Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCC[C@H]1C(O)=O.[Li]CCCC.[CH3:14][C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.O>CCOCC>[CH:16]1([CH:15]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(c1ccccc1)C1C=CC=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 1.4 g. of l-proline (12 mmol) in 40 mL of ether was added 15 mL of n-BuLi (1.6M solution in hexanes, 24 mmol) at 0° C. This solution was stirred overnight at room temperature and then cooled to -78° C. 6-Methyl-6-phenylfulvene, 2.0 g, (12 mmol) in 5 mL of ether was added dropwise at -78° C. The resulting solution was stirred 6 h at -78° C. Water, 20 mL, was added dropwise at -78° C. and the solution warmed to room temperature. The organic layer was separated and washed with aqueous NaHCO3, H2O and then dried over MgSO4. Removal of the solvent gave 2.0 g (99% yield) of 1-cyclopentadienyl-1-phenylethane as a light yellow oil. D =3.0° (CHCl3), 8.7% ee.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][NH:22][C:23]([C:25]2[CH:26]=[N:27][C:28]3[C:33]([C:34]=2[OH:35])=[CH:32][C:31]([CH2:36][CH2:37][CH2:38]O)=[CH:30][C:29]=3[F:40])=[O:24])=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:4]([O:3][C:1]([NH:8][CH:9]([CH:10]([CH3:11])[CH3:12])[C:13]([O:15][CH2:38][CH2:37][CH2:36][C:31]1[CH:32]=[C:33]2[C:28](=[C:29]([F:40])[CH:30]=1)[N:27]=[CH:26][C:25]([C:23]([NH:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([Cl:16])=[CH:42][CH:41]=1)=[O:24])=[C:34]2[OH:35])=[O:14])=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(CCCO)cc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Boc-valine (0.13 g) is added to a solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxypropyl)-3-quinolinecarboxamide from example 110 (0.15 g), EDC hydrochloride (0.11 g), and DMAP (0.016 g) in 4 mL pyridine. The reaction is stirred at room temperature overnight. The solvent is removed in vacuo and the residue partitioned between CH2Cl2 and H2O. The organic layer is washed once with water, and once with brine. The organic layer is then dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow liquid. The residue is adsorbed onto silica and purified by chromatography on a Biotage Flash 40S column (eluent 1% MeOH:CH2Cl2 (1 L) followed by 2% MeOH:CH2Cl2 (2 L)). The product is obtained as a white solid which is further purified by recrystallization with CH2Cl2 /hexanes (0.17 g, 74%).
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][C@@:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1.Br[C:26]1[S:27][C:28]([C:31]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][N:30]=1>>[C:34]([NH:33][C:31]([C:28]1[S:27][C:26]([N:13]2[CH2:14][CH2:15][CH2:16][C@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:24])[CH3:23])([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:9][C:8]3=[O:10])[CH2:12]2)=[N:30][CH:29]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCNC2)C(=O)O1
Reactant: CC(C)(C)NC(=O)c1cnc(Br)s1
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCN(c3ncc(C(=O)NC(C)(C)C)s3)C2)C(=O)O1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one and 2-bromo-N-tert-butylthiazole-5-carboxamide following a procedure analogous to that described in Example 13. LC-MS Method 2 tR=1.23 min, m/z=515.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([N:21]1[C:25]([C:26]#[N:27])=[C:24]([CH:28]=O)[N:23]=[C:22]1[N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)[C:18]#[C:19][CH3:20].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:17]([N:21]1[C:25]([C:26]#[N:27])=[C:24]([CH:28]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:23]=[C:22]1[N:30]1[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]1)[C:18]#[C:19][CH3:20]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C#N
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=CC(=O)OCC)c1C#N
Reaction time: 0.5 h
Yield: 102.5 %

Procedure:
0.038 g of sodium hydride was added to a 5 ml tetrahydrofuran solution of 0.243 g of ethyl diethylphosphonoacetate at 5° C. under a nitrogen atmosphere. 0.310 g of t-butyl 4-[1-(2-butynyl)-5-cyano-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate dissolved in 5 ml of tetrahydrofuran was added, and the mixture was stirred for 30 minutes. 50 ml of ethyl acetate and 25 ml of 0.1N sodium hydroxide were added to the solution. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.380 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3:7).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[CH3:8][C:9]1([CH3:27])[O:14][C:13]2[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:12]=2[C@@H:11]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C@@H:10]1[OH:26]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:8][C:9]1([CH3:27])[O:14][C:13]2[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:12]=2[C@@H:11]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C@@H:10]1[O:26][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2)[C@@H]1O
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)O[C@H]1[C@H](N2CCCC2)c2cc(C#N)ccc2OC1(C)C

Procedure:
To a solution of 4-dimethylaminopyridine (0.98 g) in dichloromethane (50 ml) was added 2,2-dimethylpropanoyl chloride (0.69 ml) dropwise and with gentle stirring, followed by crude trans-2,2-dimethyl-4-pyrrolidino-6-cyano-3,4-dihydro-2H-benzo[b]-pyran-3-ol (2.50 g) in dichloromethane (50 ml) during 4 minutes. The resulting red solution was heated under reflux for 40 hours before cooling and evaporation of solvent. The orange residue was taken up in ethyl acetate and washed with water, dried and evaporated leaving a mustard coloured solid (2.97 g) which was separated by chromatography on silica gel (110 g) with mixtures of ethyl acetate and 60°-80° petroleum ether using a gradient elution technique, into crude ester (1.12 g) and starting material (1.13 g). Recrystallization of the crude material from 60°-80° petroleum ether gave trans-2,2-dimethyl-3-(2,2-dimethylpropanoyloxy)-4 pyrrolidino-6-cyano-3,4-dihydro-2H-benzo[b]pyran (0.73 g) as white crystals of m.p. 109°-110° C.; IR absorptions at 1730, 2220 cm-1 ; nmr (CDCl3) δ 1.24 (9H), 1.29 (3H), 1.41 (3H), 1.75 (4H, broad m), 2.73 (4H, broad m), 4.09 (1H, d, J=9), 5.33 (1H, d, J=9), 6.86 (1H, d, J=8), 7.43 (1H, q, J=8, 2), 7.74 (1H, d, J=2). Anal. Calcd. for C21H28N2O3 : C, 70.76; H, 7.92; N,7.86. Found: C, 70.74; H, 8.03, N, 7.76%.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[NH:17]CC1C=CC(OC)=CC=1)[C:12]#[N:13].C(=O)([O-])O.[Na+]>ClCCl>[NH2:17][C:16]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[F:8]
Reactant: COc1ccc(CNc2ccc(C#N)cc2F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(N)c(F)c1
Temperature: 0 °C
Yield: 47.5 %

Procedure:
Trifluoroacetic acid (1 ml) was added dropwise to a solution of 3-fluoro-4-[(4-methoxybenzyl)amino]benzonitrile (1.0 g, 3.9 mmol), obtained in Example 25(1), in anhydrous dichloromethane (20 ml) cooled to 0° C. with stirring. The resulting mixture was stirred at room temperature overnight. At the end of this time, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution at 0° C. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual oil was chromatographed on a silica gel column using ethyl acetate-hexane (1:6) as the eluant to afford 4-amino-3-fluorobenzonitrile (252 mg, yield 47%) as a pale orange solid which was recrystallized from ethyl acetate-hexane to give white powdery crystals. Melting point: 84° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1)([O-])=O>[Pd].O1CCOCC1>[C:10]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)([C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)([CH3:12])[CH3:11]
Reactant: CC(C)(c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C)(c1ccc(N)cc1)c1ccc(N)cc1
Temperature: 60 °C
Yield: 96.1 %

Procedure:
A mixture of 294 g of 2,2-bis(4-nitrophenyl)propane (1.03 mol; prepared as in step c) was charged in an autoclave along with 2 liters of 1,4-dioxane and 25 g of 5% palladium on carbon. The autoclave was purged with nitrogen, then heated at 60° C. for six hours under 500 psi hydrogen pressure. The product mixture was filtered to remove the catalyst, then stripped of solvent by rotary evaporation at reduced pressure. The solid residue was triturated with a small amount of hexane, then collected and dried by suction filtration under a blanket of nitrogen to afford 224.0 g (0.99 mol, 96% of theory) of 4,4'-isopropylidenedianiline (bisaniline-A), m.p. 130-131.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[F:12][C:13]1[CH:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([NH2:24])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:24][C:16]1[C:17](=[CH:23][C:13]([F:12])=[CH:14][CH:15]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:11]
Reactant: CCOC(=O)c1cc(F)ccc1N
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc(F)ccc1NC(=O)Nc1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of 2,4-dichlorophenyl isocyanate (47.0 g, 0.25 mol) in xylene (130 ml) is metered at room temperature into a solution of ethyl 5-fluoroanthranilate (45.2 g, 0.25 mol) in xylene (210 ml). After addition is complete, the mixture is stirred at 90° C. for 2 hours. Triethylamine (3.5 ml, 2.55 g, 0.025 mol) is metered in. The mixture is stirred at 90° C. for a further 2 hours. After cooling, the product is filtered off with suction and washed with 3×30 ml of xylene and dried. 86.9 g of ethyl N-(2,4-dichlorophenylcarbamoyl)-5-fluoroanthranilate of melting point 219° to 223° C. (decomposition) are obtained. The cyclization product 3-(2,4-dichlorophenyl)-6-fluoro-2,4(1H,3H)-quinazolinedione cannot be detected by thin-layer chromatography.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=[N:2]1.[I:10](O)(=O)=O.II>C(O)C>[I:10][C:4]1[CH:3]=[N:2][NH:1][C:5]=1[NH:6][C:7](=[O:9])[CH3:8]
Reactant: [O-][I+2]([O-])O
Reactant: CC(=O)Nc1ccn[nH]1
Agent: II
Solvent: CCO
Product: CC(=O)Nc1[nH]ncc1I
Temperature: 60 °C
Yield: 348.6 %

Procedure:
A suspension of N-(1H-pyrazol-5-yl)acetamide (60 g, 0.48 mol), iodic acid (21.1 g, 0.12 mol) and iodine (61 g, 0.24 mol) in ethanol (1.6 L) was heated at 60° C. for 1.5 h and cooled to room temperature. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and 2 M Na2S2O3 aq. solution. The layers were separated and the aqueous extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to provide the title compound as a solid (105 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([CH2:38][C:39]2[CH:48]=[CH:47][C:42]([C:43]([NH:45]O)=[NH:44])=[CH:41][CH:40]=2)[CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32][C:31]2=[O:37])(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:43]3[N:44]=[C:4]([CH2:3][O:2][CH3:1])[O:6][N:45]=3)=[CH:47][CH:48]=2)[CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32][C:31]2=[O:37])(=[O:27])=[O:28])=[CH:22][CH:21]=1
Reactant: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: COCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COCc1nc(-c2ccc(CN(C3CCCCNC3=O)S(=O)(=O)c3ccc(Cl)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.1 %

Procedure:
To a solution of methoxyacetic acid (86 μl, 1.10 mmol) in 5 ml dimethylformamide were added 1,1′-carbonyl-diimidazole (0.18 g, 1.10 mmol). The mixture was stirred at room temperature for 10 minutes, heated to 40° C. for a few minutes and cooled to room temperature. 4-{[(4-Chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine (0.45 g, 1.00 mmol) was added and the mixture was stirred at 100° C. for 5 hours and then poured into water. Filtration and chromatography on silicagel with ethylacetate/heptane (1/1 to 4/1) yielded 0.46 g (90%) 4-chloro-N-[4-(5-methoxymethyl-[1,2,4]oxadiazol-3-yl)-benzyl]-N-(2-oxo-azepan-3-yl)-benzenesulfonamide as white solid, MS: m/e (%)=505.0 (MH+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(Br)cc1
Yield: 59.3 %

Procedure:
To a suspension of 4-bromotoluene (60 g) and N-bromosuccinimide (69 g) in carbon tetrachloride (300 ml) was added 2,2'-azobis(isobutylonitrile) (0.1 g). The resulting mixture was heated under reflux for 2 hours. After the reaction mixture was cooled, succinimide so precipitated was removed by filtration, and the filtrate was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, followed by removal through distillation. The oily substance so obtained was crystallized from n-hexane, whereby 52 g of the title compound was obtained.
Reaction SMILES: C([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([P:16]([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=2)[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)[N:7]=1)(C)(C)C>C(O)=O>[CH3:23][C:21]1[CH:22]=[C:17]([P:16]([C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=2)[C:8]2[NH:7][C:6](=[O:5])[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:18]=[C:19]([CH3:24])[CH:20]=1
Reactant: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2cc3ccccc3c(OC(C)(C)C)n2)c1
Solvent: O=CO
Product: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2cc3ccccc3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
1-tert-butoxy-3-(bis(3,5-dimethylphenyl)phosphino)isoquinoline (0.96, 2.2 mmol) is dissolved in neat concentrated formic acid (9 mL), and the solution is stirred at ambient temperature for 1 hour. Precipitation of the isoquinolone was induced by dilution with H2O (25 mL), and the suspension is filtered through a glass frit. The white flakes are washed with 70% formic acid solution (3×5 mL). The combined aqueous formic acid filtrates are concentrated under reduced pressure, and the opaque residue is crystallized from acetone yielding 3-bis(3,5-dimethylphenyl)phosphino-2H-isoquinolin-1-one (0.55 g, 66%).
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[CH2:23][CH2:22][CH2:21][CH2:20]1.[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([O-])=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[Na+]>CN(C)C=O>[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:25][CH2:24][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: Nc1ccccc1OCCN1CCCC1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 273 mg of 2-(2-pyrrolidin-1-yl-ethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 2 hours, and then concentrated under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH3:3].[NH2:12][C:13]1[CH:20]=[C:19](F)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C(N(CC)CC)C>CCO>[NH2:12][C:13]1[CH:20]=[C:19]([N:8]2[CH2:7][CH2:6][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])([OH:11])[CH2:10][CH2:9]2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CN(C)CC1(O)CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)CC1(O)CCN(c2cc(N)ncc2C#N)CC1
Temperature: 80 °C

Procedure:
A mixture of 4-[(dimethylamino)methyl]-4-piperidinol (1.0 g, 4.33 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 593 mg, 4.33 mmol) and triethylamine (3.62 ml, 26.00 mmol) was heated at 80° C. in a septum sealed reaction vessel under argon for 28 h. The reaction mixture was cooled, EtOH (5 ml) added and heated at 80° C. for 18 h. The reaction mixture was then evaporated, partitioned between aqueous NaHCO3 solution and DCM, extracted 5× with DCM containing 10% MeOH, the combined DCM layers dried over MgSO4 and evaporated. The residue was triturated with Et2O (20 ml) and DCM (1 ml) to give the title compound as a beige solid. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 5.82 (s, 1H), 4.70 (s, br, 2H), 3.65-3.58 (m, 2H), 3.27-3.20 (m, 2H), 2.38 (s, 6H), 2.26 (s, 2H), 1.68-1.62 (m, 4H). (UPLC-MS 6) tR 0.25; ESI-MS 276.3 [M+H]+.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].N1C=CC=CC=1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>C(Cl)Cl>[S:26]([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCO)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.2 %

Procedure:
25 g (88.5 mmol) of hexaethyleneglycol was stirred at 0° C. in 200 mL of CH2Cl2, and 14.3 mL of pyridine (177 mmol; 2 eq.) was added to the mixture followed by 17.4 g (88.5 mmol) of tosylchloride. The reaction mixture was stirred at room temperature for 24 hours and partitioned between 400 ml of 1N HCl and 200 ml of CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated to provide 31 g of a light yellow oil. Purification by silica gel chromatography (CH2Cl2/MeOH) provided 15.32 g (40%) of 1 as a light yellow oil: 1H NMR (CDCl3) δ2.45 (s, 3H), 3.55-3.75 (m, 22H), 4.15 (t, 2H), 7.35 (d, 2H), 7.80 (d, 2H); HRMS (FAB) calculated for C19H33O9S (M+H): 437.1845. Found: 437.1834.
Reaction SMILES: [N:1]1([CH:10](O)[CH:11]([OH:13])C)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.I([O-])(=O)(=O)=O.[Na+]>O>[N:1]1([CH2:10][CH:11]=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(O)C(O)n1cnc2ccccc21
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: O=CCn1cnc2ccccc21
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
The intermediate, N-benzimidazolyl-1,2-propanediol (0.66 g, 3.4 mmol) from above was dissolved in water (25 mL) and treated with sodium periodate (0.88 g, 4.1 mmol) with stirring for 1.5 hours. The solution was then extracted with dichloromethane, dried (MgSO4), filtered and concentrated to yield 2-(benzimidazol-1-yl)-ethanal (0.22 g, 1.4 mmol) which was used immediately without further purification in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([N:13]3[CH2:18][CH2:17][C:16]([CH3:20])([OH:19])[CH2:15][CH2:14]3)[CH2:9]2)=[C:4]([F:21])[CH:3]=1.[O:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35](=O)[O:34][CH2:33][CH2:32]2>>[F:21][C:4]1[CH:3]=[C:2]([N:1]2[CH2:33][CH2:32][C:31]3[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH2:27][C@@H:23]4[CH2:24][CH2:25][CH2:26][O:22]4)[CH:30]=3)[C:35]2=[O:34])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:14][CH2:15][C:16]([OH:19])([CH3:20])[CH2:17][CH2:18]2)[CH2:9]1
Reactant: CC1(O)CCN([C@@H]2CCN(c3ccc(N)cc3F)C2)CC1
Reactant: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Product: CC1(O)CCN([C@@H]2CCN(c3ccc(N4CCc5cc(OC[C@@H]6CCCO6)ccc5C4=O)cc3F)C2)CC1

Procedure:
1-[(R)-1-(4-Amino-2-fluoro-phenyl)-pyrrolidin-3-yl]-4-methyl-piperidin-4-ol was reacted with 6-[(S)-1-(Tetrahydro-furan-2-yl)methoxy]-isochroman-1-one by method AC. The product with the molecular weight of 523.65 (C30H38FN3O4) was obtained in this way; MS (ESI): 524 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[O:14][N:13]=[C:12]([C:15]3[N:16]4[C:20]([C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=3)=[CH:19][CH:18]=[CH:17]4)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:65][CH2:66][C:67]1[CH:68]=[CH:69][C:70]2[C:74]3([CH2:78][CH2:77][CH2:76][CH2:75]3)[O:73][B:72]([OH:79])[C:71]=2[CH:80]=1>CN(C=O)C>[OH:79][B:72]1[C:71]2[CH:80]=[C:67]([CH2:66][NH:65][C:24]([C:21]3[C:20]4[N:16]([CH:17]=[CH:18][CH:19]=4)[C:15]([C:12]4[CH2:11][C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=5)([C:27]([F:28])([F:29])[F:30])[O:14][N:13]=4)=[CH:23][CH:22]=3)=[O:25])[CH:68]=[CH:69][C:70]=2[C:74]2([CH2:75][CH2:76][CH2:77][CH2:78]2)[O:73]1
Reactant: NCc1ccc2c(c1)B(O)OC21CCCC1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
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
Product: O=C(NCc1ccc2c(c1)B(O)OC21CCCC1)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.67 mmol) and DIPEA (346 mg, 2.68 mmol) in DMF (10 mL) can be stirred at rt for 5 min and then HATU (510 mg, 1.34 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-1H-spiro[benzo[c][1,2]oxa-borole-3,1′-cyclo-pentan]-1-ol hydrochloride (202 mg, 0.80 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified on column chromatography and prep-HPLC to provide the title product.