Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([CH:35]=[CH:36][CH:37]=1)[O:21][CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)=[O:11])=O)(C)(C)C.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>ClCCl>[NH2:8][C@@H:9]([CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:37]=[CH:36][CH:35]=[C:20]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=1)=[O:11].[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)NCCCC#Cc1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1cccs1)C(=O)NCCCC#Cc1cccc(OC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of the purified (S)-tert-butyl 4-(3-(5-(2-(tert-butoxycarbonylamino)-3-(thiophen-2-yl)propanamido)pent-1-ynyl)phenoxy)piperidine-1-carboxylate (0.26 g, 0.47 mmol) in dichloromethane (1.6 ml) was added TFA (0.4 ml) and the resulting mixture was stirred at room temperature for 1 hr. The resulting solution was concentrated and the residue purified over Gilson HPLC to yield (S)-2-amino-N-(5-(3-(piperidin-4-yloxy)phenyl)pent-4-ynyl)-3-(thiophen-2-yl)propanamide as its corresponding TFA salt, as a deep colored oil. MH+ 412.25. 1H NMR (300 MHz, DMSO), δ: 8.50 (1H, d), 8.23 (1H, s), 7.43 (1H, d), 7.30 (1H, m), 6.90 (3H, m), 4.65 (1H, m), 3.96 (1H, m), 2.96-3.30 (8H, m), 2.35 (2H, m), 2.10 (2H, m), 1.60-1.80 (4H, m)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH:12](OCC)(OCC)OCC>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][CH:12]=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NNC(=O)c1ccc(Br)cc1
Product: Brc1ccc(-c2nnco2)cc1
Reaction time: 8 h

Procedure:
12.3 mmol of 4-bromo-benzoic acid hydrazide were dissolved in 26 ml of triethyl orthoformate. The reaction mixture was stirred overnight at 140°, evaporated and the residue crystallized from ethanol to give the title compound as a colorless solid. MS (m/e): 225.0 (MH+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:24]=[C:25]([CH:34]=[CH:35][CH:36]=1)[O:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:36]=[CH:35][CH:34]=[C:25]([O:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: Brc1cccc(OCCN2CCCC2)c1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4cccc(OCCN5CCCC5)c4)nnc3c2)c1
Yield: 65 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.113 g, 0.377 mmol, 1 equiv), 1-[2-(3-bromo-phenoxy)-ethyl]pyrrolidine (0.153 g, 0.565 mmol, 1.5 equiv), cesium carbonate (0.368 g, 1.13 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.044 g, 0.0753 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.034 g, 0.0376 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (8 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 18 hours, then filtered hot and the solvents were diluted with ethyl acetate and washed with brine. The brine layer was back extracted once with fresh ethyl acetate. The organic phases were combined and dried over sodium sulfate (Na2SO4). Filtration followed by evaporation and column chromatography (1:5 MeOH/DCM) provided desired product as a yellow powder (0.12 g, 65% yield). MS (ESI+): m/z=491.1, LC retention time: 2.94 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][C@@H:19]3[CH3:24])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]([O:27][CH3:28])=[O:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][CH2:36]I>CN(C)C=O.O>[CH2:35]([N:21]1[CH2:22][CH2:23][N:18]([C:17]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:25]([O:27][CH3:28])=[O:26])=[CH:12][CH:11]=3)[C@@H:19]([CH3:24])[CH2:20]1)[CH3:36]
Reactant: CCI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCNC[C@@H]3C)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2nc3cc(C(=O)OC)ccc3nc2-c2ccc(F)cc2)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 2-(4-fluorophenyl)-3-(2-methylpiperazin-1-yl)quinoxaline-6-carboxylate (160 mg, 0.42 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (174 mg, 1.26 mmol) and CH3CH2I (68.8 mg, 0.44 mmol), and the reaction was stirred overnight at room temperature. The reaction solution was diluted with water (150 mL), extracted with dichloromethane (3×30 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1% methanol in dichloromethane) to afford (S)-methyl 3-(4-ethyl-2-methylpiperazin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as light yellow oil (80 mg, crude).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.COCCN(S(F)(F)[F:23])CCOC.[NH4+].[Cl-]>C(Cl)Cl>[F:23][C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[CH2:11][O:10][CH2:9]1
Reactant: OC1(c2cccc(I)c2)COC1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: FC1(c2cccc(I)c2)COC1
Reaction time: 1 h

Procedure:
To a solution of 500 mg (1.81 mmol) 3-(3-iodo-phenyl)-oxetan-3-ol in 10.6 mL DCM was added 1.17 mL (2.72 mmol) [bis(2-methoxyethyl)amino]sulfur trifluoride at RT under argon atmosphere. The resulting mixture was stirred for 1 h. The mixture was worked up by adding saturated NH4Cl solution. Phases were separated. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (PE/EtOAc=9/1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=2)=[C:4]([O:26]C)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=2)=[C:4]([OH:26])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reaction time: 16 h
Yield: 62 %

Procedure:
To a stirred solution of 2-(4-chloro-2-methoxy-phenyl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (1.95 g, 5 mmol) in dichloromethane (40 ml) was added boron tri bromide (1M solution in dichloromethane; 21 ml, 21 mmol) at 25° C., and the resulting mixture was allowed to stir for 16 h at the same temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate solution and further diluted with dichloromethane (30 ml). The organic layer was washed with water, and then with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford the crude material. Crude product was purified by column chromatography using silica gel (5-10% ethyl acetate/n-hexane) to give the desired compound as a colorless powder (62%). MS (Turbo Spray): m/z=376.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Br:26])[C:5]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.[Br:27]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]([Br:26])[C:5]([C@@H:8]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][C:7]=1[Br:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1ncc(N)cc1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(Br)c(N)cc1Br
Reaction time: 0.08 h

Procedure:
A solution of (S)-tert-butyl (1-(5-amino-3-bromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (46A, 960 mg, 2.24 mmol) in 20 mL of acetonitrile was cooled to 0° C. and treated with N-bromosuccinimide (399 mg, 2.24 mmol) as a solution in 20 mL of acetonitrile. After 5 min, the reaction mixture was partitioned with EtOAc and saturated aqueous NaHCO3. The organic layer was separated and washed with brine, then dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with EtOAc/hexanes to afford the title product. MS (m/z): 507.52 [M+H]+.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][C:12]([CH3:26])=[CH:13][CH2:14][CH2:15]/[C:16](/[CH3:25])=[CH:17]/[CH2:18][CH2:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>[Pd].[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC>[OH:24][C:20]([CH2:19][CH2:18][CH:17]=[C:16]([CH2:15][CH2:14][CH:13]=[C:12]([CH3:26])[CH3:11])[CH3:25])([CH:22]=[CH2:23])[CH3:21]
Reactant: C#CC(C)(O)CC/C=C(\C)CCC=C(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: C=CC(C)(O)CCC=C(C)CCC=C(C)C
Yield: 90.6 %

Procedure:
Further, 0.5 ml of quinoline and 20 g of 0.25% Pd-Lindlar catalyst was added in a solution of 1,280 g of the said dehydronerolidol in 2,000 ml of n-hexane and the mixture was hydrogenated at room temperature and normal pressure. After post-treatment, the reaction mixture was subjected to vacuum distillation to give 1,170 g of nerolidol having b.p. 105° - 110° C. (0.5 mmHg).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[N+:8]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:8]([C:11]1[CH:16]=[C:15]([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: Clc1cnccn1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2cnccn2)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
To a suspension of 2-chloropyrazine (1.14 g), 3-nitrophenylboronic acid (2.00 g) and tetrakis(triphenylphosphine)-palladium (346 mg) in 1,2-dimethoxyethane (30 ml) was added an aqueous solution of sodium carbonate (2M, 12 ml) followed by stirring at 80° C. for 18 hours. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with methanol and collected by filtration. The obtained product was washed with methanol and diisopropyl ether and dried to give 2-(3-nitrophenyl)pyrazine (1.78 g, 88.6%).
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[C:15]([O:17]C(=O)C)([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[O:12]1)(=O)C1C=CC=CC=1.CO>N>[CH:33]1([NH:32][C:28]2[N:27]=[CH:26][N:25]=[C:24]3[C:29]=2[N:30]=[CH:31][N:23]3[CH:13]2[O:12][C@H:11]([CH2:10][OH:9])[C:15]([CH3:16])([OH:17])[C@:14]2([F:22])[CH3:21])[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCCC4)ncnc32)[C@]1(C)F
Agent: N
Solvent: CO
Product: CC1(O)[C@@H](CO)OC(n2cnc3c(NC4CCCC4)ncnc32)[C@]1(C)F
Yield: 91.2 %

Procedure:
A solution of ((2R,4R)-3-acetoxy-5-(6-(cyclopentylamino)-9H-purin-9-yl)-4-fluoro-3,4-dimethyltetrahydrofuran-2-yl)methyl benzoate (about 0.31 g, 0.60 mmol) in methanolic ammonia (25% w/w 15 ml) was stirred at room temperature for overnight. Completion of the reaction monitored by thin-layer chromatography and methanol was removed under reduced pressure then water added to the crude and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, concentrated under reduced pressure and purified by silica gel column chromatography using 5% methanol in dichloromethane to afford the title compound (0.2 g) as a colorless solid. Yield: 90%; 1H NMR (300 MHz, CDCl3): δ 8.33 (s, 1H), 7.92 (d, 1H, J=3.6 Hz), 6.62 (d, 1H, J=22.2 Hz), 5.83 (bs, 1H), 5.55 (s, 1H), 5.43 (bs, 1H), 4.58 (bs, 1H), 4.25-4.21 (m, 2H), 4.14-4.10 (m, 1H), 2.15-2.09 (m, 1H), 1.78-1.52 (m, 8H), 1.42-1.25 (m, 6H); ES Mass: [M+1]+ 366 (100%), 367 (45%); IR cm−: 3306, 2959, 1624, 1475, 1232, 1056, 938, 812; HPLC: 98.2%.
Reaction SMILES: [OH:1][C:2]([C:26]1[N:30](COCC[Si](C)(C)C)[C:29]2[CH:39]=[C:40]([C:43]#[N:44])[CH:41]=[CH:42][C:28]=2[N:27]=1)([C:4]1[C:12](SC)=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2S(C1C=CC(C)=CC=1)(=O)=O)[CH3:3].OC(C1N(COCC[Si](C)(C)C)C2C=CC(C#N)=CC=2N=1)(C1C(SC)=CC(C)=C2C=1C=CN2[S:60]([C:63]1C=CC(C)=CC=1)(=[O:62])=[O:61])C>>[OH:1][C:2]([C:26]1[NH:27][C:28]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][C:29]=2[N:30]=1)([C:4]1[C:12]([S:60]([CH3:63])(=[O:62])=[O:61])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH3:3]
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Product: Cc1cc(S(C)(=O)=O)c(C(C)(O)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12

Procedure:
A mixture of (±)-2-(1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile was transformed into the title compound using the same reaction conditions as described in Example 10-B and Example 10-C. 1H NMR (400 MHz, DMSO-d6) δ 12.24-12.49 (m, 1H), 11.46 (br. s., 1H), 8.17-8.32 (m), 7.70-7.84 (m, 2H), 7.54 (m, 1H), 7.45 (m), 7.18 (t, J=2.91 Hz, 1H), 6.49-6.69 (m, 1H), 5.63 (dt, J=1.83, 3.82 Hz, 1H), 3.55 (s, 3H), 2.51 (s, 3H), 2.27 (s, 3H). HRMS calcd. for C20H18N4O3S (M+H)+ 395.1173. found 395.1173.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[S:18][C:17]2[C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:16]3[C:17]4[S:18][C:10]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[CH:11][C:12]=4[N:13]=[CH:14][N:15]=3)=[CH:21][CH:22]=2)=[CH:28][CH:29]=1
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(Nc2ccc(Nc3ncnc4cc(Br)sc34)cc2)cc1
Product: COc1ccc(Nc2ccc(Nc3ncnc4cc(-c5cccs5)sc34)cc2)cc1

Procedure:
The title compound was prepared from 2-thiophene boronic acid and N-(6-bromo-thieno[3,2-d]pyrimidin-4-yl)-N′-(4-methoxy-phenyl)-benzene-1,4-diamine by a procedure analogous to example 2. M.P. 231-40° C. ; LC-MS: 431 (MH+); HPLC RT: 6.740 minutes.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([CH:6]([OH:7])[C@H:5]1[O:8][C@@H:1]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=c1ccn([C@H]2C[C@H](O)[C@@H](C(O)C(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Temperature: 100 °C

Procedure:
A mixture of 2'-deoxyuridine (11.4 g, 0.05 mole) and trityl chloride (13.95 g, 0.05 mole) in dry pyridine 55 ml) was heated at 100° C. for 40 min. After cooling, the mixture was poured into an ice-water mixture (1 l), the precipitate filtered, washed with water, dissolved in chloroform, dried (MgSO4), and then evaporated to a syrup (20.5 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[O:5][CH2:6][C@@H:7]1[C@:16]2([CH3:17])[C@H:11]([C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][CH2:15]2)[CH2:10][CH2:9][C@@:8]1([CH3:21])O.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH3:27][O:26][C:24]1[CH:23]=[C:22]2[C:4](=[C:3]([O:2][CH3:1])[CH:25]=1)[O:5][CH2:6][C@H:7]1[C@@:8]2([CH3:21])[CH2:9][CH2:10][C@@H:11]2[C@:16]1([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]2([CH3:19])[CH3:18]
Reactant: COc1ccc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c(OC)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(OC)c2c(c1)[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CO2
Temperature: -78 °C
Yield: 80.2 %

Procedure:
To a solution of (1S,2R,4aS,8aS)-1-(2,4-dimethoxyphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (41) (0.90 g, 2.4 mmol) in CH2Cl2 (20 mL), cooled to −78° C., a solution of SnCl4 (1.11 mL, 9.56 mmol) in CH2Cl2 (10 mL) was added dropwise. The temperature was maintained at −78° C. for 4 h then the mixture was allowed to warm to room temperature overnight. The reaction was quenched with water (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 4:1) gave (1R,10R,11S,16S)-4,6-dimethoxy-1,11,15,15-tetramethyl-8-oxatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 42) (0.69 g, 80%) as a viscous yellow oil. 1H NMR (CDCl3): δ 6.33 (d, 1H), 6.00 (d, 1H), 4.45 (m, 1H), 4.18 (t, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 2.25 (m, 1H) 1.80-1.38 (m, 7H), 1.35 (s, 3H), 1.25-1.00 (m, 4H) 0.92 (s, 3H), 0.87 (s, 3H), 0.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:4]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:6])=[CH:7][C:8]([F:11])=[CH:9][N:10]=1
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: c1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(F)cnc1Cl)N1CCCc2ccccc21
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-5-fluoro-nicotinic acid (0.60 g, 3.42 mmol, 1.0 equiv; [CAS RN 38186-88-8]) in anhydrous DMF (5 mL) was added 1,2,3,4-tetrahydro-quinoline (0.55 g, 0.52 mL, 4.10 mmol, 1.2 equiv; [CAS RN 635-46-1]), N-ethyldiisopropylamine (2.21 g, 2.91 mL, 17.09 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (1.56 g, 4.10 mmol, 1.2 equiv; [CAS RN 148893-10-1]). The reaction mixture was heated by microwave irradiation to 100° C. for 10 min. To the residue was added a sat. solution of NaHCO3 (50 mL) and the solution extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over Na2SO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate affording 0.51 g (52%) of the title compound as a light yellow solid. MS (ISP): 291.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9]Br)=[CH:4][CH:3]=1.[C-:17]#[N:18].[Na+]>O.C(O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1Oc1ccc(Br)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccccc1Oc1ccc(Br)cc1

Procedure:
457.8 g of the crude 2-(4-bromophenoxy)benzyl bromide are added over a period of one hour to a mixture that is boiling under reflux of 171.0 g of sodium cyanide in 160 ml of water and 44 ml of ethanol; at the same time 362 ml of ethanol are added dropwise. The mixture is subsequently boiled under reflux for a further 3 hours and then diluted with 1500 ml of water. The aqueous ethanolic phase is washed with 1000 ml of diethyl ether and the ether phase is separated off, washed twice with 200 ml of water, dried over magnesium sulphate and concentrated to dryness under 11 mm Hg. The residue is crystallised from a mixture of diethyl ether and petroleum ether and yields 2-(4-bromophenoxy)phenyl acetonitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([F:35])([F:34])([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:23]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:16][C:17]([O:19][CH2:21][C:22](=[O:23])[C:24]2[CH:29]=[CH:28][C:27]([S:30]([F:35])([F:31])([F:32])([F:33])[F:34])=[CH:26][CH:25]=2)=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1(NC(=O)OCc2ccccc2)COC1
Reactant: O=C(CBr)c1ccc(S(F)(F)(F)(F)F)cc1
Product: O=C(CC1(NC(=O)OCc2ccccc2)COC1)OCC(=O)c1ccc(S(F)(F)(F)(F)F)cc1

Procedure:
Prepared by Method E using (3-{[(benzyloxy)carbonyl]amino}oxetan-3-yl)acetic acid (Preparation 25, 0.647 g, 2.44 mmol) and 2-bromo-1-[4-(pentafluoro-λ6-sulfanyl)phenyl]-ethanone (Preparation 40, 0.793 g, 2.44 mmol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]=3[CH:9]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)Sc1ccc(Cl)cc1CC2Cl
Reactant: O=C1OCCN1CCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)Sc1ccc(Cl)cc1CC2N1CCN(CCN2CCOC2=O)CC1

Procedure:
20 G. of 2,10-dichloro-10,11-dihydro-7-methyl-dibenzo[b,f]thiepin are stirred with 41 g. of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone and 400 ml. of chloroform at the boiling temperature for 20 hours. The solution is cooled and washed successively with 2N sodium hydroxide and with water. The organic phase is decanted and extracted with dilute methanesulfonic acid. The acid solution is made alkaline with sodium hydroxide and the oil which separates out is shaken out with ether. The ether solution is washed with water, dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained 3-{2-[4-(2-chloro-10,11-dihydro-7-methyl-dibenzo[b,f]-thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone (melting point 161°-163°C.) which is converted into the corresponding dimethanesulfonate (melting point 187°-189°C.) by reaction with methanesulfonic acid.
Reaction SMILES: [Cl:1][CH:2]([C:9]([O:11][CH3:12])=[O:10])[CH2:3][S:4][CH2:5][C:6]([NH2:8])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>O>[Cl:1][CH:2]([C:9]([O:11][CH3:12])=[O:10])[CH2:3][S:4][CH2:5][C:6]#[N:8]
Reactant: COC(=O)C(Cl)CSCC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Product: COC(=O)C(Cl)CSCC#N
Reaction time: 8 h

Procedure:
To the mixture obtained from Example 4, tosyl chloride (39.34 g) was added in portions with vigorous stirring and heat was evolved. The mixture was stirred for 9.5 hours, stood overnight, then poured into water (500 ml), and extracted with dichloromethane. The combined extracts were washed with water (×2) and saturated brine, dried (magnesium sulphate) and evaporated to yield the title compound as a dark red oil (27.05 g).