Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[S:20])[C:3]([F:9])=[N:4][CH:5]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1cc(Br)cnc1F
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)cnc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 3-amino-5-bromo-2-fluoropyridine (1.0 g, 5.23 mmol) in acetone (15.0 mL) was added benzoylisothiocyanate (0.85 mL, 6.25 mmol) and the resulting reaction mixture was stirred at room temperature for 30 min. After the completion of the reaction (TLC monitoring), acetone was removed under reduced pressure and the residue was washed with hexane and filtered to obtain the desired product (1.68 g, 91%). 1H NMR (400 MHz, DMSO-d6): δ 7.55 (t, J=7.60 Hz, 2H), 7.68 (t, J=7.60 Hz, 1H), 8.0 (d, J=7.60 Hz, 2H), 8.31 (s, 1H), 8.84 (dd, J=2.0 and 8.40 Hz, 1H), 12.03 (br s, 1H) and 12.60 (br s, 1H).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([CH2:10][CH3:11])[O:7][C:5]1=[O:6])(=[O:3])[CH3:2].S(Cl)([Cl:15])(=O)=O.O>C1C=CC=CC=1>[Cl:15][C:4]1([C:1](=[O:3])[CH3:2])[CH2:9][CH:8]([CH2:10][CH3:11])[O:7][C:5]1=[O:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCC1CC(C(C)=O)C(=O)O1
Solvent: O
Solvent: c1ccccc1
Product: CCC1CC(Cl)(C(C)=O)C(=O)O1
Temperature: 25 °C

Procedure:
Into a solution of 58.2 g (0.37 moles) of α-acetyl-γ-ethyl-γ-butyrolactone [prepared according to J. Pharm. Sci. 52, 733 (1963)] in 60 cm3 benzene 50 g of (0.37 moles) of sulphuryl chloride are added dropwise under stirring and cooling in 2 hours, keeping the temperature of the reaction mixture between 5 and 10° C. After completing the addition the reaction mixture is let to warm to room temperature and stirred at this temperature until the gas formation ceases. Then it is poured into 400 cm3 of water, the phases are separated and the water is extracted with 200 cm3 of benzene. The benzene containing solution is washed with 100 cm3 of 5% sodium hydrogencarbonate solution. After evaporation the residual oil is distilled in vacuo. The title compound is obtained in the form of a colourless liquid in an amount of 58.9 g (82.5%), its boiling point is 91° C. at a pressure of 80 Pa, nD20 =1,4623.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:21]=[CH:22][C:2]([NH:1][C:30]([NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])=[CH:3][CH:4]=1)#[N:18]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4)cc3)c2cc1C#N

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-methoxyquinoline (148 mg) was added to 5.5 ml of toluene, and the mixture was heated to reflux. After then adding phenyl isocyanate (0.08 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene=1/1 to obtain 150 mg of the title compound as light brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([Cl:10])[CH:3]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(Br)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cc(Br)ccc1CN1CCCCC1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a pre-stirred solution of 4-bromo-2-chlorobenzaldehyde (1.01 g, 4.6 mmol) and piperidine (500 μL, 5.0 mmol) in DCM (20 mL) at 0° C. was added sodium triacetoxyborohydride (1.46 g, 6.9 mmol) in portions. The reaction mixture was allowed to warm to ambient temperature and then partitioned between water (50 mL) and dichloromethane (50 mL). The organic phase was separated, washed with saturated aqueous sodium carbonate (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant residue was loaded onto a 20 g SCX-2 cartridge which was washed with methanol then 2N ammonia in methanol. Concentration of the combined basic fractions in vacuo afforded the title compound as a colourless oil (1.15 g, 87%). 1H NMR (CDCl3, 400 MHz): 7.50-7.48 (m, 1H); 7.40-7.33 (m, 2H); 3.50 (s, 2H); 2.46-2.38 (m, 4H); 1.62-1.53 (m, 4H); 1.49-1.40 (m, 2H). LCMS (Method B): RT=2.03 min, M+H+=288.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][C@H:13]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:12]([CH2:23][C:24]([N:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([C:35]([F:40])([F:39])[CH2:36][CH2:37][CH3:38])[CH:33]=3)[C:28]([CH3:42])([CH3:41])[CH2:27]2)=[O:25])[CH2:11][C@H:10]1[CH3:43])=O)(C)(C)C>O1CCOCC1.CCOC(C)=O>[ClH:1].[ClH:1].[F:39][C:35]([C:32]1[CH:33]=[C:34]2[N:26]([C:24](=[O:25])[CH2:23][N:12]3[CH2:11][C@@H:10]([CH3:43])[NH:9][CH2:14][C@@H:13]3[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[CH2:27][C:28]([CH3:42])([CH3:41])[C:29]2=[N:30][CH:31]=1)([F:40])[CH2:36][CH2:37][CH3:38]
Reactant: CCCC(F)(F)c1cnc2c(c1)N(C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1CN1CCOC[C@H]1C)CC2(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCC(F)(F)c1cnc2c(c1)N(C(=O)CN1C[C@@H](C)NC[C@@H]1CN1CCOC[C@H]1C)CC2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4N HCl in dioxane (35 mL) was added to a solution of (2R,5S)-4-{2-[6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (2.1 g) in EtOAc (10 mL). The resulting suspension was stirred for 1 h at room temperature. The solvent was then removed in vacuo. The solid was triturated in Et2O, collected by filtration, washed with Et2O and dried in vacuo to give the title compound (1.7 g) as a yellow solid. 1H NMR (Me-d3-OD): 8.77 (1H, s), 8.52 (1H, s), 4.36-3.91 (9H, m), 3.91-3.41 (8H, m), 3.18-2.99 (1H, m), 2.34-2.15 (2H, m), 1.67-1.36 (15H, m), 1.00 (3H, t). MS: [M+H]+=494.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][NH:23][C:22]4=[O:27])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:31]=O>>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][N:20]([CH3:31])[C@@H:21]4[CH2:26][CH2:25][CH2:24][NH:23][C:22]4=[O:27])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN[C@@H]1CCCNC1=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)[C@@H]1CCCNC1=O

Procedure:
(3R)-3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]piperidin-2-one (Example 87) was reacted with 37% aqueous formaldehyde using an analogous method to that described for the equivalent step in Example 86 to give the title product; 1H NMR Spectrum: (DMSO d6) 1.77 (m, 3H); 2.02 (m, 1H); 2.40 (s, 3H); 3.09 (m, 2H); 3.29 (dd, 1H); 3.95 (s, 5H); 7.18 (s, 1H); 7.28 (t, 1H); 7.40 (brs, 1H); 7.48 (t, 1H); 7.55 (m, 1H); 8.35 (s, 1H); 8.42 (s, 1H); 9.76 (s, 1H). Mass Spectrum: (M+H)+ 444.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([C:13]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1B(O)O
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccnc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A mixture of 2-methoxypyridin-3-ylboronic acid (1.00 g, 6.54 mmol), methyl 2-bromo-5-nitrobenzoate (2.21 g, 8.50 mmol), cesium carbonate (6.39 g, 17.6 mmol) and bis(triphenylphosphine)palladium(II) dichloride (230 mg, 0.33 mmol) was suspended in anhydrous N,N-dimethylformamide (15 mL), and then the mixture was stirred under nitrogen atmosphere at 80° C. overnight. After cooling down, water (100 mL) was added thereto, and then the whole was extracted with ethyl acetate (80 mL, twice). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.54 g) as a yellow solid. (Yield 81%)
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](F)=[CH:18][CH:17]=1)#[N:15]>>[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([CH3:1])=[CH:3][C:4]2=3)=[CH:18][CH:17]=1)#[N:15]
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Reactant: N#Cc1ccc(F)c2ccccc12
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccc(C#N)c2ccccc12

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-cyano-1-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[CH:3]=1.[CH3:16][N:17]([CH3:29])[C:18]([CH2:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)=[O:19]>>[CH3:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[NH:8][C:4]1[CH:3]=[C:2]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:18](=[O:19])[N:17]([CH3:16])[CH3:29])=[CH:28][CH:27]=2)[N:7]=[CH:6][N:5]=1
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: CN(C)C(=O)COc1ccc(N)cc1
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC(=O)N(C)C)cc3)ncn2)c1
Yield: 15 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 6-chloro-4-(3'-methylanilino)pyrimidine (0.410 g) was reacted with 4-(N,N-dimethylcarbamoylmethoxy)aniline (0.420 g). The product was chromatographed on silica and recrystallised from a mixture of methylene chloride and hexane to give 4-(3'-methylanilino)-6-[4'-(N,N-dimethylcarbamoylmethoxy)anilino]pyrimidine in 15% yield, m.p. 135°-138° C.;
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1.CN(C=O)C>[CH2:17]([N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])[CH2:18][CH2:19][CH3:20]
Reactant: O=C1NC(Cc2ccccc2)CO1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCN1C(=O)OCC1Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 5.005 g of 2-amino-3-phenylpropanol and 3 g of ethylene carbonate in 50 ml of toluene in a round bottom flask with a Dean-Stark trap was refluxed for 48 hours and the reaction was followed by tlc. At the end of the reaction the solution was washed with water and brine and concentrated to dryness to give 5.86 g of light yellow oil. The racemic 4-benzyloxazolidin- 2-one was dissolved in 20 ml of THF and was added to 1.98 g of 60% NaH in 40 ml of THF and 10 ml of DMF. After the initial reaction had subsided the reaction mixture was refluxed for 2 hours. After cooling to r.t. 5.44 g of 1-bromobutane in 20 ml of THF was added and the reaction mixture was refluxed overnight. It was then poured into ice-water and extracted twice with ethyl acetate. Combined organic extracts were washed three times with water, followed by brine. After drying, the solution was concentrated to give 7.625 g of crude oil. This was kugelrohr distilled (155°-160° C./0.3 mm) to give 6.54 g (84.7% overall yield) of product.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH2:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[O:24]1[CH2:26][CH:25]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:23][CH2:26][CH:25]([OH:24])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CO1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN)ccc3c2)CC1
Solvent: CCO
Product: CCOC(=O)C(O)CNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1

Procedure:
(6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methanamine (311 mg, 1.0 mmol, 1.0 eq.) and ethyl oxirane-2-carboxylate (116 mg, 1.0 mmol, 1.0 eq.) was dissolved in EtOH (5 mL). Then the mixture was refluxed for 2 h. The mixture was concentrated and purified by silica gel column chromatography using DCM/MeOH (10/1) as eluent to give product as a slight yellow oil (311 mg, 35%). EDI-MS (M+1)+: 428.1. HPLC: 92.02%. 1H NMR (400 MHz, CDCl3) δ 7.70-7.64 (m, 3H), 7.38 (dd, 1H), 7.13-7.11 (m, 2H), 4.31-4.21 (m, 4H), 3.93 (q, 2H), 3.06-2.88 (AB, 2H), 2.60 (b, 2H), 2.28-2.26 (m, 2H), 1.90-1.87 (m, 2H), 1.45-1.41 (m, 2H), 1.26 (t, 3H), 1.20-1.09 (m, 3H), 0.89 (s, 9H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:10](O)[CH2:11][CH2:12][CH3:13].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:1]([N:3]([CH2:10][CH2:11][CH2:12][CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCCCO
Reactant: CCNc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCCCN(CC)c1ccccc1
Yield: 69 %

Procedure:
182 parts of N-ethylaniline, 150 parts of n-butanol and 10 parts of triphenyl phosphite are heated for 20 hours at 230° C in a stirred autoclave. The autoclave is then let down and the water of reaction formed, unconverted ethylaniline and excess alcohol are distilled off. 183 parts of N-ethyl-N-butyl-aniline, corresponding to a yield of 69% of theory, distil at a boiling point of 88° - 91° C/5 mm Hg.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[CH:9][C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)=[C:5]2[CH:4]=[N:3]1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[CH:7][N:8]=[CH:9][C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([NH:19][C:27]([NH:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:28])[CH:16]=[CH:17][CH:18]=3)=[C:5]2[CH:4]=[N:3]1
Reactant: Cn1ncc2c(C#Cc3cccc(N)c3)cncc21
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cn1ncc2c(C#Cc3cccc(NC(=O)Nc4ccccc4)c3)cncc21

Procedure:
In analogy to GP 5, 100 mg of 3-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-ylethynyl)-phenylamine (Intermediate 3.1, 0.26 mmol, 1 eq.) were treated with 31 μL phenyl isocyanate (0.29 mmol, 1.1 eq.) in 2.6 mL DCM at rt. Aqueous work-up followed by HPLC purification provided the target compound.
Reaction SMILES: Cl.[CH:2]12[O:10][CH:6]([CH2:7][NH:8][CH2:9]1)[CH2:5][N:4]([CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH2:3]2.Br[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:27]([O:26][C:25](=[O:31])[NH:24][CH2:23][CH2:22][CH2:21][N:8]1[CH2:9][CH:2]2[O:10][CH:6]([CH2:5][N:4]([CH2:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:3]2)[CH2:7]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: N#Cc1ccc(CN2CC3CNCC(C2)O3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCN1CC2CN(Cc3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
A suspension of 4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl-methyl)benzonitrile hydrochloride (6.8 g, 0.021 mol; see Preparation J above), tert-butyl (3-bromopropyl)carbamate (3.93 g, 0.017 mol; see Preparation I above) and dry K2CO3 (8.24 g, 0.059 mol) in 27 mL of dry acetonitrile was stirred at 60° C. overnight under a N2 atmosphere. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to give 7.5 g of the sub-title compound as pale a liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1)([CH3:17])[CH3:16].O>C1COCC1>[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])([OH:28])[CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1)([CH3:17])[CH3:16]
Reactant: CC(C)C(=O)c1ccc(C(C)C)cc1
Reactant: COc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(O)(c1ccc(C(C)C)cc1)C(C)C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To a solution of 2-bromoanisole (5.0 g, 26.7 mmol) in THF (50 mL) was added n-butyllithium (1.6 M, 18 mL, 29 mmol) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction solution was added 1-(4-isopropylphenyl)-2-methylpropan-1-one (5.70 g, 30.0 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture which was extracted with ethyl acetate, and the combined organic layer was washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 3.4 g (yield 43%) of the title compound. Melting point: 85-86° C. (methanol).
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][C@@H:7]1[CH2:14][N:13]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:12][CH2:11][C:8]21[CH2:10][CH2:9]2)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][CH:23]([O:26][CH3:27])[CH:24]=O.[BH4-].[Na+]>CO>[C:1]([Si:5]([CH3:20])([CH3:19])[O:6][C@@H:7]1[CH2:14][N:13]([CH2:15][CH2:16][CH2:17][NH:18][CH2:24][CH:23]([O:26][CH3:27])[O:22][CH3:21])[CH2:12][CH2:11][C:8]21[CH2:10][CH2:9]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CN(CCCN)CCC12CC2
Reactant: COC(C=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(CNCCCN1CCC2(CC2)[C@H](O[Si](C)(C)C(C)(C)C)C1)OC
Yield: 69.6 %

Procedure:
A solution of 3-[(S)-4-(tert-butyl-dimethyl-silanyloxy)-6-aza-spiro[2.5]oct-6-yl]-propylamine (234 mg, 0.78 mmol) and dimethoxyacetaldehyde (45% solution in TBME, 0.20 mL, 0.78 mmol) in MeOH (3 mL) was stirred for 5 h at RT, then sodium borohydride (47 mg, 1.25 mmol) was added, then after 15 min the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chromatography (IST Isolute® Flash NH2; EtOAc) afforded the title compound (210 mg, 69%). Light yellow gum, MS: 387.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC(C)C)=O)[C:4]2[C:5]([N:21]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=1)[CH:9]=2.Cl[C:30]1[C:39]2[CH2:38][C:37]([CH3:41])([CH3:40])[CH2:36][CH2:35][C:34]=2[N:33]=[C:32]([CH2:42][N:43]([CH2:54][CH2:55][F:56])C(=O)OCC2C=CC=CC=2)[N:31]=1>>[CH3:40][C:37]1([CH3:41])[CH2:36][CH2:35][C:34]2[N:33]=[C:32]([CH2:42][NH:43][CH2:54][CH2:55][F:56])[N:31]=[C:30]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([C:8]5[CH:9]=[C:4]6[NH:3][C:2]([CH3:1])=[N:21][C:5]6=[N:6][CH:7]=5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)[C:39]=2[CH2:38]1
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Reactant: CC1(C)CCc2nc(CN(CCF)C(=O)OCc3ccccc3)nc(Cl)c2C1
Product: Cc1nc2ncc(-c3ccc4c(c3)CN(c3nc(CNCCF)nc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared by the method of example 6 using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and benzyl (4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)methyl(2-fluoroethyl)carbamate (reagent preparation 17) in step 3 followed by Cbz deprotection. 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 0.5H), 12.55 (s, 0.5H), 8.57 (d, 0.5H), 8.49 (d, 0.5H), 8.09 (d, 0.5H), 7.97 (d, 0.5H), 7.73 (d, 1H), 7.54 (dd, 1H), 7.03 (dd, 1H), 4.68 (s, 2H), 4.45 (t, 1H), 4.38-4.25 (m, 3H), 3.93-3.82 (m, 2H), 3.66 (s, 2H), 2.85-2.65 (m, 4H), 2.57-2.52 (m, 3H), 2.46 (s, 2H), 1.59 (t, 2H), 0.86 (s, 6H); MS (EI) for C29H34FN7O: 516 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C)C=O>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCNC(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 3 grams of (3-Amino-propyl)-carbamic acid tert-butyl ester in 15 ml of dimethylformamide was added 3 grams of N-benzyloxycarbonyl glycine, 4.7 mL of N-methylmorpholine and 5.06 grams of TBTU. The reaction was cooled to 0 degrees C. for 30 minutes then allowed to stir at room temperature overnight. The volatiles were removed under reduced pressure and the resulting material was dissolved in ethyl acetate and washed with 10% citric acid. The aqueous was extracted an additional two times with ethyl acetate, combined and washed with water, saturated aqueous sodium bicarbonate, water, brine and dried over MgSO4. The volatiles were removed under reduced pressure and the resulting material was crystallized from EtOAc/hexane affording 4.55 grams of the desired product as a tan solid. LRMS found 388.3=(M+Na)+