Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:24]B1OBOBO1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: CB1OBOBO1
Reactant: COC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1nc(C)c2cc(Sc3ccccc3)ccc2c1O
Yield: 28.2 %

Procedure:
1-Bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid methyl ester (0.2 g), tetrakis(triphenylphosphine)palladium (60 mg), methyl boroxine (65 mg), and potassium carbonate in 1,4-dioxane (4 ml) were heated in a microwave reactor (sealed tube) for 10 min at 140° C. After cooling reaction mixture was concentrated and partitioned between 1 N hydrochloric acid and ethyl acetate. Organic layer dried over magnesium sulfate and filtered. Filtrate concentrated and separated by silica gel chromatography (eluting with 2% ethyl acetate in methylene chloride) to give the title compound (47 mg). MS-(+)-ion M+1=326.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH:23]=[CH:24][C:25]([O:27][CH2:28]C)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Mg]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C[C@@H]1C[C@@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Agent: [Mg]
Solvent: CO
Product: COC(=O)CC[C@@H]1C[C@@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 110.5 %

Procedure:
In analogy to literature [Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G. Tetrahedron Lett. (1987), 28(44), 5287–90] a solution of 0.35 g (0.84 mmol) (2S,4R)-2-(2-ethoxycarbonyl-vinyl)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 20 ml MeOH was treated with 0.122 g (5.04 mmol) magnesium and stirred at room temperature for 5 h. The reaction was evaporated, suspended twice in EtOAc and filtered to give 0.38 g (quantitative) of (2R,4R)-4-(4-methoxy-benzylsulfanyl)-2-(2-methoxycarbonyl-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 410 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[C@@H:6]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:26][C:24]([F:25])([F:27])[C:21]1[CH:20]=[CH:19][C:18]([C@@H:6]2[C@@H:5]([CH2:4][C:3]([O:2][CH3:1])=[O:28])[CH2:10][CH2:9][CH2:8][NH:7]2)=[CH:23][CH:22]=1
Reactant: COC(=O)C[C@H]1CCCN(C(=O)OC(C)(C)C)[C@@H]1c1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C[C@H]1CCCN[C@@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the resulting tert-butyl (2S,3R)-3-(2-methoxy-2-oxoethyl)-2-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate (2.8 g, 7.0 mmol) in DCM (50 mL) was treated with TFA (2.7 mL, 35 mmol) and stirred at ambient temperature for 16 hours. The reaction mixture was evaporated in vacuo and partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated in vacuo to give methyl {(2S,3R)-2-[4-(trifluoromethyl)phenyl]piperidin-3-yl}acetate. LC/MS (EIMS, M+H)=302.1.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[CH:29]=3)=[C:26]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[N:25]=[CH:24]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[OH-].[Na+]>CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:29]=3)=[C:26]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[N:25]=[CH:24]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(Cl)c2)CC1
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(Nc3ccccc3)c2)CC1
Temperature: 120 °C

Procedure:
To a suspension of NaH (130 mg, 3.3 mmol) in DMA (2 mL) was added aniline (0.58 mL, 6.1 mmol) and stirred until bubbling ceased. To this solution was added 1-(1-t-butoxycarbonyl-4-piperidinyl)-4-(4fluorophenyl)-5-(2-chloro-4-pyridinyl)imidazole (0.30 g, 0.66 mmol) and the resulting solution was heated at 120° C. until no evidence of starting material was observed by mass spectroscopy (1-3 days). To the cooled reaction mixture 1M NaOH was added and the resulting mixture extracted three times with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated under reduced pressure to afford a yellow residue which was chromatographed with 50-80% EtOAc/hexanes. The resulting solid was triturated with Et2O to give the title compound as a light yellow solid; yield 180 mg (53%): ESMS m/z=514 (M+ +H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:35]=[C:36]([CH2:40][OH:41])[CH:37]=[CH:38][CH:39]=1.[I-].[Na+].CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][OH:41])[CH:35]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: CC(C)(N)Cc1cccc(CO)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(Cc1cccc(CO)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)quinolin-2 (1H)-one (0.518 g) and (3-(2-amino-2-methylpropyl)phenyl)methanol (0.19 g) (example 275, step c) and sodium iodide (0.159 g) and Hunig's Base (0.555 mL) in acetonitrile (3 mL) was heated at reflux under nitrogen for 2 days. Further (3-(2-amino-2-methylpropyl)phenyl)methanol (0.19 g) and Hunig's Base (0.185 mL) were added and heating at reflux continued for 1 day. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and brine, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography eluting with 3% methanol and 1% triethylamine in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.44 g.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:18]4=[O:31])[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C[Sn](C)(C)[C:34]1[CH:39]=[N:38][CH:37]=[C:36]([CH3:40])[N:35]=1>CN(C)C(=O)C>[CH3:40][C:36]1[N:35]=[C:34]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([N:17]5[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28])[C:18]5=[O:31])[CH:14]=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:39]=[N:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)C1=O
Reactant: Cc1cncc([Sn](C)(C)C)n1
Solvent: CC(=O)N(C)C
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3=O)n2)n1
Temperature: 145 °C

Procedure:
A solution of tert-butyl N-[(3S)-1-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]-2-oxo-3-piperidyl]carbamate (125 mg, 0.282 mmol) and palladium(0)tetrakis(triphenylphosphine) (32 mg, 0.028 mmol) in N,N-dimethylacetamide 5.0 mL was added trimethyl-(6-methylpyrazin-2-yl)stannane (145 mg, 0.565 mmol). The reaction mixture heated at 145° C. for 40 min in CEM microwave. The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc then washed with water. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was carried to next step. MS (ESI) m/z: 501.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]([CH3:43])[N:40]=[CH:41][CH:42]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]([CH3:43])[N:40]=[CH:41][CH:42]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cn1nccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnn3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (160 mg, 0.5 mmol) and 3-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K7) (150 mg, 0.5 mmol) according to the general procedure M. Obtained as a yellow foam (90 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[S:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[N:22][N:23]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][NH:18][C:19]1[S:20][C:21]([C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[N:22][N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Reactant: CCCNC(=O)c1nnc(N)s1
Solvent: Cc1ccccc1
Product: CCCNC(=O)c1nnc(NCc2cc(Br)ccc2OCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-benzyloxy-5-bromobenzaldehyde (4.2 g) and 2-amino-N-propyl-1,3,4-thiadiazole-5-carboxamide (2.7 g) in toluene (200 mL) was heated under reflux for 2 hours. The solvent was evaporated and residue was dissolved in ethanol (100 mL) and was heated under reflux for 3 hours then allowed to cool to ambient temperature. Sodium borohydride (0.53 g) was added and the reaction mixture was stirred for 16 hours then poured into water (500 mL). The aqueous mixture was extracted 4 times with ethyl acetate (50 mL each time), the combined extracts were washed 3 times with water (100 mL each time) and dried (MgSO4). The residue obtained on removal of the solvent was subjected to chromatography on silica, eluting with a mixture of ethyl acetate and dichloromethane (1/5 v/v), to give 2-[N-(2-benzyloxy-5-bromobenzyl)amino]-N-propyl-1,3,4-thiadiazole-5-carboxamide, yield 0.81 g, mp 154° C.
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:13][C:14]#[N:15]>>[N:1]1([CH:6]2[CH2:11][CH2:10][N:9]([CH2:13][C:14]#[N:15])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: N#CCBr
Product: N#CCN1CCC(N2CCCC2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Pyrrolidin-1-yl-piperidine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=194.1: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.75-2.70 (m, 2H), 2.45-2.40 (m, 4H), 2.20-2.10 (m, 2H), 1.90-1.75 (m, 3H), 1.65-1.60 (m, 4H), 1.45-1.30 (m, 2H).
Reaction SMILES: ClCC(O)=[O:4].[C:6]1([CH3:21])[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[C:14](=[O:20])[NH:15][C:16](=S)[NH:17][CH:18]=2)[CH:7]=1>Cl>[C:6]1([CH3:21])[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[C:14](=[O:20])[NH:15][C:16](=[O:4])[NH:17][CH:18]=2)[CH:7]=1
Reactant: O=C(O)CCl
Reactant: Cc1cccc(Oc2c[nH]c(=S)[nH]c2=O)c1
Agent: Cl
Product: Cc1cccc(Oc2c[nH]c(=O)[nH]c2=O)c1
Yield: 92 %

Procedure:
To a solution of 73.3 g (0.744 mol) chloroacetic acid in 700 ml 12N HCl was added 28.6 g (0.122 mol) of 5-m-tolyloxy-2-thiouracil. The slurry was heated at reflux for 35 hours and filtered while still hot. The resulting white solid was washed well with H2O and dried to give 24.5 g of 5-m-tolyloxyuracil (m.p. 291°-295°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C[Si](C)(C)C1C=CC([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH:21]=[CH:22][CH2:23]3)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH:21]=[CH:22][CH2:23]3)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)c1ccc(-c2cccc3c2C=CC3)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Clc1ccc(-c2cccc3c2C=CC3)cc1
Yield: 69 %

Procedure:
The synthesis was performed by the same procedure as in Metallocene Compound A (1-1) by using 4-chlorophenylboronic acid in place of 4-trimethylsilylphenylboronic acid in the synthesis of 4-(4-trimethylsilyl-phenyl)-indene to obtain a white solid of 4-(4-chloro-phenyl)-indene in a yield of 69%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:6]=[C:5]([C:18]([OH:20])=O)[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>>[NH:35]1[C:34]([NH:33][C:18]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=3)[N:6]=2)=[O:20])=[N:38][N:37]=[N:36]1
Reactant: Nc1nnn[nH]1
Reactant: COc1cc(C(=O)O)nc(-c2cccc([N+](=O)[O-])c2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc(-c2cccc([N+](=O)[O-])c2)c1
Yield: 62.3 %

Procedure:
In the same manner as described in Example 1-(1), 4-methoxy-6-(3-nitrophenyl)-2-pyridinecarboxylic acid (0.4 g), carbonyldiimidazole (0.22 g) and 5-aminotetrazole (0.15 g) are reacted to give N-(5-tetrazolyl)-4-methoxy-6-(3-nitrophenyl)-2-pyridinecarboxamide (0.31 g). M.P. 269°-272.5° C. (decomp.) (wetted from about 250° C.) (recrystallized from dimethylformamide-ethyl acetate)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[CH:3]=1.[Li]CCCC.[CH3:19][Si:20]([CH3:23])(Cl)[Cl:21]>CCOCC.CCCCCC>[Cl:21][Si:20]([CH3:23])([CH3:19])[CH:7]1[C:5]2[S:6][C:2]([CH3:1])=[CH:3][C:4]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: C[Si](C)(Cl)Cl
Reactant: Cc1cc2c(s1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc2c(s1)C([Si](C)(C)Cl)c1ccccc1-2
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Suspension of 1.86 g (0.01 mol) 2-methyl-8H-indeno[2,1-b]thiophene in 25 mL ether was treated dropwise with 6.25 mL (0.01 mol) of 1.6M BuLi in hexane at −40° C. under stirring. Then the mixture was stirred in additional 3 h. The resulting mixture was treated with 1.20 mL (0.01 mol) of dimethyldichlorosilane in 5 mL of ether at −70° C.; then it was allowed to warm to r.t. and stirred overnight. The solution was isolated and evaporated to give 2.47 g (89%) of the crude product that was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[NH:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([O-])=O.[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:36]=[CH:35][C:32]([C:33]3[NH:20][C:19]4[CH:18]=[CH:17][C:6]([NH:7][C:8](=[O:16])[C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[OH:15])=[CH:5][C:4]=4[N:1]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccccc1O
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)c1ccccc1O

Procedure:
Compound 427 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(2-hydroxybenzoyl)aniline and 4-morpholinobenzaldehyde. [M+H]+ calcd for C24H22N4O3: 415.18; found: 414.98.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[Br:15][CH2:2][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc2c(c1)NC(=O)CC2
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1CCc2ccc(C(=O)CBr)cc2N1
Temperature: 20 °C

Procedure:
9.45 Grams of 7-acetyl-3,4-dihydrocarbostyril was dissolved in 30 ml of glacial acetic acid with stirring at 20° C., then a mixture of 2.6 ml of bromine with 10 ml of glacial acetic acid was added dropwise at a room temperature for 30 minutes with stirring. The reaction mixture was ice-cooled to precipitate crystals, and recrystalized from 50%-ethanol aqueous solution to obtain 7-α-bromoacetyl-3,4-dihydrocarbostyril. Yield: 9.4 g. Melting point: 202°-203° C. Colorless needle-like crystals
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:23])([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:9][NH:10][C:11](=[O:14])[CH2:12]Cl)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH2:9][NH:10][C:11](=[O:14])[CH2:12][O:23]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C(O)(CNC(=O)CCl)c2ccc(Br)cc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: COc1cccc(C2(c3ccc(Br)cc3)CNC(=O)CO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of N-[2-(4-bromo-phenyl)-2-hydroxy-2-(3-methoxy-phenyl)-ethyl]-2-chloro-acetamide (3.67 g, 9.2 mmol), in benzene (205 mL) at room temperature was added t-BuOK (4.54 g, 40.5 mmol). The reaction mixture was stirred at room temperature for 2 h. To the mixture was added water (40 mL) and the aqueous layer was washed with CH2Cl2 (2×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (3:1) afforded 3.34 g of 6-(4-bromo-phenyl)-6-(3-methoxy-phenyl)-morpholin-3-one. 1HNMR (400 MHz, CDCl3) δ 7.46-7.41 (comp, 2H), 7.27-7.17 (comp, 2H), 6.89-6.70 (comp, 3H), 6.69 (br, 1H), 4.10 (s, 2H), 3.93-3.80 (comp, 2H), 3.76 (s, 3H); MS (M+1) 362.1, 364.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O1CCCC1>CO.[Pd].[H][H]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Yield: 99.7 %

Procedure:
To a solution of 2.54 g of tert-butyl 1,2,3,6-tetrahydro-4-(3-nitrophenyl)pyridine-1-carboxylate (which was prepared by the method as described in Synthesis, 1991, 993-995) in 20 ml of methanol, 250 mg of 10% palladium-on-carbon catalyst was added, and stirred for an hour in hydrogen atmosphere at ambient temperature and pressure. After addition of 20 ml of tetrahydrofuran to the reaction liquid, the liquid was filtered with Celite. Distilling the solvent off under reduced pressure, 2.30 g of the title compound was obtained.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[I:41])[CH:36]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH2:25]([O:32][C:33]1[CH:34]=[C:35](/[CH:36]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:38]=[CH:39][C:40]=1[I:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(I)c(OCc2ccccc2)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(I)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
5.0 g (14.95 mmol, 1.8 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 3.25 g (8.2 mmol, 1 eq) of 3-benzyloxy-4-iodobenzaldehyde in 15 ml of toluene. The reaction mixture is stirred for 1 hour at 90° C. The solvent is evaporated off and the residual oil is then chromatographed on silica gel (8/2 heptane/ethyl acetate) and recrystallized from dichloromethane/heptane. 2.59 g of methyl (E)-3-(3-benzyloxy-4-iodophenyl)acrylate are obtained in solid form. Yield=68%
Reaction SMILES: [H-].[Na+].[OH:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].Cl[CH2:16][CH2:17][CH2:18][N:19]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23]>CN(C)C=O>[CH2:24]([N:19]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH2:17][CH2:16][O:3][N:4]1[C:5](=[O:14])[C:6]2=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]2[C:8]1=[O:9])[CH2:25][CH2:26][CH3:27]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCCN(CCCC)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(CCCC)CCCON1C(=O)c2ccccc2C1=O
Yield: 96.6 %

Procedure:
To a suspension of 1.75 g of sodium hydride in ml of N,N-dimethylformamide was added a mixture of 11.9 g of N-hydroxyphthalimide and 60 ml of N,N-dimethylformamide, and then the mixture was stirred for minutes. To the reaction solution was added a mixture of 15 g of 3-chloropropyldibutylamine and 10 ml of N,N-dimethylformamide, and then the mixture was heated at reflux for 5 hours. After evaporation of the solvent, ethyl acetate was added to the residue, and the mixture was washed with water. Evaporation of the solvent gave 23.4 g of N-(3-dibutylaminopropoxy)-phthalimide, which was then dissolved in 200 ml of methylene chloride. To the solution was added 20 ml of hydrazine monohydrate, and the mixture was stirred at room temperature for 3 hours. After removal of the insolubles by filtration, the filtrate was concentrated under reduced pressure and distilled under reduced pressure to give 10.3 g of O-(3-dibutylaminopropyl)hydroxylamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.C(N(CC)CC)C.[O:24](C(OC(C)(C)C)=O)[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:25](=[O:24])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
To a mixture of Example 260a (2.60 g, 7.39 mmol) and triethylamine (1.340 mL, 9.61 mmol) in tetrahydrofuran (50 mL) was added BOC2O (1.78 g, 8.13 mmol) at 0° C. The ice bath was removed and the reaction was stirred at room temperature for 90 minutes. The reaction was diluted with EtOAc and washed with brine and sat. NaHCO3. The organic layer was dried over MgSO4, filtered, concentrated, and purified on an 80 g column using the ISCO Companion flash system eluting with hexane/EtOAc (8:2 to 6:4) to give 1.78 g of the title compound.