Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]2[C:9]([CH3:16])([CH3:15])[CH2:8][CH2:7][C:6]([CH3:18])([CH3:17])[C:5]=2[C:4]=1[OH:19])=[O:2].[OH-].[K+].S(OC)(O[CH3:26])(=O)=O.Cl>C1(C)C=CC=CC=1>[CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]2[C:9]([CH3:15])([CH3:16])[CH2:8][CH2:7][C:6]([CH3:18])([CH3:17])[C:5]=2[C:4]=1[O:19][CH3:26])=[O:2]
Reactant: Cc1c(C)c2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1c(C=O)c(C)c(C)c2c1C(C)(C)CCC2(C)C
Temperature: 55 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
Methylation. 2-Formyl-1-hydroxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene (8.7 g, 0.0335 mol) was stirred with toluene (60 mL), and potassium hydroxide 85% (3.1 g, 0.047 mol) was added in one portion. The mixture was heated to 55° C., dimethyl sulfate (6.3 g, 0.05 mol) added during 0.5 h at 55°-60° C., and the heating continued at 55°-60° C. for 4 h. The mixture was cooled to 20° C., neutralized with 5% hydrochloric acid, then washed with water (10 mL), and finally washed with brine (10 mL). The solvent was removed by distillation and the residue distilled to give 2-formyl-1-methoxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene (5.8 g), GLC purity 97%. Crystallization from hexane gave 3.5 g material with GLC purity 100%. 1H-NMR (CDCl3) δ10.40 (1H, s), 3.78 (3H, s), 2.40 (3H, s), 2.37 (3H, s), 1.64 (4H, s), 1.45 (6H, s), 1.42 (6H, s). 13C-NMR (CDCl3) δ193.5 (1C, d), 162.9 (1C, s), 151.6 (1C, s), 137.7 (1C, s), 136.7 (1C, s), 132.5 (1C, s), 126.9 (1C, s), 65.7 (1C, q), 40.3 (1C, t), 38.2 (1C, t), 36.2 (1C, s), 35.2 (1C, s), 30.2 (2C, q), 29.8 (2C, q), 19.7 (1C, q), 15.8 (1C, q). IR (KBr) 1244, 1271, 1682 cm-1, MS (m/e) 274.2 (M+, 34.9), 259.1 (100.0), 260.2 (21.7), 189.1 (21.5).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:13]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1ccccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccccn2)sc2ccccc12
Yield: 43.8 %

Procedure:
Methyl thiosalicylate (1.6 g, 9.51 mM) and 2-cyanopyridine (1.0 g, 9.60 mM) were dissolved in toluene (2 ml), and triethylamine (2 ml, 14.4 mM) was added to the solution. After heating for 8 hours under reflux, toluene was removed by distillation. Ethanol was added to the residue and the precipitates were taken out by filtration to give crude crystals (1.7 g). The crude crystals were purified by silica gel column chromatography (hexane:chloroform=5:1→chloroform) to give the title compound as crystals (1.0 g, 43.4%).
Reaction SMILES: C([O-])(=[O:3])C.[K+].Cl[C:7]1[N:12]=[N:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:32])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[C:33]([C:35]1[CH:45]=[C:44]([CH3:46])[C:38]2[N:39]([CH3:43])[C:40](=[O:42])[O:41][C:37]=2[CH:36]=1)=[O:34]>C(O)(=O)C>[CH3:43][N:39]1[C:38]2[C:44]([CH3:46])=[CH:45][C:35]([C:33]([C:8]3[C:7](=[O:3])[NH:12][N:11]=[C:10]([N:13]4[CH2:14][CH2:15][CH:16]([N:19]5[CH2:25][CH2:24][C:23]6[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:22]=6[NH:21][C:20]5=[O:32])[CH2:17][CH2:18]4)[CH:9]=3)=[O:34])=[CH:36][C:37]=2[O:41][C:40]1=[O:42]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c(Cl)nn3)CC1)C(=O)N2
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c(=O)[nH]n3)CC1)C(=O)N2
Reaction time: 16 h

Procedure:
0.10 g (1.02 mmol) potassium acetate were added to 0.13 g (0.20 mmol) 3-{1-[6-chloro-5-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-pyridazin-3-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one (mixture) in 2 mL acetic acid and the mixture was boiled for 16 h under a nitrogen atmosphere. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16](Br)[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][N:10]3[CH:20]=[CH:21][CH:22]=[C:9]23)[CH2:4][CH2:3]1.[CH3:23][N:24](C)C=O.C1C=CC=CC=1.[C-]#N.[Na+]>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:23]#[N:24])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][N:10]3[CH:20]=[CH:21][CH:22]=[C:9]23)[CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CN1CCC(=C2c3cc(Br)ccc3C=Cn3cccc32)CC1
Agent: [C-]#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CN1CCC(=C2c3cc(C#N)ccc3C=Cn3cccc32)CC1
Reaction time: 1 h

Procedure:
1-Methyl-4-[9-bromo-11H-pyrrolo[2,1-b] [3]benzazepin-11-ylidene]piperidine (6.3 g., 0.017 mole) and cuprous cyanide (3.2 g., 0.035 mole) in 25 ml. of dry dimethylformamide are refluxed under nitrogen for five hours. The mixture is cooled to an internal temperature of 50° and treated with 60 ml. each of benzene and aqueous saturated sodium cyanide solution. After stirring one hour the contents are transferred to a separatory funnel with the aid of additional benzene and water. The aqueous phase is extracted two times with benzene, once with ether and the combined benzene-ether extracts are washed successively with dilute sodium cyanide, water, dilute ammonium hydroxide, and water. Upon drying over sodium sulfate the solvents are evaporated in vacuo to give 1-methyl-4-[9-cyano-11H-pyrrolo[2,1-b] [3]benzazepin-11-ylidene]piperidine as an oil (5.0 g., 94%). Trituration with acetonitrile gives a solid (3.6 g., m.p. 156°-159° C.). An analytical sample is obtained after one recrystallization from acetonitrile, m.p. 158°-161° C.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[C:13]2[CH2:14][CH2:15][C@@H:16]3[C@H:21]([C:12]=2[CH:11]=[CH:10][C:9]=1[O:23][CH3:24])[CH2:20][NH:19][C:18](=O)[CH2:17]3.[ClH:25]>CCOCC.CCO>[ClH:25].[CH3:6][O:7][C:8]1[C:13]2[CH2:14][CH2:15][C@@H:16]3[C@H:21]([C:12]=2[CH:11]=[CH:10][C:9]=1[O:23][CH3:24])[CH2:20][NH:19][CH2:18][CH2:17]3
Reactant: COc1ccc2c(c1OC)CC[C@H]1CC(=O)NC[C@@H]21
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1OC)CC[C@H]1CCNC[C@@H]21
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.6 %

Procedure:
A flame-dried 1-neck flask was charged with 50 mL of distilled THF and 0.130 g (0.498 mmol) of the cis lactam 15a were added. A 1.0 M solution of BH3 in THF (2.49 mL, 2.49 mmol) was added dropwise to the flask and the reaction was heated at reflux overnight. The reaction was then cooled to room temperature, quenched carefully with H2O, and evaporated to about one-third the volume. Following the addition of 10 mL 2N HCl, the solution was stirred at ambient temperature for 4 h. The aqueous solution was washed once with Et2O, basified with NH4OH, and extracted with CH2Cl2 (3×25 mL). The organic layers were combined, dried over Na2SO4, filtered, and evaporated to yield a colorless residue, which was dissolved in Et2O and acidified with 6N HCl in EtOH. The solid that formed was collected by filtration to yield 0.084 g (0.297 mmol, 59.6%) of the isoquinoline HCl 17a as a white powder; mp 186° C. (dec). 1H NMR: (500 MHz, DMSO): δ 8.80 (bs, 2H, NH2); 6.87 (m, 2H, ArH); 3.75 (s, 3H, ArOCH3); 3.66 (s, 3H, ArOCH3); 3.18-3.15 (dd, 1H, J=4.2, 12.4 Hz, ArCHCH2NH2); 3.12-3.05 (m, 2H, CH2NH2CH2); 2.99-2.82 (m, 3H, ArCHCH2NH2CH2, ArCH2); 2.59-2.48 (m, 1H, ArCH2); 2.10-1.89 (m, 3H, ArCH2CH2CHCH2); 1.76-1.68 (bd, 1H, J=11.8 Hz, NH2CH2CH2); 1.62-1.54 (m, 1H, ArCH2CH2). ESIMS (M+H)=248.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:18]3[O:17][CH:16]=[CH:15][C:14]=3[CH:13]=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.N[CH2:23][C@H]1CCCN1CC>>[CH2:2]([N:1]1[CH2:6][CH2:5][CH2:23][C@@H:7]1[CH2:8][NH:9][C:10]1[C:18]2[O:17][CH:16]=[CH:15][C:14]=2[CH:13]=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1)[CH3:3]
Reactant: CCN1CCC[C@@H]1CN
Reactant: O=[N+]([O-])c1cc(NCCN2CCOCC2)c2occc2c1
Product: CCN1CCC[C@@H]1CNc1cc([N+](=O)[O-])cc2ccoc12
Yield: 100 %

Procedure:
The title compound was prepared according to the procedure described for Intermediate 27 using (R)-2-aminomethyl-1-ethylpyrrolidine. Yield: 100%, HPLC purity=90%, m/z=290 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[CH:15]1([NH:14][C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[C:21]([F:20])[CH:22]=4)[CH:7]=3)[CH:13]=[CH:12][N:11]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Clc1cc(-c2ccnc(NC3CCCC3)n2)ccn1
Reactant: Nc1cccc(F)c1
Product: Fc1cccc(Nc2cc(-c3ccnc(NC4CCCC4)n3)ccn2)c1

Procedure:
The title compound was prepared in the same fashion as described in Example 7, Step D using 4-(2-chloro-4-pyridinyl)-N-cyclopentyl-2-pyrimidinamine (i.e., the product of Step A) and 3-fluoroaniline.
Reaction SMILES: S(=O)(=O)(O)O.O.[F:7][C:8]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:10]([C:11]([O:13]C)=[O:12])[C:9]=1[C:21]([O:23]C)=[O:22]>C(O)(=O)C>[F:7][C:8]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:10]([C:11]([OH:13])=[O:12])[C:9]=1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1C(=O)OC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Yield: 73.3 %

Procedure:
Sulfuric acid (99%, 45 ml) was added cautiously to water (45 ml) and the resulting solution mixed with glacial acetic acid (450 ml). To this solution was added dimethyl 3,4,5,6-tetrafluorophthalate (90.0 g) and the resulting mixture heated at reflux for six hours. The solution was concentrated under reduced pressure to remove acetic acid and water. Fresh acetic acid (450 ml) and water (75 ml) were added to the residue and refluxing continued overnight (16 hours). The solution was concentrated again under reduced pressure to a semisolid. Hydrochloric acid (37%, 150 ml) was added and the mixture warmed until all the solids dissolved. The solution was concentrated under reduced pressure to 125 ml. Cooling gave crystals which were collected and washed with 37% hydrochloric acid. Recrystallization from 130 ml 24% hydrochloric acid followed by drying under vacuum at room temperature gave tetrafluorophthalic acid (59 g, 73%); mp 159°-161° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][NH:35][CH3:36]>>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][N:32]([CH3:31])[CH2:33][CH2:34][NH:35][CH3:36])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CNCCNC
Product: CNCCN(C)Cc1cn(CC2CC2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12

Procedure:
The title compound was prepared as a solid by the method of Example 59 step iv) using product of Example 59 step iii) and N1,N2-dimethylethane-1,2-diamine.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[N+:9]=[N-:10])=[CH:5][CH:4]=1.C(Cl)[Cl:14]>>[Cl:14][CH2:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[N+:9]=[N-:10])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CN=[N+]=[N-])cc1
Reactant: ClCCl
Product: [N-]=[N+]=NCc1ccc(SCCl)cc1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(methylthio)benzylazide (0.359 g, 2 mmol) in CH2Cl2 was cooled in ice and treated slowly with SO2Cl2 (0.297 g, 2.2 mmol). The reaction mixture was stirred at 5° C. for 1.5 h and then evaporated to dryness. The crude compound was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:18])[CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[C:5]([Cl:19])=[CH:4][N:3]=1.Cl.[CH3:21][N:22]1[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23]1.C(N(C(C)C)C(C)C)C>CCCCO>[Cl:19][C:5]1[C:6]([N:8]([CH3:18])[CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)=[N:7][C:2]([NH:27][C:25]2[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=2)=[N:3][CH:4]=1
Reactant: CN(c1nc(Cl)ncc1Cl)C1COC2C(O)COC21
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1COC2C(O)COC21
Temperature: 150 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a suspension of 6-((2,5-dichloropyrimidin-4-yl)(methyl)amino)hexahydrofuro[3,2-b]furan-3-ol (342.2 mg, 1.12 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (185.0 mg, 1.38 mmol) in n-BuOH (5 mL) was added N-ethyldiisopropylamine (358.8 mg, 2.78 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/40) to give the title compound as a beige solid (156 mg, 38.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[C:15]([C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1)=[O:16]>C1COCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:29]=[CH:28][CH:27]=[C:14]([C:15]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][C:22](=[O:26])[NH:23]3)=[CH:19][CH:18]=2)=[O:16])[CH:13]=1)=[O:5]
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A dry flask was charged with 2-Methyl-benzoyl chloride (3.00 g, 19.41 mmol) and THF (200 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 4.895 g, 19.4 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF (15 mL) and collected to afford the 2-Methyl-N-[3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-benzamide as a solid (5.174 g, 13.97 mmol, 72%).
Reaction SMILES: [C:1]1([C:7]#[C:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCCCCCCCCCCCC>C1COCC1.[Zn+2].[Br-].[Br-]>[C:1]1([C:7]#[C:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccccc1
Reactant: Br[Mg]C#Cc1ccccc1
Agent: CCCCCCCCCCCCC
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
A solution of phenylethynylmagnesium bromide (4.0 ml; 4.00 mmol; 1.0 M in THF) in was treated at room temperature with a solution of ZnBr2 (0.473 g; 2.10 mmol) in THF (1 ml) and stirred for 30 min. This solution was then added to a room temperature solution of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0282 g; 5 mol %), and tridecane (0.244 ml; 0.184 g; 1.00 mmol) in THF (1 ml). The reaction mixture was then heated to 65° C. and stirred for 46 h; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 0.63 mmol (31% yield) of diphenylacetylene and 0.36 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15]I)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[CH3:25])[NH2:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Zn]>[NH2:21][C:20]1[CH:19]=[CH:18][C:24]([CH3:25])=[C:23]([CH2:15][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:22]=1
Reactant: COC(=O)C[C@H](CI)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(N)cc1I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Zn]
Product: COC(=O)C[C@H](Cc1cc(N)ccc1C)NC(=O)OC(C)(C)C
Yield: 65 %

Procedure:
Following the General Procedure of Description 15 (Part B), the zinc insertion product of (5c) was used in situ to cross couple with commercial 3-iodo-4-methyl-aniline (583 mg, 2.5 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (57 mg, 0.03 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (76 mg, 0.25 mmol, 10 mol-%) in anhydrous degassed DMF (6 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography with ethyl acetate (EtOAc)/hexane mixtures (EtOAc/hexane=7:3→1:1, v/v) furnished 1.04 g (65% yield) of the title compound (5d) as a yellow viscous oil. Rf˜0.28 (EtOAc/hexane=1:1, v/v). 1H NMR (400 MHz, CDCl3): δ 6.89 (d, J=8.4 Hz, 1H), 6.48-6.44 (m, 2H), 5.10-5.02 (br. m, 1H), 4.18-4.08 (m, 1H), 3.65 (s, 3H), 3.30 (br. s, 2H), 2.82-2.78 (br. dd, 1H), 2.70 (dd, J=10.2, 6.0 Hz, 1H), 2.51 (dd, J=16.0, 5.2 Hz, 1H), 2.45 (dd, J=16.0, 5.6 Hz, 1H), 2.19 (s, 3H), 1.38 (s, 9H) ppm. LC/MS: Rt=1.320 min. LC/MS: m/z=323.20 (M+H+)+, 345.15 (M+Na+)+.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]#[CH:7])[C:2]#[CH:3]>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH2:1]1[C:2]2[C:6](=[CH:7][C:2]([CH2:1][OH:4])=[CH:3][CH:3]=2)[CH2:5][O:4]1
Reactant: C#CCOCC#C
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: OCc1ccc2c(c1)COC2
Temperature: 70 °C
Reaction time: 24 h
Yield: 115.3 %

Procedure:
In a round bottom flask with reflux condenser were placed 1.0 g of 3-Prop-2-ynyloxy-propyne and 2.08 g of propargylic alcohol in 10 ml ethanol, followed by the addition of 9.8 mg of tris(triphenylphosphine)rhodium chloride (Wilkinson catalyst) at room temperature. The reaction was heated up to 70° C., while the reaction colour turned yellow rapidly. After 1 day stirring at r.t., TLC analysis showed complete conversion of the starting material. The solvent was evaporated, diluted with DCM and extracted with H2O, dried over MgSO4. The brown mixture was purified by flash chromatography using 8/2 cyclohexane/AcOEt as mobile phase affording (1,3-Dihydro-isobenzofuran-5-yl)-methanol as a colourless pure solid (0.92 g, 60%).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[CH:20]3[CH2:21][C:7]4([CH2:11][N:10]([CH2:12][CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH:8]4[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=43)[C:6]=2[CH:26]=1.N([O-])=O.[Na+].[BrH:31]>O>[Br:31][C:2]1[CH:3]=[CH:4][C:5]2[CH:20]3[CH2:21][C:7]4([CH2:11][N:10]([CH2:12][CH:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)[CH2:9][CH:8]4[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=43)[C:6]=2[CH:26]=1
Reactant: Nc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.0 g (14.55 mmoles) of 5-amino-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole, (Example 64), in 25 ml of 40% hydrobromic acid, cooled at 5°, was diazotized with a solution of 1.1 g (16 mmoles) of sodium nitrite in 5 ml of water. The reaction mixture was allowed to warm to room temperature, filtered, and then added dropwise to a solution of 4.0 g (27.7 mmoles) of cuprous bromide in 25 ml of 48% hydrobromic acid. After standing overnight, dilution with water gave a precipitate which was collected by filtration. The solids were extracted with methylene chloride, and the organic layer washed with 1N aqueous sodium hydroxide solution was then with water. The extract was dried over potassium carbonate and evaporated to give 1.2 g of 5-bromo-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]-cyclohepta[1,2-c]pyrrole as an oil; nmr spectrum δ 1.0-4.0 (m, 19); 6.8-7.5 (m, 7).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:23]([N:30]([C:38](=[O:40])[CH3:39])[C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:22][C@@H:21]3[CH3:41])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)=[O:4].C(O)C.[OH-].[Na+]>O1CCCC1>[C:38]([N:30]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C@H:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:7]3[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)=[O:19])[C@@H:21]([CH3:41])[CH2:22]1)(=[O:40])[CH3:39]
Reactant: COC(=O)c1ccc(COc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCc3ccc(C(=O)O)o3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2S,4R)-5-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxymethyl)-furan-2-carboxylic acid methyl ester (0.145 g, 0.25 mmol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and sodium hydroxide (1N) was added. The mixture was stirred at room temperature 4 hours. The mixture was cooled to rt, acidified to form a white precipitate. The solid was filtered to give (2S,4R)-5-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxymethyl)-furan-2-carboxylic acid as a white solid.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:7][SiH2:8][Cl:9]>>[CH2:1]([SiH:8]([Cl:9])[Cl:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cl[SiH2]Cl
Reactant: C=CCCCC
Product: CCCCCC[SiH](Cl)Cl
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Zero point eight nine mol of 1-hexene and 0.1 mol % (relative to dichlorosilane) of catalyst NiCl2 (PPh3)2 were introduced into a 500 ml pressure-proof stainless reactor and after closing said reactor, was cooled in a dry ice-methanol bath. After introducing 0.64 mol of dichlorosilane through an introducing pipe, the reactor was sealed and reaction was carried out with stirring in an oil bath at 110° C. for one hour to produce n-hexyldichlorosilane (n-C6H13SiHCl2). After reaction, n-C6H13SiHCl2 having a boiling point of 100°-102° C./100 mmHg and nD20 of 1.4412 was obtained by distillation. The yield was as shown in Table 1 and there was no by-product formed.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[OH:23][CH:24]([CH3:45])[CH2:25][N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[C:27]1=[O:44]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:31]3[CH:32]=[C:33]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:44])[N:26]([CH2:25][CH:24]([OH:23])[CH3:45])[CH2:34]4)[C:16]2=[CH:15][N:14]=1
Reactant: CC(O)CN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(CC(C)O)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(2-hydroxypropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=482.1.