Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.O.[NH2:19][NH2:20]>C(O)C>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:19][NH2:20])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
1.181 g (5.00 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was placed into a 25 ml flask equipped with a magnetic stirring bar. About 5 ml absolute ethanol was added and then 2.50 g (50.00 mmol) of hydrazine hydrate was added and the solution was stirred at room temperature in a closed flask. A large amount of precipitate formed after about 30 minutes and the solution was allowed to stand overnight. The solution was filtered by vacuum and the white solid was washed with ethanol and then with ether. Upon drying, 0.890 g of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid hydrazide (AIT-0056) as a white solid was obtained. Yield: 80%.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[C:6]2=[N:11][CH:12]=[CH:13][N:5]2[N:4]=1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:14][C:13]1[N:5]2[C:6]([C:7]([S:9][CH3:10])=[N:8][C:3]([S:2][CH3:1])=[N:4]2)=[N:11][CH:12]=1
Reactant: CSc1nc(SC)c2nccn2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(SC)c2ncc(Br)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
A mixture of 2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (5.27 g, 24.82 mmol) and 1-bromopyrrolidine-2,5-dione (6.19 g, 34.8 mmol) in DMF (15 mL) was stirred at RT for 2 hours. The reaction was diluted with water, and the product extracted with dichloromethane (3×50 mL). The organic layer was washed with brine, dried and concentrated. The crude product mixture was purified via ISCO (0-50% of ethyl acetate/dichloromethane in 10 minutes, 80 g silica column) to give the pure product 7-bromo-2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine (4.61 g, 15.83 mmol, 63.8% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].CS(O)(=O)=O.[C:23]1([CH2:29][CH:30]2[NH:34][CH2:33][C:32](=[O:35])[CH2:31]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:34]1[CH:30]([CH2:29][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:31][C:32](=[O:35])[CH2:33]1)=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CNC(Cc2ccccc2)C1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Product: O=C1CC(Cc2ccccc2)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Yield: 12.5 %

Procedure:
3,5-di(trifluoromethyl)benzoyl chloride (0.03 mol) was added to intermediate 23 (0.027 mol). The mixture was stirred and triethylamine (0.1 mol) was added. The mixture was stirred at RT for 18 hours and then washed with water, NaOH and a saturated NaCl solution. The organic layer was separated, washed with a saturated NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 1.4 g of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinone (intermediate 24).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Cl)=[CH:50][CH:49]=1>>[CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][Si:27]([C:40]([CH3:41])([CH3:43])[CH3:42])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[O:44][CH2:52][C:51]1[CH:54]=[CH:55][C:48]([Cl:47])=[CH:49][CH:50]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CO[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccc(Cl)cc1
Yield: 48.3 %

Procedure:
General procedure A using using methyl 3,4-di-O-benzyl-6-O-(tert-butyldiphenylsilyl)-β-D-glucopyranoside (0.124 g, 0.202 mmol), NaH (15 mg, 0.303 mmol, 60% in mineral oil) and 4-chlorobenzylchloride (34.2 mg, 0.212 mmol) and gave 72 mg (48%) of 23 as a colorless oil after purification by flash column chromatography on silica gel (10% EtOAc/Hexanes). [α]24D: +6.9° (c 1.16, CH2Cl2); IR (thin film) 2929, 1492, 1428, 1072 cm−1; 1H-NMR (CDCl3) δ 7.82 (dd, J=1.5, 7.9 Hz, 2H), 7.76 (dd, J=1.2, 7.9 Hz, 2H), 7.49–7.31 (m, 18H), 7.27–7.24 (m, 2H), 4.97–4.88 (m, 4H), 4.76 (d, J=10.7 Hz, 1H), 4.75 (d, J=11.3 Hz, 1H), 4.37 (d, J=7.6 Hz, 1H), 3.99 (s, 2H), 3.83 (dd, J=9.2, 9.5 Hz, 1H), 3.71 (dd, J=9.2, 9.2 Hz, 1H), 3.64 (s, 3H), 3.49 (dd, J=7.9, 8.8 Hz, 1H), 3.41–3.39 (m, 1H), 1.12 (s, 9H); 13C-NMR (CDCl3) δ 138.7, 138.4, 137.4, 136.1, 135.8, 135.0, 133.8, 133.5, 133.3, 129.8, 129.5, 128.7, 128.6, 128.1, 128.0, 127.9, 127.8, 104.6, 84.8, 82.7, 77.9, 76.1, 75.8, 75.4, 74.1, 62.8, 56.9, 27.0, 26.8, 19.5; FAB MS m/z (M)+: calcd 759.2885, obsd 759.2881.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>C(Cl)Cl>[C:22]([NH:26][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8])([CH3:25])([CH3:24])[CH3:23]
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: CC(C)(C)N
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Nc1nc2ccncc2nc1Cl
Reaction time: 48 h
Yield: 87.9 %

Procedure:
Combined 2,3-dichloropyrido[3,4-b]pyrazine (1 g, 5.00 mmol) and DIPEA (1.75 mL, 10.00 mmol) in DCM (10.00 mL) and cooled to 0° C. and added tert-butylamine (1.590 mL, 15.00 mmol) and stirred for 48 h. The reaction mixture was poured into saturated aqueous NH4Cl and extracted twice with EtOAc. The organic extracts were combined, filtered through MgSO4, and concentrated in vacuo. The residue was redissolved in EtOAc, filtered through a one inch plug of silica, washing with EtOAc, and concentrated gave N-(tert-butyl)-3-chloropyrido[3,4-b]pyrazin-2-amine (1.04 g, 88%).
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9]2)[CH:4]([OH:15])[CH2:3][CH2:2]1.Cl.[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21]Cl>>[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][O:15][CH:4]1[CH:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9][CH:10]2[CH2:1][CH2:2][CH2:3]1
Reactant: CN(C)CCCCl
Reactant: OC1CCCC2Oc3ccccc3OC12
Agent: Cl
Product: CN(C)CCCOC1CCCC2Oc3ccccc3OC12
Yield: 55.6 %

Procedure:
In an analogous manner as described in Example 5, but starting with 10 g (0.048 mole) of the alcohol of Example 1 and 6.6 g (0.042 mole) of 3-dimethylamino-1-chloropropane hydrochloride, there were obtained 6.8 g of the title-compound of boiling point 165° C. at a pressure of 1.33 Pa, having the elementary analysis:
Reaction SMILES: C[Si](C)(C)CCOC(=O)C1C=CC=CC=1[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1.[CH3:25][Si:26]([CH3:52])([CH3:51])[CH2:27][CH2:28][O:29][C:30](=[O:50])[C:31]1[CH:36]=[C:35](Br)[C:34]([Cl:38])=[CH:33][C:32]=1[O:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>>[CH3:25][Si:26]([CH3:52])([CH3:51])[CH2:27][CH2:28][O:29][C:30](=[O:50])[C:31]1[CH:36]=[C:35]([B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[C:34]([Cl:38])=[CH:33][C:32]=1[O:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]
Reactant: CC1(C)OB(c2ccccc2C(=O)OCC[Si](C)(C)C)OC1(C)C
Reactant: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(Br)cc1C(=O)OCC[Si](C)(C)C
Product: CC(C)(C)OC(=O)CCCOc1cc(Cl)c(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCC[Si](C)(C)C

Procedure:
2-(3-tert-Butoxycarbonyl-propoxy)-4-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl-benzoic acid-2-trimethylsilanyl-ethyl ester (2.7 g) was similarly prepared according to Step 2D from 5-bromo-2-(3-tert-butoxycarbonyl-propoxy)-4-chloro-benzoic acid 2-trimethylsilanyl-ethyl ester (3.2 g). MS ion (APCl): 513.2, 459.1; tR=3.62 min. (method 1)
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][O:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[C:4]([CH3:14])[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:4]1[CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:13]=[CH:12][C:5]=1[CH2:6][O:7][Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1cc(Br)ccc1CO[Si](C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cc(C#C[Si](C)(C)C)ccc1CO[Si](C)(C)C
Temperature: 70 °C
Yield: 65.1 %

Procedure:
Using General Procedure D; (4-bromo-2-methyl-benzyloxy)-trimethylsilane (Intermediate 134, 550.0 mg, 2.01 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (38.0 mg, 0.20 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (1.05 g, 10.6 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (142.0 mg, 0.20 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (380.0 mg, 65%) was isolated by chromatography (0-2% EtOAc—hexanes) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](Cl)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[C:10]([CH3:15])[CH:9]=3.CCN(CC)CC.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>O1CCOCC1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[C:10]([CH3:15])[CH:9]=3
Reactant: Cc1cc2nc(Cl)c3ccc(Br)cc3c2c(Cl)n1
Reactant: NCc1ccccn1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc2nc(NCc3ccccn3)c3ccc(Br)cc3c2c(Cl)n1
Temperature: 120 °C

Procedure:
To a solution of 9-bromo-1,6-dichloro-3-methyl-benzo[c][1,6]naphthyridine (0.12 g, 0.35 mMol) in anhydrous dioxane (4 mL) was added anhydrous Et3N (0.07 mL, 0.53 mMol), followed by 2-aminomethylpyridine (0.038 g, 0.35 mMol). The resulting reaction mixture was heated in a sealed tube at 120° C. for 5 hours. The reaction mixture was concentrated to a crude solid that was redissolved in EtOAc (10 mL). The EtOAc layer was washed with water (2×5 mL), brine (1×10 mL) and dried over MgSO4. The filtrate was concentrated and the resulting residue was purified by flash chromatography using an EtOAc/Hexanes gradient to afford 9-bromo-1-chloro-3-methyl-N-(pyridin-2-ylmethyl)benzo[c]-1,6-naphthyridin-6-amine. 1H NMR (400 MHz, DMSO-d6) 9.88 (d, 1H), 8.65 (bs, 1H), 7.97 (d, 1H), 7.83-7.80 (dd, 1H), 7.75 (t, 1H), 7.64 (bs, 1H), 7.43 (s, 1H), 7.41 (s, 1H), 7.27 (s, 1H), 4.99 (d, 2H), 2.62 (s, 3H). LRMS calculated for C19H14BrClN4 [M+H]+, 415.0; found 415.1.
Reaction SMILES: C(O[K])(C)(C)C.F[C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1.Cl>C1COCC1>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:8]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:21]=1
Reactant: Nc1cccnc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C(F)(F)F)cc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
tert-Butoxy potassium was added to a mixture of 2-fluoro-4-(trifluoromethyl)benzonitrile, 3-pyridine amine and THF, followed by stirring at room temperature for 7 hours. After neutralizing the reaction liquid by adding 1 M hydrochloric acid thereto and subsequent extraction with chloroform, the solvent was evaporated under a reduced pressure. The residue was purified by column chromatography to obtain 2-(pyridine-3-ylamino)-4-(trifluoromethyl)benzonitrile.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][CH:17]([CH2:34][OH:35])[CH2:18][C:19]([CH3:33])([CH3:32])[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:21].[C:36]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:36]([NH:46][C@H:47]([C:51]([O:35][CH2:34][CH:17]([OH:16])[CH2:18][C:19]([CH3:32])([CH3:33])[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)=[O:21])=[O:52])[CH:48]([CH3:50])[CH3:49])([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)C(C)(C)CC(O)CO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C(C)(C)CC(O)COC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a mixture of DCC (14.8 g, 72 mmol), DMAP (0.88 g, 7.2 mmol) and 4-methoxybenzyl 4,5-dihydroxy-2,2-dimethyl-valerate (20.3 g, 72 mmol) in CH2Cl2 (400 mL) at 0° C., was added dropwise a solution of N-CBz-L-valine (16.2 g, 65 mmol) in CH2Cl2 (100 ml). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5 h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 2→5% MeOH in CH2Cl2), to give 22.4 g 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-4-hydroxy-2,2-dimethylvalerate.
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([CH2:14][C@H:15]([NH:19][CH:20]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:21]([F:24])([F:23])[F:22])[C:16]([OH:18])=O)(=[O:13])=[O:12].Cl.[NH2:34][C:35]1([C:38]#[N:39])[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:38]([C:35]1([NH:34][C:16](=[O:18])[C@@H:15]([NH:19][C@@H:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:21]([F:23])([F:22])[F:24])[CH2:14][S:11]([CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH:2]([F:1])[F:32])(=[O:13])=[O:12])[CH2:37][CH2:36]1)#[N:39]
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1ccccc1OC(F)F)NC(c1ccc(F)cc1)C(F)(F)F
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)Cc2ccccc2OC(F)F)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 3-(2-difluoromethoxyphenylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]propionic acid (157 mg, 0.325 mmol) in DMF (5 mL) was added 1-aminocyclopropanecarbonitrile hydrochloride (46.4 mg, 0.39 mmol), HATU (186.3 mg, 0.49 mmol) and DIPEA (63.2 mg, 0.49 mmol). After 1 h, the reaction mixture was extracted with ethyl acetate (100 mL) and washed with satured NaHCO3 and brine. After drying with MgSO4, the solvent was removed and the residue was purified by column chromatograph yield the title compound (125 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:19])([F:18])[F:17])[O:13]2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[Cl:25]Cl>CCOC(C)=O.C(Cl)Cl>[Cl:25][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[C:3]([CH3:5])([CH3:4])[CH2:2][OH:1])[O:13][CH:12]([C:16]([F:18])([F:19])[F:17])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10]2
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)CO)cc2OC1C(F)(F)F
Reactant: ClCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)CO)cc2OC1C(F)(F)F

Procedure:
A single treatment of ethyl 7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (5.4 g 16 mmoles) with Cl2 was performed as described in Example 115 Step 2. Chromatography of the residue using a gradient of 0-10% EtOAc—DCM as eluent gave the title compound, 3.7 g, as a nearly colorless oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]1[CH:20]2[CH:16]1[CH2:17][N:18]([C:21]1[N:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][N:22]=1)[CH2:19]2)(=[O:13])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:52][CH2:53][N:54]1[CH:58]=[CH:57][N:56]=[C:55]1[CH3:59].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:59][C:55]1[N:54]([CH2:53][CH2:52][N:14]([S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:13])=[O:12])[CH:15]2[CH:16]3[CH:20]2[CH2:19][N:18]([C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][N:22]=2)[CH2:17]3)[CH:58]=[CH:57][N:56]=1
Reactant: Cc1nccn1CCO
Reactant: CCOC(=O)c1cnc(N2CC3C(C2)C3NS(=O)(=O)c2ccc3ccccc3c2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N2CC3C(C2)C3N(CCn2ccnc2C)S(=O)(=O)c2ccc3ccccc3c2)nc1
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of ethyl 2-[6-(naphthalene-2-sulfonylamino)-3-aza-bicyclo[3.1.0]hex-3-yl]-pyrimidine-5-carboxylate (0.182 g, 0.47 mmol) in DCM (10 ml) was added triphenylphosphine (0.26 g, 1 mmol) and 1-(2-hydroxyethyl)-2-methylimidazole (0.084 mg, 0.75 mmol). Diisopropylazodicarboxylate (0.167 ml, 0.85 mmol) was then added and the solution stirred overnight. The mixture was loaded directly onto a silica gel column and purified eluting with 2% MeOH/DCM to give the title compound (0.242 g, 90%). 1H NMR (300 MHz, CDCl3) δ: 1.36 (3H, t), 1.60-1.80 (3H, m), 2.57 (3H, s), 3.43 (2H, t), 3.48-3.62 (2H, m), 3.70 (2H, d), 4.35 (2H, t), 4.33 (2H, q), 6.90 (1H, d), 6.98 (1H, d), 7.60-7.80 (2H, m) 7.82 (1H, dd), 7.95 (1H, dd), 8.02 (2H, d), 8.43 (1H, s), 8.72 (2H, s).
Reaction SMILES: [CH3:1][C:2]1([C:21](O)=[O:22])[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.CCN=C=NCCCN(C)C.[CH3:54][O:55][C:56]1[CH:68]=[CH:67][C:59]([CH2:60][C:61]2[NH:65][N:64]=[C:63]([NH2:66])[N:62]=2)=[CH:58][CH:57]=1>C(#N)C>[CH3:54][O:55][C:56]1[CH:57]=[CH:58][C:59]([CH2:60][C:61]2[N:62]=[C:63]([NH2:66])[N:64]([C:21]([C:2]3([CH3:1])[CH2:17][C:10]4([N+:18]([O-:20])=[O:19])[C:11]5[C:16]([CH:3]3[C:4]3[C:9]4=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:15][CH:14]=[CH:13][CH:12]=5)=[O:22])[N:65]=2)=[CH:67][CH:68]=1
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Reactant: COc1ccc(Cc2nc(N)n[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cc2nc(N)n(C(=O)C3(C)CC4([N+](=O)[O-])c5ccccc5C3c3ccccc34)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.3 %

Procedure:
To a stirred solution of 15-methyl-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxylic acid (25 mg, 0.08 mmol, prepared according to WO04009017), 1-hydroxybenzotriazole (16 mg, 0.12 mmol), and N-ethyl-N,N-diisopropylamine (0.1 mL) in anhydrous acetonitrile (1 mL) was added EDCI (38 mg, 0.2 mmol) at RT under argon. After the mixture was stirred at RT for 5 min, 5-(4-methoxybenzyl)-1H-1,2,4-triazol-3-amine (21 mg, 0.1 mmol) was added. The reaction mixture was stirred at RT overnight and at 80° C. for 1 h. After the solvents were removed, the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with methylene chloride. The combined organic solutions were dried (Na2SO4), concentrated and purified by silica gel chromatography to give 35 mg (87% yield) of the title compound as a white solid. (M+H)+=496.20
Reaction SMILES: C(Cl)[Cl:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])=[N:13][C:14]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)=[C:15]([CH:19]=2)[C:16]([OH:18])=O)=[CH:7][CH:6]=1.C(Cl)(=O)C(Cl)=O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])=[N:13][C:14]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([F:28])[CH:22]=3)=[C:15]([CH:19]=2)[C:16]([Cl:2])=[O:18])=[CH:9][CH:10]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Oc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dried round bottom flask was added methylene chloride (2 mL), the product of Example 86 (0.110 g; 0.217 mmol), oxalyl chloride (0.02 mL, 0.217 mmol), and DMF (1 drop; cat.). The reaction mixture was stirred for 1.5 hours at room temperature. Toluene (1 mL) was added to the reaction mixture and the volatiles were removed in vacuo.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.Br[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH2:19][N:17]([CH2:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[C:15]2[CH:14]=[CH:13][C:12]3[NH:8][CH:9]=[N:10][C:11]=3[CH:16]=2)=[CH:21][CH:22]=1)#[N:25]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)n1cnc2cc(N)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(CN(Cc2ccc(C#N)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N1-Boc-benzimidazol-5-amine (233 mg; 1 mmol; 1 eq.), 4-bromomethylbenzonitrile (490 mg; 2.5 mmol; 2.5 eq.) and K2CO3 (345 mg; 2.5 mmol; 2.5 eq.) according to method 4; Yield: 0.176 g (48.4%); MS m/z: 364.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 4.80 (s, 4H); 6.66-6.68 (m, 2H); 7.34 (d, 1H, 3J=8.7 Hz); 7.47 (d, 4H, 3J=8.3 Hz); 7.78 (d, 4H, 3J=8.3 Hz); 7.92 (s, 1H); 11.95 (br s, 1H); HPLC (METHOD [A]): rt 13.50 min (100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][CH3:13].C(Cl)(Cl)Cl.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:13])[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=1
Reactant: CNCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CN(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 55 %

Procedure:
To a mixture of 0.42 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(methylamino)propyloxy)benzene, 0.18 ml of triethylamnine and 10 ml of chloroform was added 0.18 ml of 4-(trifluoromethyl)benzoyl chloride, while stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was dissolved in 50 ml of ethyl acetate, and the ethyl acetate layer was successively washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(N-methyl-4-(trifluoromethyl)benzamido)propyloxy)benzene (55% yield), nD24.5 1.5461.