Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.CN1CC[O:20][CH2:19]C1.C(#N)C.[Cl:26][C:27]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>O1CCCC1>[Cl:26][C:27]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:28]=1[CH2:29][N:30]1[C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[NH:1][C:19]1=[O:20]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: CN1CCOCC1
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3Cl)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of dimethyl 2-aminoterephthalate (4.18 g), N,N′-carbonyldiimidazole (3.89 g) and N-methylmorpholine (4.0 ml) in tetrahydrofuran (30 ml) was stirred at room temperature for 21 hr. After concentration of the reaction mixture, acetonitrile (70 ml) and 2,4-dichlorobenzylamine (5.47 g) were added and the mixture was stirred at reflux temperature for 2 hr. The precipitated solid was washed with water (50 ml) and acetonitrile (50 ml) and dried to give the objective compound (4.64 g).
Reaction SMILES: Br[C:2]1[C:3]([F:25])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH3:23])[CH:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:24]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C@:32]([OH:36])([C:34]#[CH:35])[CH3:33])[N:28]=1>>[F:25][C:3]1[C:2]([C:35]#[C:34][C@@:32]([OH:36])([C:29]2[N:28]=[C:27]([CH3:26])[O:31][N:30]=2)[CH3:33])=[CH:24][C:6]2[C:7]3[N:8]([C:12]([C:18]4[NH:22][N:21]=[C:20]([CH3:23])[CH:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: Cc1cc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(Br)cc2-3)[nH]n1
Product: Cc1cc(-c2c(C(N)=O)nc3n2CCOc2cc(F)c(C#C[C@@](C)(O)c4noc(C)n4)cc2-3)[nH]n1

Procedure:
10-bromo-9-fluoro-3-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2-tert-butoxycarbonyl-5-methyl-pyrazol-3-yl)boronic acid similarly to as described in Example 4 to produce crude 10-bromo-9-fluoro-3-(3-methyl-1H-pyrazol-5-yl)-5,6dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide. 10-bromo-9-fluoro-3-(3-methyl-1H-pyrazol-5-yl)-5,6dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 5.8 mg (6.6%) 9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-3-(3-methyl-1H-pyrazol-5-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase purification. M+1=478.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:31][CH:30]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([F:42])[CH:40]=3)[NH:35][CH:34]=2)[CH2:29]1.C(N(CC)CC)C>CS(C)=O>[F:42][C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[CH2:32][CH:30]1[CH2:31][N:28]([CH2:16][CH:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH2:29]1
Reactant: Fc1ccc2[nH]cc(CC3CNC3)c2c1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC(Cc2c[nH]c4ccc(F)cc24)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.35 g,.0.80 mmol), 3-azetidin-3-ylmethyl-5-fluoro-1H-indole (0.19 g, 0.96 mmol) and triethylamine (0.16 mL, 1.2 mmol) in dimethylsulfoxide (20 mL) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×80 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The resulting crude oil was column chromatographed on silica gel (3% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.090 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate and collected as 0.068 g of a yellow solid, m.p. 125° C. (dec).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH:5][CH2:6][CH2:7][NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1.N.[H][H]>[Ni].C(O)C>[NH2:4][CH2:1][CH2:2][CH2:3][NH:17][CH2:16][CH:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][CH2:7][CH2:6][OH:5])[CH2:11][CH2:12]1
Reactant: C=CC#N
Reactant: NCC1CCC(CNCCO)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCCCNCC1CCC(CNCCO)CC1
Temperature: 90 °C

Procedure:
Acrylonitrile (10.6 g., 0.2 mole) is added dropwise over a 15 minute period to N-(2-hydroxyethyl)-1,4-cyclohexanebis(methylamine) (37.2 g., 0.4 mole) with stirring and ice bath cooling. After complete addition, the reaction mixture is stirred an additional 2 hours at 5° C., allowed to gradually warm over a 1 hour period. heated 2 hours at 45° C. and finally 1 hour at 90° C. It is then fractionated under reduced pressure up to an internal temperature of 170° C. The residue is dissolved in 200 ml. ethyl alcohol, cooled in an ice bath and saturated with ammonia gas at 0° C. Approximately 5 ml. of sponge nickel catalyst (W. R. Grace Co., Davison Chem. Division) is added and the mixture shaken under hydrogen at 150 psi until no further hydrogen uptake. The catalyst is removed by suction, filtration under nitrogen, the solvent stripped away and the residue fractionally distilled under reduced pressure. The trimaine product is readily distinguished from cyanoethylated diamine by its lower Rf on silica gel using a solution of 1 volume concentrated aqueous ammonium hydroxide in 4 volume methyl alcohol. The synthesis is an adaptation of the method of M. Israel et al, J. Med. Chem., 7, 710 (1964) for the preparation of polymethylenepolyamines.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH2:23]([O+](CC)CC)[CH3:24]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C:13]([O:17][CH2:23][CH3:24])=[N:14][CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[O+](CC)CC
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC1=NCCN(C(=O)OCc2ccccc2)C1
Reaction time: 72 h
Yield: 94.2 %

Procedure:
To a solution of 3-oxo-piperazine-1-carboxylic acid benzyl ester (2.0 g, 8.54 mmol, Maybridge) in dichloromethane (18 mL) at room temperature was added triethyloxonium tetrafluoroborate (4.1 g, 21.3 mmol). This mixture was allowed to stir for about 3 days then quenched by the addition of ice chips followed by saturated aqueous sodium bicarbonate until a neutral pH was obtained. The organic layer was separated and the aqueous layer was extracted with chloroform (3×). The combined organic extracts were washed with brine (1×), dried over sodium sulfate, and concentrated to give 2.11 g (95%) of the title compound of Example 259, Step A as a slightly yellow oil that was sufficiently pure to carry on to the next step. 1H NMR (CDCl3, 300 MHz) δ 7.43-6.97 (c, 5H), 5.17 (s, 2H), 4.10 (q, 2H), 3.98 (s, 2H), 3.60-3.40 (c, 4H), 1.27 (t, 3H); MS (APCI) 263 (MH+).
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.BrBr.[NH2:14][C:15]([NH2:17])=[S:16].N.[CH3:19]O>C(OCC)C>[NH2:14][C:15]1[S:16][C:6]([CH3:7])=[C:2]([C:3]([O:5][CH3:19])=[O:4])[N:17]=1
Reactant: CO
Reactant: NC(N)=S
Reactant: CCC(=O)C(=O)O
Agent: BrBr
Agent: N
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1nc(N)sc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution of 2-oxobutyric acid (12 g, 120 mmol) in methanol was added thionyl chloride (40 mL, 330 mmol), and the mixture was stirred at the same temperature for 3 hr. The solvent was evaporated under reduced pressure. Under a nitrogen atmosphere at 0° C., to a solution (50 mL) of the residue in diethyl ether was slowly added dropwise a solution (50 mL) of bromine (10 g, 130 mmol) in diethyl ether, and the mixture was stirred overnight while allowing the mixture to spontaneously warm. The solvent was evaporated under reduced pressure. An aqueous solution (120 mL) of the residue and thiourea (6.3 g, 83 mmol) was heated under reflux for 3 hr, and cooled to room temperature. The reaction mixture was neutralized with 20% aqueous ammonia solution. The resulting crude title compound was collected by filtration, washed with water to give the title compound (3.3 g, 23%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[I:12]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[I:12]
Reactant: II
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1nc(Cl)c(I)cc1[N+](=O)[O-]
Yield: 89.6 %

Procedure:
To a suspension of 6-chloro-3-nitropyridin-2-amine (6.3 g, 36.3 mmol) in ethanol (110 mL), 9.2 g (36.3 mmol) of iodine and 11.32 g (36.3 mmol) of silver sulphate were added. The crude mixture was stirred at room temperature overnight and the precipitate formed was filtered off. The solid isolated was purified by flash chromatography (1:1 hexane/ethyl acetate) to give the title compound (9.74 g, 88% of yield).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:21]([OH:23])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:49][O:50][C:51](=[O:58])[C@H:52]([CH2:54][CH:55]([CH3:57])[CH3:56])[NH2:53].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:49][O:50][C:51](=[O:58])[C@@H:52]([NH:53][C:21](=[O:23])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:15][CH:16]=1)[CH2:54][CH:55]([CH3:57])[CH3:56]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N—BOC—O-allyl-tyrosine (obtained from NeoMPS, San Diego, Calif. 92126, USA) (10.0 g, 32.5 mmol), HATU (12.4 g, 35.8 mmol) and leucine methyl ester hydrochloride (5.90 g, 65.0 mmol) were dissolved in anhydrous DMF (50 mL). DIPEA (22.7 mL, 130 mmol) was added and the reaction mixture was stirred at rt for 18 h before being partitioned between EtOAc and 1M hydrochloric acid. The organic phase was then washed sequentially with 1M hydrochloric acid and brine before being dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/5 EtOAc/(50/70) petroleum ether to 100% EtOAc to yield a white solid, 8.45 g, 58%. Rf=0.33 (1/3 EtOAc/(50/70) petroleum ether).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:8][CH2:7]1)=[O:5].[N:30]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C@H:31]1[C:40](O)=[O:41].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>>[C:46]([O:45][C:43]([N:30]1[C@H:31]([C:40]([NH:2][C@H:3]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=3[C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:11]2)=[O:5])=[O:41])[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:39]1)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reactant: COC(=O)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared according to the procedure described in Preparation V by using methyl 2-{4-[(2R)-2-amino-3-(4-chlorophenyl)propanoyl] piperazinyl}-benzoate hydrochloride (2.6 g, 5.9 mmol), Boc-L-Tic-OH (Bachem) (1.8 g, 6.5 mmol), HOAT (Aldrich) (810 mg, 5.9 mmol), and EDC (Aldrich) (2.3 g, 12 mmol) and DIEA (Aldrich) (1.0 mL, 5.9 mmol). The title compound was isolated and purified by column chromatography (CH2Cl2 with 1.5% NH3 2M in MeOH) (2.8 g). MS (ESI, pos. ion) m/z: 661 (M+H). Calc'd for C36H41ClN4O6: 660.27.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=O.[C:12]([O:16][C:17]([O:19]C(OC(C)(C)C)=O)=O)([CH3:15])([CH3:14])[CH3:13].[CH3:27][NH:28][CH3:29].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:27][N:28]([CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:19])[CH:7]=[CH:6]2)[CH3:29]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(C)Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Yield: 36.2 %

Procedure:
In a similar manner to Step 1 of Reference Example 4, 5-formylindole (5.27 g, 36.3 mmol) was dissolved in acetonitrile (100 mL), and the solution was treated with di-tert-butyldicarbonate (9.17 mL, 39.9 mmol) and DMAP (44.0 mg, 0.360 mmol), then the mixture was treated with 51% aqueous dimethylamine solution (72.0 mL, 724 mmol), acetic acid (41.6 mL, 727 mmol) and sodium triacetoxyborohydride (46.2 g, 218 mmol), followed by purification by slurry using diisopropyl ether to obtain 5-(dimethylaminomethyl)-1-(tert-butoxycarbonyl)indole (3.61 g, yield 36%).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8](Cl)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].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>[C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:13]=[CH2:14])[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1cncc(Cl)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=Cc1cncc(OC(C)(C)C)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
After dissolving 5.25 g of 2-tert-butoxy-6-chloropyrazine in 80 ml of N,N-dimethylformamide, 9.66 g of tributyl(vinyl)tin and 0.97 g of dichlorobis(triphenylphosphine)palladium(II) were added and the mixture was stirred for 8 hours and 30 minutes at 80° C. under a nitrogen atmosphere. Saturated brine and ethyl acetate were added to the reaction solution, and the insoluble portion was filtered off. The ethyl acetate layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (4.24 g, 85% yield).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl.C(OCC)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Diisopropylethylamine (DIEA, 0.7 mL, 2 mmol) was added to a solution of 4-(aminomethyl)-1-tert-butoxycarbonylpiperidine (200 mg, 0.93 mmol) in 5 mL of CH2Cl2 under nitrogen. (4-fluorophenyl)sulfonyl chloride (195 mg, 1 mmol) was then added, and the reaction mixture was stirred at room temperature for 30 min. The solution was diluted with diethyl ether, washed with 1N HCl, 1N NaOH, and brine, and then dried over MgSO4. The solution was then concentrated to afford 284 mg (82% yield) of the title compound, which could be purified by recrystallization from diethyl ether. 1H NMR (300 MHz, CDCl3). δ 1.00-1.13 (m, 1H), 1.42 (s, 9H), 1.61-1.70 (m, 3H), 2.58-2.70 (m, 2H), 2.80-2.84 (m, 2H), 4.02-4.16 (m, 2H), 4.46-4.52 (m, 1H), 7.17-7.22 (m, 2H), 7.82-7.90 (m, 2H).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:5]([O:7][CH2:8][C:9]([Cl:12])([Cl:11])[Cl:10])=[O:6])[CH2:3][OH:4].Cl[C:31](Cl)(Cl)[C:32](=N)[O:33][C:34]([CH3:38])([CH3:37])[C:35]#[CH:36].[C:42](S(O)(=O)=O)(F)(F)F.ClC(Cl)(Cl)C(=N)[O-]>C(Cl)Cl.CCCCCC>[CH3:31][C:32]([O:33][C:34]([CH3:38])([CH3:37])[C:35]#[CH:36])([CH3:42])[C:2]#[CH:3].[NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[C@H:2]([C:5]([O:7][CH2:8][C:9]([Cl:10])([Cl:11])[Cl:12])=[O:6])[CH2:3][OH:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: C#CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: N=C([O-])C(Cl)(Cl)Cl
Agent: O=C(N[C@@H](CO)C(=O)OCC(Cl)(Cl)Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCCCCC
Product: C#CC(C)(C)OC(C)(C)C#C
Reaction time: 96 h

Procedure:
Fmoc-Ser-OTce (0.83 g, 1.8 mmol) was dissolved in CH2Cl2-Hexane (2:1, 4 mL), and 1,1-dimethylpropinyl trichloroacetimidate (0.41 g, 1.8 mmol, 1 equiv) and CF3SO3H (40 μl) were added under N2 atmosphere. The reaction mixture was allowed to stir for 4 days adding the same quantities of the trichloroacetimidate and CF3SO3H every 24 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo, dissolved in EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (2×10 mL), H2O (2×10 mL) and brine (2×10 mL). The organic solution was dried (MgSO4) and concentrate in vacuo to obtain the 1,1-dimethylpropinyl ether of Fmoc-Ser-OTce (0.95 g), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:15][C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23](C)(C)[CH3:24])=[O:21])[CH2:16]3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.O1CCOCC1.CCN(CC)CC.ClC(OCC)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:15][C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]3)[CH2:13]2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(C2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)CC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C2CC3(CCN(C(=O)OCC)C3)C2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 92.7 %

Procedure:
LCMS (Method A): m/z 367 (M+H)+ (ES+), at 1.97 min, UV inactive. tert-Butyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.080 g, 0.22 mmol) was stirred in DCM (10 mL) at rt and treated with 4 M HCl/dioxane (1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was conc. in vacuo to give a yellow solid that was used directly without further purification. The residue was dissolved in DCM (10 mL) and NEt3 (0.066 g, 0.1 mL, 0.66 mmol) and ethyl chloroformate (0.036 g, 0.03 mL, 0.32 mmol) were added and the reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 8% MeOH in DCM]) to give ethyl 2-[4-(ethoxycarbonyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.069 g, 93%) as an amber oil.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([C:13]2([CH3:26])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][CH:14]2[CH3:25])[CH:10]=[CH:11][CH:12]=1)=O.O.[NH2:29]N>CO.O>[CH2:19]([N:16]1[CH2:17][CH2:18][C:13]([CH3:26])([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:5]3[CH:4]=[CH:3][NH:2][N:29]=3)[CH:8]=2)[CH:14]([CH3:25])[CH2:15]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCN1CCC(C)(c2cccc(C(=O)C=CN(C)C)c2)C(C)C1
Reactant: NN
Solvent: CO
Solvent: O
Product: CCCCCCN1CCC(C)(c2cccc(-c3cc[nH]n3)c2)C(C)C1
Temperature: 25 °C

Procedure:
To a solution of 4-(3-(3-dimethylaminopropenoyl)phenyl)-1-hexyl-3,4-dimethylpiperidine (Preparation 38, 117 mg, 0.32 mmol) in a mixture of methanol (5.0 mL) and water (1.0 mL) was added hydrazine hydrate (0.1 mL, 3.2 mmol). The mixture was heated at reflux for 2 h and then cooled to room temperature. The mixture was concentrated in vacuo and saturated aqueous sodium hydrogencarbonate (10 mL) was added. The aqueous layer was extracted with dichloromethane (3×10 mL), the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate:hexane:0.88 ammonia (90:10:1). The title compound was isolated as clear oil (85 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9]([CH3:11])=[O:10])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([CH3:15])[CH:3]=1.[H][H].[S]>C(O)C.[Ni]>[CH3:15][C:4]1[C:5]([NH2:12])=[CH:6][C:7]([NH:8][C:9]([CH3:11])=[O:10])=[C:2]([CH3:1])[CH:3]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(C)cc1C
Agent: [Ni]
Agent: [S]
Solvent: CCO
Product: CC(=O)Nc1cc(N)c(C)cc1C

Procedure:
2,4-Dimethyl-5-nitroacetanilide (20.8 g., 100 mmole) in ethanol (400 ml.) was reduced over Raney nickel at about 45 psi of hydrogen gas. After the hydrogen uptake was complete, the mixture was deactivated with elementary sulfur, filtered, and the filtrate was evaporated under reduced pressure to give the product as a solid, m.p. 163°-164° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]3[NH:21][C:22]([C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28](Br)[CH:27]=4)=[O:25])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][N:34]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]3[NH:21][C:22]([C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([C:36]5[C:37]6[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH:33]=[N:34][CH:35]=5)[CH:27]=4)=[O:25])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc3nc(C(=O)c4ccnc(Br)c4)[nH]c3n2)CC1
Reactant: OB(O)N1C=Cc2ccccc2C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc3nc(C(=O)c4ccnc(-c5cncc6ccccc56)c4)[nH]c3n2)CC1
Temperature: 120 °C
Yield: 34.1 %

Procedure:
The mixture of [4-[2-(2-bromo-pyridine-4-carbonyl)-3H-imidazo[4,5-b]pyridine-5-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (40 mg, 0.08 mmole), 2-isoquinoline boronic acid (13.8 mg, 0.08 mmole), Pd(Ph3)4 (27.6 mg, 0.24 mmole), 2 molar of K3PO4 aqueous (0.08 ml, 0.16 mmole), and dioxane (3.0 ml) was degassed and heated to 120° C. for 20 minutes in microwave. Reaction solution was diluted with water and extracted with EtOAc. EtOAc layer was concentrated. Residue was purified by using silica gel chromatography, eluting with 50% to 100% of EtOAc in CH2Cl2 to afford [4-[2-(2-isoquinolin-4-yl-pyridine-4-carbonyl)-3H-imidazo[4.5-b]pyridine-5-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (15 mg, 34%). 1H NMR (400 MHz, CD2Cl2) δ 1.27 (d, 9H), 1.89 (m, 2H), 325 (m, 2H), 3.51 (m, 2H), 3.66 (m, 2H), 3.78 (m, 2H), 6.65 (d, J=9.03 Hz, 1H), 7.61 (t, J=7.53 Hz, J=7.53 Hz, 1H), 7.69 (t, J=7.53 Hz, J=7.53 Hz, 1H), 7.84 (d, J=9.03 Hz, 1H), 8.03 (d, J=8.03 Hz, 1H), 8.27 (d, J=8.03 Hz, 1H), 8.39 (d, J=4.52 Hz, 1H), 8.66 (s, 1H), 8.71 (s, 1H), 8.95 (d, J=5.02 Hz, 1H), 9.28 (s, 1H). HR-MS m/z 550.2570 [M+1].