)C(O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)COC(C#N)C(Oc1ccccc1OC)c1ccccc1
Temperature: 50 °C
Yield: 100 %

Procedure:
2.69 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile in 25 ml of anhydrous DMA was stirred with 6.68 g of ethyl bromoacetate in the presence of 2.76 g of anhydrous potassium carbonate. The mixture was heated at 50° C. for 16 hours, poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and concentrated to dryness, to obtain 3.55 g of 2-ethoxycarbonylmethyloxy-3-phenyl-3-(2-methoxyphenoxy)-propionitrile (oil) (Yield 100%), which was used as such for the reaction described in the previous example.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:35])=[C:30]([CH:33]=O)[NH:31][CH:32]=2)=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:30]2[NH:31][CH:32]=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:35])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.4 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-{4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (29 mg, 25%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[N:19][CH:20]=1>C(Cl)Cl>[F:24][C:14]([F:13])([F:23])[C:15]1[CH:16]=[C:17]2[NH:22][C:1](=[O:2])[NH:21][C:18]2=[N:19][CH:20]=1
Reactant: Nc1cc(C(F)(F)F)cnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=c1[nH]c2cc(C(F)(F)F)cnc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add 1,1′-carbonyldiimidazole (1.0 g, 6.17 mmol)to a solution of 5-trifluoromethyl-pyridine-2,3 diamine (0.90 g, 5.08 mmol) in CH2Cl2 (10 mL) and stir at room temperature for 18 hours. Heat the solution to reflux for 2 hours and filter the precipitate to obtain 6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][CH:24]([O:30][CH2:31][CH3:32])[C:25]1[N:29]=[CH:28][NH:27][N:26]=1)[CH3:22].C(N(CC)CC)C>ClCCl>[CH2:31]([O:30][CH:24]([O:23][CH2:21][CH3:22])[C:25]1[N:29]=[CH:28][N:27]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:26]=1)[CH3:32]
Reactant: CCOC(OCC)c1nc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(OCC)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 3 h
Yield: 42.3 %

Procedure:
A solution of trityl chloride (43.4 g) in dichloromethane (120 ml) was added dropwise, over thirty minutes, to a stirred solution of 1,2,4-triazole-3-carboxaldehyde diethyl acetal (21.67 g, prepared as described by Mukahami et al, Heterocycles, 1981, 15, 301) and triethylamine (25 ml) in dichloromethane (200 ml). After stirring for a further three hours, the mixture was washed with water, dried over magnesium sulphate and evaporated under reduced pressure. A solution of the residual oil in ether (250 ml) crystallised to give 1-trityl-1,2,4-triazole-3-carboxaldehyde diethyl acetal (22.14 g, m.p. 120-124° C.). Trimethylsilyl bromide (14 ml) was added rapidly to a stirred solution of this acetal (6.2 g) in toluene (80 ml). After a further fifteen minutes, the solution was poured into a rapidly-stirred mixture of saturated sodium carbonate solution (200 ml), solid sodium carbonate (10 g) and ethyl acetate (150 ml). The mixture was stirred rapidly for ten minutes, the phases separated and the organic layer washed with water, dried over magnesium sulphate, and evaporated under reduced pressure. The residual oil was chromatographed on silica, using dichloromethane-ether (25:1) as eluant, to give the title compound (2.57 g). The deacetalation can also be carried out using pyridinium p-toluenesulphonate in acetone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>>[C:13]1([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]=2[C:10]([OH:12])=[O:11])[CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1[nH]c2ccccc2c1C1=CCCC1

Procedure:
Condensation of the indole carboxylic acid with cyclopentanone in the presence of aqueous sodium hydroxide gave the 3-cyclopenteneyl indole carboxylic acid, which was subjected to hydrogenation in the presence of catalytic amount of palladium on carbon to afford the corresponding cyclopentyl carboxylic acid in 80% overall yield. Double methylation of the carboxylic acid and the nitrogen with methyl carbonate in NMP at 130° C. provided the N-methyl indole carboxylate methyl ester in 90% yield. Bromination of the indole carboxylate with bromine in acetonitrile furnished the 2-bromo-3-cyclopentyl indole carboxylate in 90% yield.
Reaction SMILES: [OH:1][CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:5](=[O:13])[C:4]2[S:14][CH2:15][CH2:16][S:17][C:3]1=2.[H-].[Na+].Cl[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22]>O1CCCC1>[CH3:29][N:26]1[CH2:27][CH2:28][N:23]([C:21]([O:13][CH:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:2](=[O:1])[C:3]3[S:17][CH2:16][CH2:15][S:14][C:4]2=3)=[O:22])[CH2:24][CH2:25]1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccccn1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccccn2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
A solution of 5-hydroxy-7-oxo-6-(pyrid-2-yl)-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (6.0 g.) in anhydrous tetrahydrofuran (60 cc.) is treated for 17 minutes at about 5°-10° C, with sodium hydride (0.64 g.), and a solution of 1-chlorocarbonyl-4-methylpiperazine (11.0 g.) in anhydrous tetrahydrofuran (80 cc.) is then added, at 5° C. The reaction mixture is stirred for 4 hours at 5° C. After evaporating the solvent under reduced pressure (20 mm.Hg), the residue is dissolved in diethyl ether (300 cc.). The diethyl ether solution is washed three times with N sodium hydroxide solution (total 450 cc.) and then three times with distilled water (total 300 cc.), treated with vegetable charcoal (0.1 g.), dried over anhydrous potassium carbonate, filtered and evaporated. The residue (7.6 g.; m.p. 145° C.) is dissolved in boiling ethanol (20 cc.). After being cooled for 2 hours at 2° C, the crystals which have appeared are filtered off, washed twice with ice-cold ethanol (total 12 cc.) and dried under reduced pressure (20 mm.Hg). 5-(4-Methylpiperazin-1-yl)carbonyloxy-7-oxo-6-(pyrid-2-yl)-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (3.9 g.), melting at 150° C, is thus obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:13]1([N:12]2[CH2:2][CH2:3][C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCCc1ccccc1CCl
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: c1ccc(N2CCc3ccccc3C2)cc1
Yield: 29.7 %

Procedure:
A mixture of 2-(2-chloroethyl)benzyl chloride (19 g), aniline (9.3 g), and triethylamine (22.22 g,) in chloroform (80 ml) was heated at reflux for 6 hrs. The reaction mixture was cooled and washed with 2M sodium hydroxide solution (3×100 ml). The chloroform layer was dried (magnesium sulphate) and evaporated in vacuo. The residue was distilled in vacuo to afford 2-phenyl-1,2,3,4-tetrahydroisoquinoline (6.2 g. b.pt. 112°-113°/0.08-0.1 mmHg) characterised by its nmr spectrum.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:16]([CH3:18])[CH3:17])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)[O:5][C:4](=[O:19])[CH:3]=1.[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[C:27]([CH3:32])=[CH:26][C:25]=1[S:33][C:3]1[C:4](=[O:19])[O:5][C:6]([CH:16]([CH3:17])[CH3:18])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)[CH2:7][C:2]=1[OH:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: Cc1csc(CCC2(C(C)C)CC(O)=CC(=O)O2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(CCC2(C(C)C)CC(O)=C(Sc3cc(C)c(CO)cc3C(C)(C)C)C(=O)O2)n1

Procedure:
The title compound was prepared according to General Method 16a using 4-hydroxy-6-isopropyl-6-[2-(4-methyl-thiazol-2-yl)-ethyl]-5,6-dihydro-pyran-2-one (Example E-6; 0.33 g, 1.2 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.51 g, 1.4 mmol), potassium carbonate (0.48 g, 3.5 mmol), and DMF (5 mL). The product was chromatographed on silica gel, eluting with 5% MeOH in CH2Cl2, to give the title compound, mp 98-100° C.