Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:16]1([O:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(Cl)Cl>[C:16]1([O:22][C:23](=[O:24])[NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(N)cn1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6-Methoxy-pyridin-3-ylamine (1.0 g, 8.06 mmol) and pyridine (18 ml) are stirred in dry CH2Cl2. To this mixture phenylchloroformate (1.9 g, 12.0 mmol) is added and stirred for 24 hours at room temperature. Water and a solution of 1:1 EtOAc/hexanes is added to the mixture and the organic layer is separated. The organic layer is washed with 1N HCl three times and with brine once. The organic layer is dried over Na2SO4, filtered, and evaporated in vacuo. Purify by flash column chromatography (0-10% EtOAc/CH2Cl2) to obtain (6-methoxy-pyridin-3-yl)-carbamic acid phenyl ester. Mass spec.: m+1=245 (AP+)
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH:15][CH2:16][CH2:17][OH:18].ClCC(OCC)=[O:22]>C1COCC1>[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[N:15]1[CH2:2][CH2:1][O:18][CH2:17][C:16]1=[O:22]
Reactant: CCOC(=O)CCl
Reactant: CC(C)(C)[O-]
Reactant: Cc1cccc(NCCO)c1Br
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cccc(N2CCOCC2=O)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of THF were added successively potassium tert-butoxide (572 mg, 5.10 mmol), 2-(2-bromo-3-methylphenylamino)ethanol (1151 mg, 5 mmol) and ethyl 2-chloroacetate (0.565 mL, 5.30 mmol). The resulting suspension was stirred for 16 h at RT. Additional KOtBu (200 mg) and ethyl 2-chloroacetate (0.15 ml) were added and the reaction mixture was heated to 36° C. for additional 2 h. The reaction was quenched with water and 1M HCl, followed by addition of EtOAc. The organic phase was separated, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (5-70% EtOAc/hexanes). 4-(2-Bromo-3-methylphenyl)morpholin-3-one was obtained as a light-yellow powder.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:14]=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[O:12][N:11]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:14]1[C:10]([CH3:9])=[N:11][O:12][C:13]=1[NH:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)cc2)cc1
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
N-bromosuccinimide (NBS) (0.178 g, 1 mmol), in one lot, was added to a stirred suspension of N-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (0.327g, 1 mmol, Example 14b) in chloroform (12 ml). The reaction mixture was stirred for 10 min then diluted with dichloromethane (50 ml). This was washed with water (2×50 ml). The organic layer was dried over MgSO4 and concentrated. The crude product was recrystallized using hexane/ethyl acetate giving N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (350 mg, 86% yield, m.p. 153-156° C.).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][O:23][CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:26]4[CH2:27][CH2:28][CH2:29][C@@H:25]4[CH2:24][O:23][CH3:22])=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COC[C@@H]1CCCN1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: COC[C@H]1CCCN1C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and (S)-(+)-2-(methoxymethyl)pyrrolidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=401.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17](=[N:19]O)[CH3:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1.[NH4+].[Cl-]>CO.CC(O)=O.[Zn]>[CH3:1][C:2]1[C:3]([CH:17]([NH2:19])[CH3:18])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][O:11]3)[C:6]=2[CH:16]=1
Reactant: CC(=NO)c1cc2ncn(C3CCCCO3)c2cc1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc2c(cc1C(C)N)ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
A mixture of 1-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanone oxime (1.1 g, 4.0 mmol), zinc (2.6 g, 40.0 mmol) and NH4Cl (2.2 g, 40.0 mmol) in MeOH (20 mL) and HOAc (4 mL) was stirred at 80° C. for 4 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. Aqueous ammonia solution (50 mL) was added to the residue, and the mixture was extracted with DCM (50 mL×3), dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH/TEA (10:1:0.2) to afford 1-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanamine (101) as a yellow solid (840 mg, 80%). MS (ESI): m/z=260.2 [M+1]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][O:18][CH2:17]1)[CH2:3][N:4]([CH3:14])[C:5](=[O:13])[O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10].C1N=CN([C:27]([N:29]2[CH:33]=N[CH:31]=[CH:30]2)=[O:28])C=1.CCN(C(C)C)C(C)C.[CH3:43][O:44][C:45](=[O:64])[NH:46][CH2:47][CH2:48][O:49][CH:50]([C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=1)[CH:51]1CCCN[CH2:52]1>C(Cl)Cl>[F:63][C:59]1[CH:58]=[C:57]([C@@H:50]([C@@H:51]2[CH2:52][CH2:31][CH2:30][N:29]([C:27](=[O:28])[NH:1][C@@H:2]([CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][O:18][CH2:17]3)[CH2:3][N:4]([C:5]([O:6][CH2:7][CH2:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:13])[CH3:14])[CH2:33]2)[O:49][CH2:48][CH2:47][NH:46][C:45](=[O:64])[O:44][CH3:43])[CH:62]=[CH:61][CH:60]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C[C@@H](N)CC1CCCOC1)C(=O)OCC[Si](C)(C)C
Reactant: COC(=O)NCCOC(c1cccc(F)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCO[C@@H](c1cccc(F)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCOC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (S)-2-amino-3-(tetrahydro-2H-pyran-3-yl)propyl(methyl)carbamate (300 mg, 0.95 mmol) and CDI (154 mg, 0.95 mmol) in anhydrous CH2Cl2 (20 mL), DIEA (612 mg, 4.7 mmol) was added with ice bath. After addition, the mixture was stirred for 1 h at 0° C., then was added to a solution of {2-[(3-fluoro-phenyl)-piperidin-3-yl-methoxy]-ethyl}-carbamic acid methyl ester (245 mg, 0.79 mmol) in anhydrous CH2Cl2 (25 mL). The reaction mixture was allowed to warm to rt and stirred overnight. After the reaction was completed, the solvent was removed in vacuo. The product was purified by preparative TLC to afford methyl 2-((R)-(3-fluorophenyl)((3R)-1-((S)-1-(N-Methyl-2-(trimethylsilyl)ethoxycarbonylamino)-3-(tetrahydro-2H-pyran-3-yl)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate (258 mg, 50% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[N:17]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[N:18]=[CH:19][N:20]=4)[S:13][C:10]=3[C:11]=2[N:12]=1.[CH3:29][N:30](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[N:17]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[N:18]=[CH:19][N:20]=4)[S:13][C:10]=3[C:11]=2[N:12]=1)#[N:30]
Reactant: CN(C)C=O
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 200 °C
Yield: 60 %

Procedure:
To solution containing 3-(2-chloro-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)-2-(2,4-difluorophenyl)-2H-1,2,4-triazole (0.030 g, 0.072 mmol), zinc cyanide (16.9 mg, 0.144 mmol), and tetrakis(triphenylphosphine)palladium(0) (4.16 mg, 0.00360 mmol) in N,N-dimethylformamide (1.00 mL, 12.9 mmol) was evacuated then back-filled with nitrogen. The reaction mixture was heated in microwave to 200° C. for 10 min. The reaction mixture was quenched with sat. NH4Cl then extracted EtOAc (3×). The crude product was purified by column chromatography (EtOAc/Hex) (eluted 50% EtOAc) to give 366 (60% yield). MS: (ESI+)=408.0
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([O:4][CH2:1][CH:2]=[CH2:3])=[O:16]
Reactant: C=CCO
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)c1ccccc1Cl

Procedure:
Sixty parts of allyl alcohol were dissolved in 240 parts of chloroform, followed by an addition of 105 parts of triethylamine. While stirring the resultant mixture at 10°-15° C., 175 parts of o-chlorobenzoyl chloride were added dropwise over 2 hours. After the resultant mixture was heated at 45°-50° C. for 3 hours, the liquid reaction mixture was poured in a separation funnel and washed first with dilute hydrochloric acid and then with water. The thus-formed light-yellowish organic layer was dried with calcium chloride and then treated with activated carbon. After driving chloroform off, the residue was distilled under reduced pressures to obtain 153 parts of allyl o-chlorobenzoate (hereinafter called "Compound A"; b.p. 101° C./3.5 mmHg).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O1CCCC1>[C:23]([O:22][C:20](=[O:21])[CH2:19][N:1]1[CH2:10][CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][CH2:2]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1CCN(CC(=O)OC(C)(C)C)CC1
Yield: 100.2 %

Procedure:
To a mixture of methyl isonipecotate (10.0 g, 69.8 mmol) and triethylamine (19.5 mL, 140 mmol) in tetrahydrofuran (200 mL) was added tert-butyl bromoacetate (10.3 mL, 69.8 mmol). The solution was heated at reflux for 24 h, concentrated under reduced pressure and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0, methanol: dichloromethane, 1:99 to 5:95) to provide the title compound (18 g). 1H NMR (400 MHz, CDC3) δ 3.61 (s, 3H), 3.04 (s, 2H), 2.84 (d, J=11.5 Hz, 2H), 2.12-2.31 (m, 3H), 1.64-1.91 (m, 4H), 1.39 (s, 9H).
Reaction SMILES: [O-2].[CH3:2][Si:3]([CH3:17])([CH3:16])[O:4][V+2:5](O[Si](C)(C)C)[O:6][Si](C)(C)C.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Si:25]([C:34]2[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=2)([C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[OH:26])=[CH:21][CH:20]=1.[CH:41]1(O)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[O-2:4].[Br:33][C:30]1[CH:31]=[CH:32][C:27]([Si:25]([C:34]2[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=2)([C:22]2[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=2)[O:26][V+2:5]([O:4][Si:3]([C:17]2[CH:21]=[CH:20][C:19]([Br:18])=[CH:24][CH:23]=2)([C:16]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)[C:2]2[CH:35]=[CH:36][C:37]([Br:40])=[CH:38][CH:39]=2)[O:6][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:28][CH:29]=1
Reactant: OC1CCCCC1
Reactant: O[Si](c1ccc(Br)cc1)(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: C[Si](C)(C)O[V+2](O[Si](C)(C)C)O[Si](C)(C)C
Agent: [O-2]
Product: Brc1ccc([Si](O[V+2](OC2CCCCC2)O[Si](c2ccc(Br)cc2)(c2ccc(Br)cc2)c2ccc(Br)cc2)(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1

Procedure:
tris-(trimethyl siloxy)-vanadium oxide is reacted with tri-(p-bromophenyl)-silanol and cyclohexanol in a mol ratio of 1:2:1 parts by volume to produce bis-[tri-(p-bromophenyl)-siloxy]-cyclohexyloxy-vanadium oxide [mol peak = 1184 ref. to79Br]; and
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])C.[NH2-].[Li+].[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:13]C#C)[CH3:11].BrCC>CCCCCC>[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:13][C:5]#[C:3][CH2:2][CH3:1])[CH3:11]
Reactant: C#CCOC(C)(C)OC
Reactant: C=CC(=C)C
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCC
Solvent: CCBr
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 105.6 %

Procedure:
259 mg (37 mmol) of granulated lithium were added within 5 minutes to 47.7 g (1.9 mol) of liquid ammonia at −40° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 4.0 ml (40 mmol) of isoprene were added portion wise within 10 minutes. The end of the formation of lithium amide could be recognized by the discoloration of the reaction mixture. 2.9 g (20 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne (88.9% GC) were added with a dropping funnel to the reaction mixture at −40° C. within 20 minutes. The reaction mixture was held at −40° C. for about 1 hour. 8.9 g (80 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 10 minutes. The reaction mixture was subsequently stirred for 1 hour. 20 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 5 hours. 20 ml of water were added to the reaction mixture at 22° C., and the mixture was stirred until all salt was dissolved. The organic layer was separated and dried over 2 g of anhydrous magnesium sulfate. The solution was concentrated under reduced pressure (40° C., 40 mbar) and the crude product was analyzed by GC. 3.3 g of crude 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne were obtained with a purity of 75.6% (yield 80.0% based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([O:11][CH3:12])[CH:4]=1)#[N:2].Cl.[C:14]([O:18][C:19](=[O:23])[CH2:20][NH:21][CH3:22])([CH3:17])([CH3:16])[CH3:15]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:21]([CH3:22])[CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:23])=[C:5]([O:11][CH3:12])[CH:4]=1)#[N:2]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: COc1cc(C#N)ccc1CBr
Agent: Cl
Product: COc1cc(C#N)ccc1CN(C)CC(=O)OC(C)(C)C

Procedure:
The title compound was prepared following the general procedure 10, starting from 4-cyano-2-methoxybenzyl bromide (Carbocore) and sarcosine tert-butyl ester hydrochloride. It was isolated as a colorless oil. 1H NMR (DMSO-d6, 300 MHz) δ 7.53 (d, J=7.7 Hz, 1H), 7.45-7.40 (m, 2H), 3.83 (s, 3H), 3.69 (s, 2H), 3.20 (s, 2H), 2.27 (s, 3H), 1.42 (s, 9H). LC/MS (Method B): 291.0 (M+H)+. HPLC (Method A) Rt 2.52 min (Purity: 93.5%).
Reaction SMILES: [C:1]([CH:4]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)[NH2:2].Cl.N[C@H](C(N)=O)CCC1C=CC=CC=1.C(N1C(=O)CCC1=O)(OCC1C=CC=CC=1)=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([CH:4]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2]
Reactant: NC(=O)C(CCc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: NC(=O)[C@@H](N)CCc1ccccc1
Agent: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: N#CC(CCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
2.78 g of benzyl (1-carbamoyl-3-phenylpropyl)carbamate, prepared from L-homophenylalanine amide hydrochloride and N-Cbz-succinimide, were dissolved in 30 ml of dry pyridine and treated with 6 ml of acetic anhydride. The reaction mixture was stirred at 75° C. for 24 h. The cooled solution was concentrated in vacuo, treated with 100 ml of ethyl acetate, and then extracted three times by shaking with 50 ml each of 5% strength citric acid solution and saturated sodium chloride solution. The organic extract was dried over magnesium sulfate, filtered, concentrated in vacuo, and chromatographed on silica gel using n-heptane/ethyl acetate (1/1). Benzyl (1-cyano-3-phenylpropyl)carbamate was obtained, which was employed in the next stage without further purification.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][NH:6][CH2:5][CH:4]1[C:8]1[NH:13][C:12](=[O:14])[C:11]2=[CH:15][N:16]=[C:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:10]2[N:9]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.[BH3-]C#N.[Na+]>ClCCCl.C(O)(=O)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:6]2[CH2:7][CH:3]([CH3:2])[CH:4]([C:8]3[NH:13][C:12](=[O:14])[C:11]4=[CH:15][N:16]=[C:17]([CH:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)[N:10]4[N:9]=3)[CH2:5]2)=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC1CNCC1c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1CN(Cc2ccc(F)cc2)CC1c1nn2c(C3CCOCC3)ncc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
To a solution of compound 9 (80 mg, 0.263 mmol) and 4-fluorobenzaldehyde (326 mg, 2.63 mmol) in 1,2-dichloroethane (15 mL) was added 2 drops of acetic acid. The resulting solution was stirred at room temperature for one hour. Then NaBH3CN (178 mg, 2.63 mmol) was added to the reaction in portions. The resulting mixture was stirred at room temperature for 16 hours. LC-MS showed that the starting material was almost consumed. The reaction mixture was quenched with water (40 mL), and extracted with CH2Cl2 (30 mL×3). The combined organic phases were washed with brine (30 mL), and dried over Na2SO4. After filtered, the filtrate was concentrated in vacuum. The residue was purified by preparative TLC to afford the desired product (20 mg, 21% yield) as a white solid. LC-MS: m/z 412.2 [M+1]+. 1H NMR (400 MHz, CD3OD-d4): δ 8.27 (s, 1H), 7.61 (s, 1H), 7.35˜7.31 (m, 2H), 7.02˜6.98 (m, 2H), 3.96˜3.93 (m, 2H), 3.79˜3.70 (m, 2H), 3.51˜3.39 (m, 3H), 3.15˜3.11 (m, 1H), 3.05˜2.95 (m, 2H), 2.84˜2.79 (m, 1H), 2.61˜2.57 (m, 1H), 2.33˜2.29 (m, 1H), 1.93˜1.87 (m, 2H), 1.80˜1.77 (m, 2H), 1.09 (d, J=6.8 Hz, 3H).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][C@H:13]([NH:15]C(OC(C)(C)C)=O)[CH2:12][N:11]([C:23]2[C:32]([N:33]3[CH2:38][C@@H:37]([NH:39]C(OC(C)(C)C)=O)[CH2:36][C@@H:35]([NH:47]C(OC(C)(C)C)=O)[CH2:34]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([N+:55]([O-])=O)[CH:29]=3)[N:24]=2)[CH2:10]1)=O)(C)(C)C.Cl>C(O)(C(F)(F)F)=O.CO>[NH2:15][C@@H:13]1[CH2:14][C@H:9]([NH2:8])[CH2:10][N:11]([C:23]2[C:32]([N:33]3[CH2:34][C@@H:35]([NH2:47])[CH2:36][C@@H:37]([NH2:39])[CH2:38]3)=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([NH2:55])[CH:29]=3)[N:24]=2)[CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc3ccc([N+](=O)[O-])cc3nc2N2C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C2)C1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2nc(N3C[C@H](N)C[C@H](N)C3)c(N3C[C@H](N)C[C@H](N)C3)nc2c1
Reaction time: 0.01 h
Yield: 31.1 %

Procedure:
2,3-Bis-((3R,5S)-3,5-bis-(tert-Butoxycarbonylamino)-piperidin-1-yl)-6-nitro-quinoxaline (245) (0.05 g, 0.135 mmol) was dissolved in TFA (3 mL) and the mixture was shaken at room temperature in a Teflon septum capped vial for 3 hours. LC-MS indicated complete de-protection at this point. The solution was concentrated to give an orange oil. The oil was dissolved in MeOH (1 mL) and HCl (1 mL, 4.0 M in dioxane) was added and the mixture was vortexed for 20 seconds. A fine suspension was observed. The mixture was concentrated to an orange powder. Ethyl ether (5 mL) was added to the powder and vortexed for 2 minutes. The solid was collected by filtration and dried under high vacuum for 16 hours to give the desired product (255) as an orange powder (0.023 g, 0.042 mmol, 31% yield, assumed 4 HCl salt). LC-MS (ESI): (exact mass: 401.23) m/e=402.2 [M+1]+. 1H NMR (400 MHz, D2O): δ 1.72 (q, 2H, J=12 Hz), 2.49 (d, 2H, J=10 Hz), 2.94 (q, 4H, J=12 Hz), 3.51–3.67 (m, 4H), 4.44 (dd, 2H, J1=12 Hz, J2=4.4 Hz), 4.57 (dd, 2H, J1=12.8 Hz, J2=3.6 Hz), 7.71 (d, 1H, J=9.2 Hz), 8.10 (dd, 1H, J1=9.2 Hz, J2=2.8 Hz), 8.44 (d, 1H, J=2.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.II.[NH3:27]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([C:23]#[N:27])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: N
Reactant: O=Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Agent: II
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 50 mL round bottom flask, 5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-carbaldehyde (0.48 g, 0.0014 mol; prepared in a similar method to that described in Example 10) and THF (10 mL) were added. To the same flask, iodine (0.39 g, 0.00154 mol) and 30% aqueous ammonia (9.6 mL) were added. The reaction mixture was stirred at 25° C. The light brown reaction mixture turned yellow after 3 h. The reaction was quenched by adding ethyl acetate (100 mL) and 10% aqueous sodium thiosulfate (40 mL) and stirred for 5 min. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The crude product was purified using column chromatography (60-120 silica gel, 10-50% ethyl acetate in hexane) to yield the desired product as a off white solid [0.31 g, 65%]. 1H NMR (300 MHz, CDCl3): δ 8.11 (s, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.24 (d, J=3.6 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H), 3.95 (s, 8H). LC-MS (ESI): Calculated mass: 340.0; Observed mass: 341.0 (RT: 1.55 min).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.2 %

Procedure:
To a suspension of 6-chloronicotinoyl chloride (10.5 g, 59.7 mmole) in dry dichloromethane (100 mL) was added 4-fluoroaniline (5.6 mL, 59.7 mmole), followed by the dropwise addition of N,N-diisopropylethylamine (21 mL, 119 mmol). After stirring for 90 min at room temperature, the mixture was diluted with ethyl acetate (20 mL) and washed with water. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by recrystallization using ethyl acetate/hexanes gave 13.8 g (92%) of a white solid. 1H NMR (300 MHz, CDCl3) δ7.09–7.12 (m, 2H), 7.47–7.50 (m, 1H), 7.56–60 (m, 2 H), 7.7 (bs, 1H), 8.15–8.18 (m, 1H), 8.84 (m, 1H); MS (EI) m/z 251.13 (M+H)+.