Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]([CH3:16])=[CH:12][C:13]=2[C:14]#[N:15])=[C:4]([N+:17]([O-])=O)[CH:3]=1.Cl.[Sn](Cl)Cl.[Sn]>CCO>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[S:10][C:11]([CH3:16])=[CH:12][C:13]=3[C:14]([NH2:15])=[N:17][C:4]=2[CH:3]=1
Reactant: Cc1cc(C#N)c(Nc2ccc(Cl)cc2[N+](=O)[O-])s1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Sn]
Solvent: CCO
Product: Cc1cc2c(s1)Nc1ccc(Cl)cc1N=C2N
Temperature: 85 °C
Reaction time: 3 h

Procedure:
Stir in a 3 neck 12 L round bottom flask 2-(4-chloro-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile (204.9 g, 0.6976 mol, 1 equiv), 3 A EtOH (2 L), and 6N HCl (2 L) for 10 min. Charge to the slurry in one portion, tin (II) chloride (404.1 g, 2.131 mol, 3.06 equiv) and heat to gentle reflux at 85° C. for 3 hours. HPLC at 3 hours shows <0.4% starting material. Allow mixture to cool and stir overnight. During the workup there is a possibility of tin salts precipitating with the product, did not cool as in lab trial, Workup includes: filtering reaction mixture, rinsing with ambient 1:1 3A EtOH/6N HCl (2×500 mL), rinsing with DI water (2×50 mL), drying in vacuum oven at 60° C. for 2 days. Wt.=231.5 g, and anaylsis. Discard some very small amount of precipitate which appears in the filtrate. Tin Removal in Hot 1 N HCl involves placing 231.5 g of the yellow crude product in 22 L flask, adding 1 N HCl (11.6 L), heating to 95° C. and holding at that temperature for 1 hour, shuting off heat and allowing to cool with heating mantle in place overnight. The next morning the temperature is 29° C. Remove mantle and replace with water bath and cool to 22° C. and filter. Rinse flask and add to cake with 1 N HCl (4 L) and follow by DI water (4 L). Pull air through the cake for 10 minutes, place in vacuum oven at 60° C. for 40 hours (Note: Only 1 gram of weight was lost over the final 16 hours of drying time.) Dry weight of title compound is 200.4 g (95.7%). Perform tin analysis. NMR is consistent with product. HPLC showed 98.5%.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@@H:9]([O:10][C:11]3[N:39](COCC[Si](C)(C)C)[C:14]4=[N:15][C:16]([C:20]5[CH:25]=[CH:24][C:23]([C:26]6[CH:31]=[CH:30][C:29]([N:32]=[S:33]([CH3:38])([N:35]([CH3:37])[CH3:36])=[O:34])=[CH:28][CH:27]=6)=[CH:22][CH:21]=5)=[C:17]([Cl:19])[CH:18]=[C:13]4[N:12]=3)[C@H:5]2[O:4][CH2:3]1.OS([O-])(=O)=O.[K+].[OH-].[Na+].Cl>C(O)=O.C(OCC)(=O)C.O1CCCC1>[OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@@H:9]([O:10][C:11]3[NH:39][C:14]4=[N:15][C:16]([C:20]5[CH:25]=[CH:24][C:23]([C:26]6[CH:27]=[CH:28][C:29]([N:32]=[S:33]([CH3:38])([N:35]([CH3:36])[CH3:37])=[O:34])=[CH:30][CH:31]=6)=[CH:22][CH:21]=5)=[C:17]([Cl:19])[CH:18]=[C:13]4[N:12]=3)[C@H:5]2[O:4][CH2:3]1
Reactant: CN(C)S(C)(=O)=Nc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CN(C)S(C)(=O)=Nc1ccc(-c2ccc(-c3nc4[nH]c(O[C@@H]5CO[C@H]6[C@@H]5OC[C@H]6O)nc4cc3Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of N′-{4-[4-(2-{[(3R,3aR,6R,6aR)-6-hydroxy-hexahydrofuro[3,2-b]furan-3-yl]oxy}-6-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-5-yl)phenyl]phenyl}-N,N-dimethyl-methanesulfonimidamide (450 mg) and KHSO4 (2 M aqueous solution, 100 μL) in formic acid (2.4 mL) is stirred for 2 h at 60° C. The mixture is cooled to 0° C. in an ice bath and the pH is adjusted to 11 by adding NaOH (10 M aqueous solution). Tetrahydrofuran (5 mL) is added and the mixture is stirred for 2 h at room temperature. Hydrochloric acid (3 M) is added until the pH reaches 6. The mixture is diluted with ethyl acetate, washed with water and brine, and dried over MgSO4. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (ethyl acetate/methanol 95:5→80:20) to give the title compound. LC (method 1): tR=0.90 min; Mass spectrum (ESI+): m/z=570 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:19][S:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:10][N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=O)(C)(C)C.[Cl:40][C:41]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:42]=1[C:43]([NH2:45])=[O:44].C(C(O)=O)(F)(F)F.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:19][SH:20])[CH2:10][N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14].[Cl:40][C:41]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:42]=1[C:43]([NH2:45])=[O:44]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)CN1CCC[C@H]1C(=O)O
Agent: CC[SiH](CC)CC
Agent: NC(=O)c1cccc(Cl)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CS)CN1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
N-[2(R)-t-Butoxycarbonylamino-3-triphenylmethylmercaptopropyl]-L-proline-2,3-dichlorobenzamide (0.097 g, 0.14 mmol) was dissolved in CH2Cl2(3 mL), CF3CO2H (1 mL) at ambient temperature, treated with triethylsilane (0.088 mL, 0.55 mmol) and stirred for 1 h. The reaction mixture was triturated with 0.1% TFA in H2O, filtered, concentrated and chromatographed by RP-HPLC and lyophilized. The residue was dissolved in MeOH (1 mL), treated with concd HCl, concentrated and triturated with Et2O to provide the title compound as the his hydrochloride salt. 1H NMR (CD3OD) δ 7.50 (d, 1H, J=6 Hz), 7.27-7.4 (m, 2H),4.60 (ABq, 2H), 4.25-4.7 (m, 1H), 3.3-3.9 (m, 5H), 2.99 (d, 2H, J=5 Hz), 2.5-2.7 (m, 1H), 2.0-2.3 (m, 3H).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[Cl:5][C:6]1[C:12]([NH:13][S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:11][C:9]([NH2:10])=[C:8]([F:19])[CH:7]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:5][C:6]1[C:12]([NH:13][S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:11][C:9]([N:10]=[C:1]=[S:2])=[C:8]([F:19])[CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: CCS(=O)(=O)Nc1cc(N)c(F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)Nc1cc(N=C=S)c(F)cc1Cl
Yield: 49.3 %

Procedure:
Under a dry nitrogen atmosphere 0.84 ml (0.011 mole) of thiophosgene was added to a stirred solution of 2.8 g (0.011 mole) of 4-chloro-2-fluoro-5-(N-ethylsulfonylamino)aniline in 250 ml of chloroform. To this mixture was added dropwise 1.6 g (0.012 mole) of triethylamine. The resultant mixture was stirred at room temperature for approximately 18 hours. The solvent was removed from the mixture by evaporation under reduced pressure leaving an oily residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride/hexane (60/40) followed by methylene chloride, to yield 1.6 g of 4-chloro-5-(N-ethylsulfonylamino)-2-fluorophenyl isothiocyanate as a solid, m.p. 104°-105° C.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>[Pd].C(O)C.O1CCCC1>[N:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])(=[O:9])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCOCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccccc1S(=O)(=O)N1CCOCC1
Reaction time: 5 h
Yield: 97.7 %

Procedure:
A mixture of 1-(morpholinylsulfonyl)-2-nitrobenzene (5.18 g, 19 mmol); as prepared in the preceding step, and 10% palladium on carbon (520 mg) in ethanol (80 mL) and tetrahydrofuran (80 mL) was stirred under hydrogen (balloon) for 5 h. The catalyst was removed by filtration through Celite. The filtrate was concentrated to give the title compound as a yellow solid (4.50 g, 98%) which was directly used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:22])([CH3:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[C:26]([F:43])=[C:27](/[CH:31]=[C:32](/[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[F:42])\[C:33]#[N:34])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[C:26]=2[F:43])[C:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[F:42])([C:33]#[N:34])[CH:9]([CH2:10][C:11]([CH3:22])([CH3:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[NH:8]1)=[O:23])([CH3:3])([CH3:2])[CH3:4]
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)(C/C=N/CC(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 61.2 %

Procedure:
In a manner similar to the method described in Example 100b, [4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 105a (1.25 g, 3.64 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (0.93 g, 3 mmol) prepared in Example 52a, AgF (0.57 g, 4.5 mmol), and triethylamine (1.05 mL, 7.5 mmol) in dichloromethane (100 mL) at room temperature for 18 h, followed by the reaction with DBU (3.6 ml) in tert-butanol (15 mL) at 100° C. for 2 h to give rac-(2R,3S,4R,5S)-5-[3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propyl]-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white solid (1.2 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[C:21](F)[CH:20]=[CH:19][N:18]=1>>[Cl:16][C:17]1[CH:22]=[C:21]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH:20]=[CH:19][N:18]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Fc1ccnc(Cl)c1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccnc(Cl)c1

Procedure:
The title compound, white crystalline solid, MS: m/e=329.2, 331.1 (M+H+) was prepared in accordance with the general method of example 1b from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (CAS: [802905-83-5]) and 2-chloro-4-fluoropyridine.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:19])[C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[N:21]([O-])=[O:22].[Na+]>C(O)C>[O:1]=[C:2]([C:8](=[N:21][OH:22])[C:9](=[O:19])[C:10]1[C:11]([CH3:18])=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=1[CH3:16])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(=O)CC(=O)c1c(C)cc(C)cc1C
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C(=NO)C(=O)c1c(C)cc(C)cc1C

Procedure:
N2O3 gas was slowly passed into a stirred solution of the product of step A (16.2 g) in 300 mL of ethanol until the disappearance of starting material was confirmed by TLC. N2O3 gas was generated by the dropwise addition of 12N aqueous HCl solution into an aqueous slurry of NaNO2. The solvent was removed from the mixture and 200 mL of water was added to the residue. The product was then extracted into ether. The ether extract was dried over Na2SO4 and evaporated to give 16.1 g of a semi-solid.
Reaction SMILES: Br[CH2:2][CH:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:21]([NH2:24])[CH2:22][NH2:23].[OH-].[K+]>>[CH2:4]([CH:3]([CH2:2][NH:23][CH2:22][CH2:21][NH2:24])[NH:23][CH2:22][CH2:21][NH2:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCC(Br)CBr
Reactant: NCCN
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCC(CNCCN)NCCN

Procedure:
A mixture of 1,2-dibromooctadecane (80 g) and anhydrous ethylenediamine (230 g) was added to 400 ml of ehtanol, and the mixture was refluxed under heating for 10 hours. Then, potassium hydroxide (30 g) was added, and the ethanol was distilled off under reduced pressure. The residue was extracted with 400 ml of benzene and recrystallized from 180 ml of ether to produce a pale yellow product.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16]CC)=[O:15])=[C:7]2[NH:19][C@@H:20]1[CH2:24][CH2:23][O:22][CH2:21]1>C1COCC1.O>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]2[NH:19][C@@H:20]1[CH2:24][CH2:23][O:22][CH2:21]1
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1N[C@@H]1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2ccc(Br)cc2c1N[C@@H]1CCOC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Sodium hydroxide (0.657 g, 16.43 mmol) was added to ethyl 6-bromo-4-[[(3R)-tetrahydrofuran-3-yl]amino]quinoline-3-carboxylate (3 g, 8.21 mmol) in THF (60 mL) and water (30 mL) and the resulting mixture stirred at 60° C. overnight. The aqueous component was removed under reduced pressure and the remaining solution was adjusted to pH 6 with 2 M HCl. The solids were collected by filtration and dried in an oven to afford the desired material as a white solid (2.1 g, 76%). NMR Spectrum: 1H NMR (300 MHz, MeOH-d4) δ 2.05-2.08 (1H, m), 2.38-2.48 (1H, m), 3.72-3.93 (4H, m), 4.83-5.01 (1H, m) 7.09 (1H, d), 8.04 (1H, d), 8.55 (1H, s), 8.95 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=339.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Cl:14][C:13]1[C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:22]3[CH:21]=[C:20]([OH:19])[CH:25]=[CH:24][CH:23]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccc2c1CCc1ccccc1C2=CBr
Reactant: OB(O)c1cccc(O)c1
Product: Oc1cccc(C=C2c3ccccc3CCc3c(Cl)cccc32)c1

Procedure:
Following procedures essentially as described in Example 219, below, and using 5-bromomethylene-1-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (100 mg, 0.313 mmol) and 3-hydroxyphenylboronic acid (47 mg, 0.344 mmol) affords 8 mg (8%) of the Z-isomer of the title compound (MS (ES) 331 (M−H). HPLC shows 95% purity. Continue to elute and isolate 27 mg (26%) of the E-isomer of the title compound, MS (ES) 331 (M−H). HPLC shows 97% purity.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([N:15]1[CH2:19][CH:18]([CH2:20][O:21][C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[O:17][C:16]1=[O:29])([CH3:14])[CH3:13]>ClCCl>[CH:12]([N:15]1[CH2:19][CH:18]([CH2:20][O:21][C:22]2[CH:23]=[N+:24]([O-:9])[C:25]([CH3:28])=[CH:26][CH:27]=2)[O:17][C:16]1=[O:29])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OCC2CN(C(C)C)C(=O)O2)cn1
Solvent: ClCCl
Product: Cc1ccc(OCC2CN(C(C)C)C(=O)O2)c[n+]1[O-]
Reaction time: 8 h

Procedure:
A solution of 4.1 g of m-chloroperbenzoic acid in 30 ml of dichloromethane is added over the course of 10 minutes to a solution of 4.8 g of 3-isopropyl-5-[(6-methylpyridin-3-yloxy)methyl]-oxazolidin-2-one in 50 ml of dichloromethane, whilst stirring, and the mixture is left to stand overnight at room temperature. After dilution with 50 ml of dichloromethane the reaction mixture is extracted with 20 ml of saturated potassium bicarbonate solution at a time, dried over sodium sulphate and evaporated in vacuo. The crystalline residue is recrystallised from dichloromethane-ether. 3-[(3-Isopropyloxazolidin-2-on-5-yl)methoxy]-6-methyl-pyridine-1-oxide, thus obtained, melts at 137°-139° C.
Reaction SMILES: N1[CH:2]=[CH:3]N2C(N)=CC=CC=12.[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]=1>>[N:11]1[CH:2]=[CH:3][N:13]2[CH:14]=[CH:15][C:16]([NH2:18])=[N:17][C:12]=12
Reactant: Nc1ccnc(N)n1
Reactant: Nc1cccc2nccn12
Product: Nc1ccn2ccnc2n1

Procedure:
Intermediate 7 was prepared using methods analogous to those described for Intermediate 6 except 2,4-diaminopyrimidine was the starting material. MS (ESI+): calcd for C6H6N4 m/z 134.06, found 135.1 (M+H)+. 1H NMR (d4-methanol): 8.27 (d, J=7.2, 1H), 7.31 (d, J=1.8, 1H), 7.18 (d, J=1.8, 1H), 6.35 (d, J=7.2, 1H).
Reaction SMILES: [C:1]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>[Pd]>[CH2:1]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC#Cc1ccccc1C=O
Agent: [Pd]
Product: CCCCCCCCCCCCc1ccccc1C=O

Procedure:
Alternatively, 2-(1-dodecyn-1-yl)benzaldehyde is hydrogenated in the presence of 10% palladium-on-charcoal (see Example 7b) to give 2-dodecylbenzaldehyde.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:29][Li]>O1CCCC1>[C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][C:15]1[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:29])[CH3:2])=[CH:9][CH:8]=2)=[CH:19][CH:18]=[CH:17][N:16]=1)#[N:28]
Reactant: [Li]C
Reactant: CC(=O)c1ccc(CC(=O)Nc2cccnc2Oc2cccc(C#N)c2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(CC(=O)Nc2cccnc2Oc2cccc(C#N)c2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a solution of 2-(4-Acetyl-phenyl)-N-[2-(3-cyano-phenoxy)-pyridin-3-yl]-acetamide (0.360 grams, 0.96 mmole) in tetrahydrofuran (15 ml) at −78° C. 1.0 M methyl lithium (2.03 ml, 2.03 mmole) in tetrahydrofuran (20 ml) was added and stirred at −78° C. for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to give a white solid which was purified by chromatography on silica eluting with 40% ethyl acetate/hexane. Recrystalization from ethyl acetate/hexane gave white crystals (0.115 g). M.P. 97-99° C.; Anal. calcd. for C23H21N3O3: C, 71.30; H, 5.46; N, 10.85. Found: C, 70.96; H, 5.30; N, 10.69.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26][N:25]=3)=[CH:17][CH:16]=2)(=O)=O)=CC=1.[F-:35].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.C1COCC1>O>[F:35][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:17][CH:16]=1
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CCOc3ncnc4ccccc34)cc2)cc1
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: FCCCCc1ccc(CCOc2ncnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(2-(4-(4-p-toluenesulfonyloxybutyl)phenyl)ethoxy) quinazoline (0.3 g, 0.63 mmol) is added to a solution of potassium fluoride/kryptofix 222 in 5 ml THF (1:1 ratio, 3.15 mmol each). After stirring at room temperature for 15 minutes the solution is then refluxed for 20 minutes. It is then cooled and water is added to it. The solution is then extracted in dichloromethane and washed with water and dried. The crude product is purified by silica gel flash chromatography (ethyl acetate/hexanes) to afford the product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2C=C)[CH:14]=[CH2:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClCCl.C(=[Ru+2])C1C=CC=CC=1.C1(P(C2CCCC2)C2CCCC2)CCCC1.C1(P(C2CCCC2)C2CCCC2)CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH:14]=[CH:15][C:18]3[C:17](=[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]4=[CH:20][CH:19]=3)[O:16]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=Cc1ccc2ccccc2c1OC(C=C)COS(=O)(=O)c1ccc(C)cc1
Agent: [Ru+2]=Cc1ccccc1
Agent: C1CCC(P(C2CCCC2)C2CCCC2)C1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2C=Cc3ccc4ccccc4c3O2)cc1

Procedure:
Treatment of 2-[(2-vinyl-1-naphthyl)oxy]but-3-enyl 4-methylbenzenesulfonate in dichloromethane with bis(tricyclopentylphosphine) benzylidene ruthenium (IV) following the conditions described for Example 1 b provides 2H-benzo[h]chromen-2-ylmethyl 4-methylbenzenesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O-]CC.[Na+].Br[CH2:17][CH:18]=[CH2:19]>C(O)C>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([CH2:19][CH:18]=[CH2:17])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
Malonic acid diethyl ester (100 g, 0.625 mol) was added dropwise at 0° C. to a mixture of sodium ethoxide (46.8 g, 0.688 mol) in ethanol (1 L). The reaction mixture was stirred for 4 hours. 3-Bromo-propene (83.2 g, 0.688 moles) was added dropwise to the mixture at 0° C. After addition, the mixture was warmed to reflux and stirred overnight. The mixture was cooled to room temperature, filtered and the solvent was removed in vacuo to afford the title compound in 86% yield, 100 g which was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:22][N:21]([C:23]5[N:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][N:24]=5)[CH2:20][CH2:19][O:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CC(O)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:18][CH2:19][CH2:20][N:21]([C:23]5[N:24]=[CH:25][C:26]([CH2:29][N:35]6[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]6)=[CH:27][N:28]=5)[CH2:22]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(C=O)cn5)CCO4)c3n2)cn1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2cnc(N3CCO[C@H](Cn4nnc5ncc(-c6cnn(C)c6)nc54)C3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
(S)-2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidine-5-carboaldehyde 16 mg(0.033 mmol) was dissolved in CH2Cl2 2 ml, and 1-methylpiperazine 7.4 μl (0.066 mmol), AcOH 2.3 μl, and NaBH(OAc)3 11 mg (0.05 mmol) were added, followed by stirring at room temperature overnight. After the completion of the reaction, the reaction mixture was adjusted to pH 8 with aq. K2CO3 (5%), and extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure. The residue was purified by column chromatography (MeOH:MC=1:10), to give (S)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)morpholine 14.1 mg, (76%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][C:18]=3[Cl:32])=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:39]1[C:44]([CH3:46])([CH3:45])[CH2:43][CH2:42][CH2:41][CH:40]=1)(=O)=O>C(OCC)C>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:43]4[C:44]([CH3:46])([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]=4)=[CH:19][C:18]=3[Cl:32])=[O:16])[CH2:6][C:5]=12
Reactant: CC1(C)CCCC=C1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)OC1(C)C
Solvent: CCOCC
Product: CC1(C)CCCC=C1c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Yield: 71.4 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 10, Step B (0.350 g, 0.780 mmol) and 6,6-dimethyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.222 g, 0.858 mmol) were reacted by the procedure described in Example 1, Step F. The crude product was purified by flash column chromatography on silica gel, eluting with 30% ethyl acetate in hexane to afford a clear oil. The oil was dissolved in diethyl ether and precipitated with petroleum ether to afford a white solid (0.240 g).