Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6][C:5]2=O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nc2ccc(F)cc2c(=O)[nH]1
Product: CCOC(=O)c1nc(Cl)c2cc(F)ccc2n1
Temperature: 25 °C

Procedure:
A stirred solution of ethyl 6-fluoro-4-oxo-3,4-dihydroquinazoline-2-carboxylate (1.2 g, 5.08 mmol) in phosphorus oxychloride (15 mL) was heated at 105° C. for 6 h. After cooling to rt, the reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in anhydrous toluene. The toluene was concentrated under reduced pressure. The residue was dissolved in a small volume of DCM and it was passed through a short pad of silica gel eluting with DCM. Ethyl 4-chloro-6-fluoroquinazoline-2-carboxylate was obtained as a solid (1.3 g, 100%). LC-MS (ESI) m/z 255 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-])=O.[H][H]>[Ni].C(O)C>[NH2:1][C:4]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1N
Yield: 65 %

Procedure:
A mixture of 25 parts of ethyl 2-nitro-4-(phenylmethoxy)benzoate and 160 parts of ethanol was hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was boiled in 2,2'-oxybispropane. After cooling, the product was filtered off and dried, yielding 14.5 parts (65%) of ethyl 2-amino-4-(phenylmethoxy)benzoate (4).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][OH:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>CCOC(C)=O.O>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][OH:10])[N:3]=2)=[CH:15][CH:14]=1
Reactant: OCCc1cccc(Cl)n1
Reactant: COc1ccc(CN)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cccc(CCO)n2)cc1

Procedure:
Chloropyridine 30-2 (150 mg, 0.95 mmol) and 4-methoxybenzylamine (4 mL, 31 mmol) were combined neat and heated in a sealed tube at 160° for 4 days. After diluting with EtOAc and water the pH was adjusted to 7 phases separated and the organic phase was washed with brine, dried (MgSO4) and concentrated. Flash chromatography (twice on silica, 50% and 40% EtOAc/hexane) provided 30-3 as a yellow semi-solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([NH2:15])([C:12]([OH:14])=[O:13])[CH2:7]2.C(N(CC)CC)C.[C:23](=O)([O:39]N1C(=O)CCC1=O)[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>C(#N)C.O>[C:23]([CH:7]1[C:8]2[C:3](=[C:2]([CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][C:6]1([NH2:15])[C:12]([OH:14])=[O:13])([O:24][CH2:25][CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39]
Reactant: Cc1cccc2c1CCC(N)(C(=O)O)C2
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
A mixture of racemic 5-methyl-2-aminotetraline-2-carboxylic acid (1.05 g, 5.12 mmole), triethylamine (0.93 ml, 6.67 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 2.24 g, 6.64 mmole) in acetonitrile (30 ml) and water (30 ml) was stirred at room temperature for 2 days. TLC analysis of the reaction indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (520 mg) was added and the mixture was stirred at room temperature for another 24 hours. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH˜3 with 10% aqueous citric acid solution, and the white emulsion was extracted twice with methylene chloride. The combined organic layers were washed with water, brine and dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 2→5→8% methanol/methylene chloride) to give racemic Fmoc-5-methyl-2-aminotetraline-2-carboxylic acid (1.62 g, 74% yield) as an light brown solid. HRMS (FAB): C27H26NO4 (M+H) calc. 428.1862; observed: 428.1844.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.Cl[C:33]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:34]>>[CH2:36]([O:35][C:33]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:34])[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)COC(=O)Cl
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C(=O)c1cnc(NC2CCN(C(=O)OCC(C)C)CC2)nc1N

Procedure:
The same procedure as described in Example 17 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and isobutyl chloroformate (Aldrich), to afford 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid iso-butyl ester. HRMS, observed: 428.2295; Calcd for (M+H)+: 428.2293
Reaction SMILES: [CH:1]1([C:13](O)=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[CH3:16][O:17][C:18]1[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:20][C:21]2[O:25][CH2:24][CH2:23][C:22]=2[CH:26]=1.C([O-])(=O)/C=C/C([O-])=O>>[CH:1]1([CH2:13][N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([O:17][CH3:16])=[CH:26][C:22]4[CH2:23][CH2:24][O:25][C:21]=4[CH:20]=3)[CH2:32][CH2:31]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O=C(O)C1Cc2cccc3cccc1c23
Reactant: COc1cc2c(cc1N1CCNCC1)OCC2
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: COc1cc2c(cc1N1CCN(CC3Cc4cccc5cccc3c45)CC1)OCC2

Procedure:
Prepared as described in Example 9, starting from acenaphthen-1-ylcarboxylic acid and 4-(2,3-dihydro-5-methoxybenzofuran-6-yl)piperazine. The fumarate of the title compound melts at 226°-228° C. (ethanol).
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:12]=[CH:11][NH:10][C:9]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:19]SC1C(C2C=NC=CC=2)=NNC=1.CI>>[CH2:1]([S:7][C:8]1[N:12]=[CH:11][NH:10][C:9]=1[C:13]1[CH2:14][N:15]([CH3:19])[CH2:16][CH2:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: CCCCCCSc1nc[nH]c1-c1cccnc1
Solvent: CI
Product: CCCCCCSc1nc[nH]c1C1=CCCN(C)C1

Procedure:
3-(5-Hexylsulfanyl-3H-imidazol-4-yl]-pyridine (77) was converted to the title compound (76B) using the methodology described for the conversion of 21A to 22A (see Scheme 3) (the quaternization however was done at room temperature with a slight excess of CH3I). Yield: 70% (oil). LCMS (method A); Rt: 1.21 min, ([M+H]+=280). 1H-NMR (400 MHz, CDCl3): δ 7.53 (s, 1H), 6.40-6.29 (m, 1H), 3.45-3.41 (m, 2H), 2.79-2.72 (m, 2H), 2.59 (t, J=6 Hz, 2H), 2.45 (s, 3H), 2.41-2.37 (m, 2H), 1.55-1.49 (m, 2H), 1.38-1.31 (m, 2H), 1.30-1.19 (m, 4H), 0.85 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[S:16])[S-:15])=[N:11][CH:12]=1.C([NH+](CC)CC)C.Cl>C(Cl)(Cl)Cl.C(OCC)C.C(Cl)Cl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[S:15])[S:16][CH2:4][CH2:3][C:2](=[O:5])[CH3:1])=[N:11][CH:12]=1
Reactant: C=CC(C)=O
Reactant: S=C([S-])Nc1ccc(Cl)cn1
Agent: CC[NH+](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(=O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 1 h
Yield: 48.1 %

Procedure:
A solution of but-3-en-2-one (25.6 g) in anhydrous chloroform (90 cc) is added, at a maximum temperature of 5° C., to a suspension of triethylammonium 5-chloropyrid-2-yldithiocarbamate (110.0 g) in anhydrous chloroform (540 cc). The reaction is allowed to proceed for 1 hour at a maximum temperature of 5° C. A 3.7 N solution of hydrogen chloride in diethyl ether (97 cc) is added, at a maximum temperature of 0° C., and the mixture is then diluted with chloroform (500 cc). The chloroform solution is washed three times with distilled water (total 450 cc), dried over sodium sulphate and evaporated. The residue obtained (95.0 g) is dissolved in methylene chloride (300 cc), silica (0.2-0.5 mm; 60.0 g) is added and the solvent is then evaporated off. The silica impregnated with the product is introduced onto a column of diameter 7.5 cm, containing silica (0.2-0.5 mm; 900 g). Elution is carried out with a mixture of cyclohexane (6 liters) and ethyl acetate (1 liter), this eluate being discarded, and then with a mixture of cyclohexane (11.4 liters) and ethyl acetate (6.6 liters), this eluate being collected and evaporated to dryness under reduced pressure (20 mmHg) at 45° C. The product obtained (65.2 g; m.p. 116° C.) is purified by two successive recrystallisations from acetonitrile (210 cc) and then from a mixture of chloroform (250 cc) and diethyl ether (250 cc). 3-Oxobutyl 5-chloropyrid-2-yldithiocarbamate (47.5 g) (structure determined by IR spectroscopy in petroleum jelly), which melts at 120° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:44][C:45]([NH:47][C:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:44][C:45](=[O:46])[NH:47][C:48]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 63 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(quinolin-8-ylmethyl)-N4-tritylsuccinamide (Compound IV-20) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N:11]1([CH:16]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH:17]([CH3:19])[CH3:18])[CH:15]=[CH:14][N:13]=[CH:12]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH:16]([N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)[CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)C(c1ccc(N)cc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)C(c1ccc(NC(=O)Nc2ccc(F)cc2)cc1)n1ccnc1
Yield: 32.4 %

Procedure:
4-Fluorophenylisocyanate (0.017 mol) was added to a solution of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.014 mol) in dry THF (100 ml) and the mixture was stirred and refluxed for 2 hours. The mixture was cooled, the precipitate was filtered off and recrystallized from 2-propanone and CH3OH, yielding 1.6 g (32%) (±)—N-(4-fluorophenyl)-N′-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]urea (compound 740).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[C:8]([O:10][C:11](=[O:12])[C:5]2=[CH:4][CH:3]=1)=[O:9].[CH3:13][OH:14]>>[C:8]([C:6]1[C:5]([C:11]([OH:10])=[O:12])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)([O:14][CH3:13])=[O:9]
Reactant: Cc1ccc2c(n1)C(=O)OC2=O
Reactant: CO
Product: COC(=O)c1nc(C)ccc1C(=O)O

Procedure:
48.9 g of 6-methylpyridine-2,3-dicarboxylic anhydride in 200 ml of methanol are refluxed for 3 hours while stirring. Evaporating down the mixture under reduced pressure gives 57.9 g of the title compound of melting point 133°-158° C. (decomposition).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:24])=[N:10][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[CH3:29][N:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[CH3:31]>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([C:35]5[CH:36]=[CH:37][C:32]([N:30]([CH3:31])[CH3:29])=[CH:33][CH:34]=5)=[CH:3][C:4]([C:25]([F:28])([F:27])[F:26])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:24])[CH2:13]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(N(C)C)cc3)c2[nH]1

Procedure:
7-Bromo-2-[(2R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (95 mg, 0.2 mmol, Example 77) and 4-(N,N-dimethylamino)phenylboronic acid (41 mg, 0.25 mmol, Aldrich) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 515 (M+1).
Reaction SMILES: [NH:1]([CH:3]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5])[NH2:2].C[C:13](C(OC(C(C)=O)=O)=O)=[O:14].[CH:23](O)=[O:24]>>[CH:13]([N:1]([CH:3]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5])[NH:2][CH:23]=[O:24])=[O:14]
Reactant: O=CO
Reactant: NNC(C(=O)O)c1cccs1
Reactant: CC(=O)C(=O)OC(=O)C(C)=O
Product: O=CNN(C=O)C(C(=O)O)c1cccs1
Reaction time: 0.5 h

Procedure:
A solution of 1 g (RS) α-hydrazino-2-thienylacetic acid in 3 ml formic acid is stirred at 4° C. and treated dropwise with a solution of 3 ml acetoformic anhydride. Stirring is continued for 20 minutes at the same temperature and for a further 30 minutes at ambient temperature, then the product is evaporated to dryness, taken up with diethyl ether and the so obtained solid is triturated with ethyl ether collected under vacuum, to give 1.26 g (RS) α-(1.2-diformylhydrazino)-2-thienylacetic acid melting at 168°-170° C. (with decomposition).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][C:15](=[O:21])[NH:14][C:13]=2[N:12]=1)(=O)=O.[Na+].[I-].CCN(CC)CC.[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[N:39]1[CH2:45][CH2:44][CH2:43][N:42](CCCCOC2C=C3C(CCC(=O)N3)=CC=2)[CH2:41][CH2:40]1>CC#N>[Cl:31][C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[N:39]1[CH2:45][CH2:44][CH2:43][N:42]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]3[C:18]([CH2:17][CH2:16][C:15](=[O:21])[NH:14]3)=[CH:19][CH:20]=2)[CH2:41][CH2:40]1
Reactant: CS(=O)(=O)OCCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Intermediate 12 (85 mg, 0.27 mmol) was dissolved in CH3CN then NaI (55 mg, 0.37 mmol), Et3N (91 mg, 0.9 mmol), and intermediate 2 (102 mg, 0.36 mmol) were added. The resulting mixture was stirred at 70° C. overnight. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 7-(4-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)butoxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (compound 3) (78 mg, 63%). 1H NMR (300 MHz, CDCl3): δ 7.64 (s, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.27-7.15 (m, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.37 (d, J=8.1 Hz, 1H), 4.36 (t, J=6.0 Hz, 2H), 3.61-3.49 (m, 7H), 3.32-3.20 (m, 5H), 2.90-2.85 (m, 2H), 2.67-2.62 (m, 2H), 2.21-2.16 (m, 2H), 1.90-1.85 (m, 2H). HPLC: 99%, RT 2.682 min. MS (ESI) m/z 463.1 [M+H]+. mp: 110-111° C.
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30].N([O-])=O.[Na+].CC#N.O.[ClH:41]>O.Cl[Cu]>[Cl:41][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30]
Reactant: Cl
Reactant: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 70 °C
Reaction time: 0.67 h

Procedure:
Ethyl 1-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.280 g, 0.64 mmol) was dissolved in a mixture of MeCN/H2O/HCl 10 mL/10 mL/4 mL at 0° C. A solution of NaNO2 (0.066 g, 0.96 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (0.32 g, 3.2 mmol) in water (2 mL) was added drop wise at 0° C. The reaction mixture was heated to 70° C. for 1 h and the solvent was evaporated. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated to give oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate as a yellow oil (0.110 g).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Br:39])[C:34]=2[F:40])=[O:12])=[C:6]([O:41][CH3:42])[CH:5]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Br:39][C:35]1[C:34]([F:40])=[C:33]([C@H:14]2[C@H:13]([C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][C:6]=3[O:41][CH3:42])=[O:12])[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Br)c2F)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid methyl ester (0.2 g, 0.3 mmol) in MeOH (3 mL) and THF (9 mL) was added an aqueous solution (1N) of NaOH (6 mL, 6 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with water (5 mL), and acidified to “pH” 5-6 by dilute aqueous HCl solution. The mixture was then extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-4-{[(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid as a white powder (Yield, 0.16 g, 82%).
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([CH:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27]O)[CH2:23][CH2:24][CH3:25]>ClCCl>[CH2:22]([CH:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][Br:1])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(CO)CCCC
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC(CBr)CCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromine (61.4 g, 384 mmol) was added into a solution of triphenylphosphine (100.7 g, 384 mmol) and 450 mL dichloromethane at room temperature under argon protection. Then 2-butylhexanol (60.8 g, 384 mmol) was added dropwise via additional funnel over 50 minutes, the reaction solution was kept to stir at room temperature overnight. Dichloromethane was evaporated, and the concentrate filtered with pentane wash. The filtrate was concentrated via rotary evaporation and the resulting crude yellow oil was purified via vacuum distillation. The title compound was collected as colorless oil (70.8 g, 83.3%). 1H NMR (CDCl3): δ 0.89-0.92 (6H, m), 1.21-1.45 (12H, m), 1.54-1.67 (1H, m), 3.45 (2H, d).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)(=[O:12])[O:7][CH2:8][CH2:9][O:10][CH3:11].[H][H]>CCO.[Pd]>[CH3:11][O:10][CH2:9][CH2:8][O:7][P:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)(=[O:12])[O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: [H][H]
Reactant: COCCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCCOC
Agent: [Pd]
Solvent: CCO
Product: COCCOP(=O)(Cc1ccc(N)cc1)OCCOC
Yield: 97.1 %

Procedure:
A mixture of bis(2-methoxyethyl)(4-nitrobenzyl)phosphonate (Compound 185B, 6.0 g, 18 mmol) and 5% Pd/C (0.8 g) in EtOH (150 mL) was hydrogenated under 40 psi hydrogen pressure at 40° C. for 6 h. The reaction mixture was filtered and the filtrate was concentrated to give the desired product (5.3 g, 97%). 1H NMR (CDCl3, 400 MHz): δ=3.04 (d, J=21.2 Hz, 2H), 3.28 (s, 6H), 3.42-3.46 (m, 4H), 3.97-4.03 (m, 4H), 6.55 (d, J=8.4 Hz, 2H), 6.99-7.02 (m, 2H).