Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6]([C:8]1[C:9]([CH:14]([F:16])[F:15])=[N:10][N:11]([CH3:13])[CH:12]=1)=[O:7])[CH3:4].Br[C:18]1[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:23]1[C:18]([O:1][CH2:2][CH:3]([NH:5][C:6]([C:8]2[C:9]([CH:14]([F:16])[F:15])=[N:10][N:11]([CH3:13])[CH:12]=2)=[O:7])[CH3:4])=[N:19][CH:20]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:22]=1
Reactant: CC(CO)NC(=O)c1cn(C)nc1C(F)F
Reactant: FC(F)(F)c1cnc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(COc1ncc(C(F)(F)F)cc1Cl)NC(=O)c1cn(C)nc1C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
A solution of 2.3 g 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide (10.0 mmol, prepared as described in example P5a) and 2.6 g 2-bromo-3-chloro-5-trifluoromethyl-pyridine (10 mmol) in dimethylformamide (30 ml) is treated at ambient temperature with 2.8 g potassium carbonate (20 mmol). The resulting suspension is stirred at 100° C. for 3 hours, cooled to ambient temperature, poured onto water (200 ml) and extracted with ethyl acetate (2×100 ml). The combined ethyl acetate layers are washed with water (20 ml) and dried over Na2SO4. After removal of the solvent the residue (4.2 g in the form of an oil) is purified by flash chromatography over silica gel (eluent: cyclohexane/ethyl acetate 3:7). 1.4 g (34% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(3-chloro-5-trifluoromethyl-pyridin-2-yloxy)-1-methyl-ethyl]-amide (compound 1.239) is obtained in form of a solid (mp. 115-118° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1>C(OCC)(=O)C>[C:11]([C:10]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:8][N:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C(=O)NNc1ccc(Cl)nn1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nnc2ccc(Cl)nn12
Temperature: 170 °C
Yield: 92.9 %

Procedure:
2.78 g of N′-(6-chloro-3-pyridazinyl)-2,2-dimethylpropionohydrazide was stirred under heating at an external temperature of 170° C. for 10 minutes. After cooling, the reaction mixture was dissolved in ethyl acetate, subjected to silica gel column chromatography, and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure; the precipitated crystal was washed with hexane and dried to yield 2.38 g of the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Cl>>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: COc1ccccc1CCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccc4ccccc4c3)cc2)C(O)C1
Product: COc1ccccc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCc2ccc3ccccc3c2)cc1

Procedure:
In analogy to the procedure described in Example 3(c), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(naphthalen-2-ylmethoxy)-phenyl]-piperidine-1-carboxylate with 2-methoxybenzyl chloride there was obtained tert-butyl (3RS,4RS)-3-(2-methoxy-benzyloxy)-4-[4-(naphthalen-2-ylmethoxy)-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 554 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][C@H:18]2[C:24]([O:26][CH3:27])=[O:25])[C:13]1=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CS(C)=O.CO>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][C@H:18]2[C:24]([O:26][CH3:27])=[O:25])[C:13]1=[O:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(C)(C)N
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
A solution of (1R,2S)-methyl 2-((S)-3-(benzyloxy-carbonylamino)-2-oxopyrrolidin-1-yl)-5-oxocyclo-hexanecarboxylate (3.1 g, 8 mmol) in DMSO (7 ml) was treated with t-butylamine (1.75 g, 24 mol) and stirred for 10 minutes before Ti(i-OPr)4 (6.8 g, 24 mol) was added and the resulting mixture was stirred at room temperature for 2.5 h. Then NaBH4 (0.3 g, 8 mol) was added and stirred for 1.5 h before diluting slowly with methanol (gas evolution) and the resulting solution stirred an additional 1 h. While stirring vigorously, a sat'd solution of NaHCO3 was added, and the resulting suspension was filtered through Celite. The filter cake was washed thoroughly with CH2Cl2 several times and the combined washes were transferred to a separatory funnel. The organic layer was separated and washed with water and brine, concentrated and the residue chromatographed on silica gel (5% MeOH/CH2Cl2-8% NH4OH/MeOH/CH2Cl2) to give 3.0 g (80%) of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexane-carboxylate. MS found: (M+H)+=446.30. Also obtained was 400 mg of the isomeric (1R,2S,5S)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexanecarboxylate. MS found: (M+H)+=446.3.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([C:5]1[S:4][C:3]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH3:1])[CH:6]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)c1sccc1C
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1sc(C(C)(C)C)cc1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 42.4 %

Procedure:
A solution of methyl 3-methylthiophene-2-carboxylate 109a (33 g, 0.211 mol) in dry CH2Cl2 (30 mL) was added dropwise to a mixture of aluminum chloride (40 g, 0.297 mol) and dry CH2Cl2 (200 mL) at −78° C., under nitrogen. The reaction mixture was stirred for 10 min at −78° C., and a solution of tert-butyl chloride (23 mL, 0.211 mol) in dry CH2Cl2 (30 mL) was added dropwise at −78° C. The reaction mixture was stirred for 1 h at −78° C., gradually allowed to warm to room temperature and stirred for 16 h at room temperature. It was poured on ice and extracted with CH2Cl2 (2×200 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated under vacuum. The obtained residue was purified by fractional distillation to yield methyl 5-tert-butyl-3-methylthiophene-2-carboxylate 109b (19 g, 43%) as a light yellow liquid.
Reaction SMILES: [CH2:1]([C:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:19](=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9](=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[CH2:29]([C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9](=[O:18])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(C=Cc1ccccc1)C(Cc1ccccc1)(Cc1ccccc1)C(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)C(Cc1ccccc1)(Cc1ccccc1)C(=O)CCc1ccccc1
Yield: 65.1 %

Procedure:
4,4-Dibenzyl-1,7-diphenyl-1, 6-heptadiene-3,5-dione (12b, 70 mg, 0.2 mmol) and palladium on activated carbon (0.10 g, 10%) were combined in ethyl acetate (25 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 5 hr at room temperature. The resulting mixture was filtered through celite and the filtrate was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to give a solid. The solid was recrystallized from hexane to give 60 mg (86%) of a white solid: mp 101-102° C. [expected mp 100.5-101.5° C.]; 1H NMR: δ 2.56 (t, 4H, J=7.4 Hz), 2.74 (t, 4H, J=6.8 Hz), 3.29 (s, 4H), 7.04 (m, 20H); 13C NMR: δ 29.6, 37.3, 42.5, 71.1, 126.1, 126.8, 128.4, 129.6, 136.0, 140.6, 207.8; Anal. Calcd for C33H32O2: C, 86.05; H, 7.00. Found: C, 86.28; H, 7.11.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:12])[C:8](=[S:11])[NH:9][N:10]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.ClCCl.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH:15]1([CH2:14][S:11][C:8]2[N:7]([CH3:12])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[N:10][N:9]=2)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: Cn1c(CCCCO)n[nH]c1=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(CCCCO)nnc1SCC1CC1
Temperature: 60 °C

Procedure:
5-(4-hydroxybutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.3 g), (bromomethyl)cyclopropane (0.17 ml) and triethyl ammine (0.27 ml) were dissolved in dimethylformamide (2 ml). Reaction was heated at 60° C. for 2 h. Dichloromethane and NaHCO3 saturated solution were added. Solvent was removed, under reduced pressure to give a crude that was purified by Silica column (eluting with DCM/MeOH from 0 to 10%) to give the title compound (0.2 g).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9](NC1CCN(C2C=CN=C(Cl)N=2)CC1)=[O:10].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([N:34]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]2)[N:33]=1)[C:29]#[N:30].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([O:40][CH:37]1[CH2:38][CH2:39][N:34]([C:32]2[CH:31]=[C:28]([C:29]#[N:30])[CH:27]=[C:26]([Cl:25])[N:33]=2)[CH2:35][CH2:36]1)=[O:10]
Reactant: N#Cc1cc(Cl)nc(N2CCC(O)CC2)c1
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ccnc(Cl)n3)CC2)c(Cl)c1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)OC2CCN(c3cc(C#N)cc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,4-Dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3, 164 mg, 0.84 mmol) was dissolved in anhydrous THF (3 ml). 2-Chloro-6-(4-hydroxypiperidin-1-yl)isonicotinonitrile (Intermediate 26), 200 mg, 0.84 mmol) was added, then DEAD (133 μl, 0.84 mmol) was added dropwise followed by triphenylphosphine (221 mg, 0.84 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, filtered and purified by semi-preparative reverse phase HPLC eluting with CH3CN/water (0.1% TFA). (135 mg).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:5]([NH:7][C@H:8]([C:10]([NH:12][C@H:13]([C:23]([NH:25][C@H:26]([C:28]([NH:30][C@H:31]([C:39]([N:41]1[CH2:84][CH2:83][CH2:82][C@H:42]1[C:43]([NH:45][C@H:46]([C:51]([NH:53][C@H:54]([C:64]([NH:66][C@H:67]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:65])[CH2:55][CH2:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:52])[CH2:47][CH:48]([CH3:50])[CH3:49])=[O:44])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29])[CH3:27])=[O:24])[CH2:14][CH2:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:11])[CH3:9])=[O:6])[CH2:3][OH:4]>[Pd].C(O)(=O)C>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:10]([NH:12][C@H:13]([C:23]([NH:25][C@H:26]([C:28]([NH:30][C@H:31]([C:39]([N:41]1[CH2:84][CH2:83][CH2:82][C@H:42]1[C:43]([NH:45][C@H:46]([C:51]([NH:53][C@H:54]([C:64]([NH:66][C@H:67]([C:75]([O:77][C:78]([CH3:79])([CH3:81])[CH3:80])=[O:76])[CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:65])[CH2:55][CH2:56][C:57](=[O:63])[O:58][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:52])[CH2:47][CH:48]([CH3:50])[CH3:49])=[O:44])=[O:40])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:29])[CH3:27])=[O:24])[CH2:14][CH2:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:11])[CH3:9])=[O:6])[CH2:3][OH:4]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Yield: 99 %

Procedure:
78.95 g. (60.15 mmoles) of Z-31-39-OtBu are dissolved in 1500 ml. of 80 % acetic acid, and the mixture is hydrogenated in the presence of palladium-on-carbon. When the reaction terminates, the catalyst is filtered off, and the filtrate is evaporated to dryness. The residue is triturated with ether and filtered. 74.35 g. (99 %) of H-31-39-OtBu are obtained. M.p.: 105°C (under decomposition), Rf7 = 0.5.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:34][CH:35]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:40]=2)[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>C(Cl)Cl>[CH:28]1([CH2:34][CH:35]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:46])=[O:47])=[C:41]([C:49]([F:51])([F:52])[F:50])[CH:40]=2)[C:36]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
A solution of triphenylphosphine (279 mg, 1.06 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (188.7 mg, 1.06 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (237 mg, 0.626 mmol) in methylene chloride (4 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-aminothiazole (188 mg, 1.88 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 to 2/1 hexanes/ethyl acetate) afforded 3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide (83 mg, 29%) as an amorphous solid: EI-HRMS m/e calcd for C20H23F3N2O3S2 (M+) 460.1102, found 460.1100.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15](/[CH:17]=[CH:18]/[C:19]3[C:27]4[C:22](=[N:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[N:20]=3)[N:14]=[C:13]([O:38][CH3:39])[C:12]=2[Cl:40])[CH:9]=1)[C:5]#[N:6].[H][H]>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[N:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)[N:20]=3)[N:14]=[C:13]([O:38][CH3:39])[C:12]=2[Cl:40])[CH:9]=1)[C:5]#[N:6]
Reactant: [H][H]
Reactant: COc1ccc(Cn2nc(/C=C/c3cc(Oc4cc(Cl)cc(C#N)c4)c(Cl)c(OC)n3)c3ccc(F)nc32)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2nc(CCc3cc(Oc4cc(Cl)cc(C#N)c4)c(Cl)c(OC)n3)c3ccc(F)nc32)cc1

Procedure:
Compound 4-1 (400 mg; 0.694 mmol) was dissolved in 6 mL THF/MeOH (1:1) and the system purged with nitrogen (3×). 10% Pd/C (739 mg; 0.694 mmol) was then added to the reaction mixture which was then purged (3×) with nitrogen and then with hydrogen (3×). The purged reaction mixture then remained under atmospheric pressure of hydrogen for 4 hours at room temperature. The reaction mixture was then filtered through celite and concentrated. The crude product was then purified by flash chromatography (40-100% EtOAc in hexane) to give the title compound. MS M+1: 577.6. 1H NMR (CDCl3): 2.12 (t, 2H), 3.32 (t, 2H), 3.76 (s, 3H), 3.90 (s, 3H), 5.53 (s, 2H), 6.30 (s, 1H), 6.65 (d, 1H), 6.68 (d, 2H), 7.08 (m, 1H), 7.12 (m, 1H), 7.20 (d, 2H), 7.42 (m, 1H), 7.94 (t, 1H).
Reaction SMILES: [NH2-].[Na+].[CH:3]1[CH2:5][CH:4]=1.I[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14].C(O)C>N.CCOCC>[CH2:14]([C:3]1[CH2:5][CH:4]=1)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH2:7]
Reactant: C=CCCCCCCI
Reactant: C1=CC1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: C=CCCCCCCC1=CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A mixture of 0.43 g (11 mmol) of sodium amide in roughly 15 ml of ammonia was cooled to −78° C. A chilled solution of cyclopropene in ammonia (1:1, 0.85 g, 10 mmol) was poured into the reaction mixture. The reaction mixture was stirred at −78° C. for ½ hour, warmed briefly to the ammonia boiling point, then recooled to −78° C. 8-Iodooct-1-ene (1.2 g, 5 mmol) was added by syringe, and the reaction mixture was warmed to reflux for ½ hour. A few ml of ethanol were added. Ether (25 ml) was slowly added while the ammonia was allowed to distill out of the reaction mixture. The reaction mixture was washed with water, 0.5M HCl (2×), water and brine. It was dried over MgSO4, filtered and stripped. The product was purified by chromatography on silica gel using hexane as the eluent. A 10 mg sample of 67% pure 1-(oct-7-enyl)-cyclopropene was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]2[N:5]([CH:6]=[CH:7][N:8]=2)[C:4]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:3]1=2.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:3]3[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]4[N:5]([CH:6]=[CH:7][N:8]=4)[C:4]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: CC1(C)CCc2nccn2-c2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)-n2ccnc2CCC3(C)C)ncc1Cl

Procedure:
2-[5-Chloro-2-(6,6-dimethyl-5,6-dihydro-4H-3,10b-diaza-benz[e]azulen-9-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 6,6-Dimethyl-5,6-dihydro-4H-3,10b-diaza-benz[e]azulen-9-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1223c. Title compound was isolated as a white solid (64 mg, 42%) LCMS 506.22 (M+H), HPLC purity 99%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.69 (s, 1H), 9.38 (s, 1H), 8.47 (m, 1H), 8.23 (s, 1H), 7.80 (d, J=6.3 Hz, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.28-7.23 (m, 2H), 2.92 (m, 2H), 2.74 (d, J=4.4 Hz, 3H), 2.15 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:24][C:25]([NH2:27])=[NH:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:24][C:25]([NH2:27])=[N:26][C:14]=2[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: N=C(N)N
Agent: Cl
Product: Nc1ncc2c(n1)CC1CCCC2N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and guanidine hydrochloride. See also: Hasan, Mashooda; Rashid, Naghmana; Khan, Khalid Mohammed; Snatzke, Guenther; Duddeck, Helmut; Voelter, Wolfgang Liebigs Annalen 1995, (5), 889-96.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(OCCOc2ccccn2)cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCCOc2ccccn2)cc1
Reaction time: 1 h

Procedure:
2-[2-(4-Nitrophenoxy)ethoxy]pyridine (100 mg, 0.38 mmol) and tin (II) chloride dihydrate (433 mg, 1.92 mmol) were dissolved in ethanol (1.5 mL) and refluxed under nitrogen for 18 h. The reaction mixture was basified to pH 12 with 3M aqueous sodium hydroxide solution. The reaction mixture was stirred for 1 h and then filtered through Celite. The reaction mixture was concentrated in vacuo and the aqueous layer was separated and extracted with CH2Cl2 (5×). The combined organic extracts were concentrated in vacuo to give 4-[2-(pyridin-2-yloxy)ethoxy]aniline as a purple glassy solid. 1H NMR (d6-DMSO, 400 MHz): δ 8.16 (ddd, J=5.2, 2.0, 0.8 Hz, 1H), 7.71 (ddd, J=9.2, 7.2, 2.0 Hz, 1H), 6.99 (ddd, J=7.2, 5.2, 1.0 Hz, 1H), 6.85 (ddd, J=8.4, 0.8, 0.8 Hz, 1H), 6.68 (ddd, J=5.6, 3.6, 3.6 Hz, 2H), 6.50 (ddd, J=5.6, 3.6, 3.6 Hz, 2H), 4.62 (brs, 2H), 4.50 (m, 2H), 4.15 (m, 2H).
Reaction SMILES: C(OC([N:11]1[CH2:18][C@@H:17]2[C@@:13]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:14][CH2:15][C@@H:16]2[F:19])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:24]([O:23][C:21]([NH:20][C@@:13]12[CH2:14][CH2:15][C@H:16]([F:19])[C@@H:17]1[CH2:18][NH:11][CH2:12]2)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@]12CC[C@H](F)[C@@H]1CN(C(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@]12CC[C@H](F)[C@@H]1CNC2
Yield: 99.4 %

Procedure:
{(1S,5R,6S)-1-tert-Butoxycarbonylamino-6-fluoro-3-azabicyclo[3,3,0]octan-3-yl}carboxylic acid benzyl ester (132 mg, 0.35 mmol) was dissolved in methanol (10 mL). 10% palladium-carbon (M, wet) (50 mg) was added, and the mixture was stirred in a hydrogen atmosphere for three hours. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure. A 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtration, the filtrate was concentrated under reduced pressure to give 85 mg of the title compound as a colorless oil.