Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:8]=1[C:18]1[CH:22]=[C:21]([S:23][CH3:24])[N:20]([CH3:25])[N:19]=1.O>C(Cl)(Cl)(Cl)Cl>[Cl:4][C:22]1[C:18]([C:8]2[C:7]([Cl:6])=[CH:12][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:10][C:9]=2[Cl:17])=[N:19][N:20]([CH3:25])[C:21]=1[S:23][CH3:24]
Reactant: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CSc1c(Cl)c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 0.3 g quantity of sulfuryl chloride was added to 1.2 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-5-methylsulfenylpyrazole (compound 1) in 5 ml of anhydrous carbon tetrachloride at room temperature, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into cold water, and the resulting mixture was extracted with methylene chloride. The organic layer was washed with 10% aqueous sodium hydrogen carbonate solution and with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was then purified by column chromatography on silica gel (eluent: ether/hexane=1/5), giving 1.0 g of the desired compound in the form of white crystals (yield 83.3%).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16](=[N:18][OH:19])[NH2:17])=[N:13][N:12]=2)[CH2:7][CH2:6]1.[C:25]([OH:33])(=[O:32])[C@H:26]([CH2:28][C:29](O)=O)[OH:27]>>[Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:15][C:14]([C:16]3[N:17]=[C:29]([CH2:28][C@H:26]([OH:27])[C:25]([OH:33])=[O:32])[O:19][N:18]=3)=[N:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: NC(=NO)c1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1
Product: O=C(O)[C@@H](O)Cc1nc(-c2nnc(N3CCC(Oc4cc(F)ccc4Br)CC3)s2)no1

Procedure:
The title compound was prepared in a similar manner as described for Example 16 from 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-N′-hydroxy-1,3,4-thiadiazole-2-carboximidamide and (S)-(−)-malic acid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:44](=O)[CH2:45][CH3:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:44][CH2:45][CH3:46])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3CCC)cc1
Reaction time: 20 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (120 mg) and propionaldehyde (0.15 ml) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.13 g) at room temperature, and the mixture was stirred for 20 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:2), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 83) (105.4 mg) as yellow crystals.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([N:31]([CH3:33])[CH3:32])[CH2:17][CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[ClH:1].[ClH:1].[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH:16]([N:31]([CH3:33])[CH3:32])[CH2:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH2:11][CH2:10]1
Reactant: CN(C)C(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C(CC1CCNCC1)CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 4N hydrogen chloride in ethyl acetate (1 ml; 4 mmol) was added to a solution in ethyl acetate (0.5 ml) of 1,3-bis(1-tert-butoxycarbonyl-4-piperidinyl)-2-(dimethylamino)propane (135 mg; 0.30 mmol) synthesized by the process described in Referential Example 4, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain crude crystals of 1,3-bis(4-piperidinyl)-2-(dimethylamino)propane trihydrochoride.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([C@@H:23]([CH2:35][NH:36]C(OC(C)(C)C)=O)[CH2:24][O:25][Si:26]([CH3:34])([CH3:33])C(C)(C)C(C)C)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])C.N1C=CN=C1.C[Si](Cl)(C)[C:51]([CH:54]([CH3:56])[CH3:55])([CH3:53])[CH3:52]>CN(C)C=O>[CH2:16]([O:15][C:11]1[CH:12]=[CH:13][C:8]2[N:7]3[C@H:23]([CH:24]([C:51]([CH3:53])([CH3:52])[CH:54]([CH3:56])[CH3:55])[O:25][SiH:26]([CH3:33])[CH3:34])[CH2:35][NH:36][C:4](=[O:5])[C:6]3=[CH:14][C:9]=2[CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1[C@@H](CNC(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C(C)C
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)C(C)(C)C(O[SiH](C)C)[C@@H]1CNC(=O)c2cc3cc(OCc4ccccc4)ccc3n21
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 8, intermediate a), from 5-benzyloxy-1-{(S)-1-(tert-butoxycarbonylamino-methyl)-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-ethyl}-1H-indole-2-carboxylic acid ethyl ester to give a mixture of the desired compound and the unprotected hydroxymethyl compound. The mixture was dissolved in N,N-dimethylformamide and 1 equivalent of imidazole was added. At 0° C., 1 equivalent of dimethylthexylsilyl chloride was added and the cooling bath was removed. The reaction mixture was poured on water and was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica gel using n-hexane:ethyl acetate (1:2 v/v) as eluant to give the desired product as a light yellow foam (35%).
Reaction SMILES: C(OC1[O:42][C@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[C@@H:16]([O:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][CH2:21][CH:22]=[CH2:23])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[CH2:48]([Cl:50])Cl>[Zn+2].[Br-].[Br-]>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][CH2:21][CH:22]=[CH2:23])[C@@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[O:42][C@@H:48]1[Cl:50])(=[O:10])[CH3:9]
Reactant: ClCCl
Reactant: C=CCO[C@H]1[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)C(OC(C)=O)O[C@@H]2COC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [Zn+2]
Product: C=CCO[C@H]1[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](Cl)O[C@@H]2COC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 1 h
Yield: 11.7 %

Procedure:
To a solution of 2 (3.5 g, 5.17 mmol) in CH2Cl2 (10 mL) Cl2CHOCH3 (0.56 mL, 6.2 mmol) and ZnBr2 (100 mg) were added under an Ar atmosphere. The mixture was stirred for 1 h, then concentrated and the residue was chromatographed on silica gel with pentane-EtOAc (6:4) to give 3 (396 mg, 85%), [α]D +93.4° (c 1.2, CHCl3); 1H NMR (CDCl3) δ 6.22 (s, 1H, J1,2 =3.9 Hz, H-1), 5.80 (m, 1H, Hc), 5.56 (t, 1H, J3,4 and J2,3 ≈9.7 Hz, H-3), 5.31 (dd, 1H, J4',3' =3.5 Hz, J4',5' =0.8 Hz, H-4'), 5.20 (1H, Hb), 5.12 (1H, Ha), 4.93 (dd, 1H, H-2), 4.86 (dd, 1H, J2',3 =10.2 Hz, H-3'), 4.58 (dd, 1H, J6a,6b =12.1 Hz, J5,6a =0.7 Hz, H-6a), 4.34 (d, 1H, J1',2' =7.7 Hz, H-1'), 4.29 (dd, 1H, J5,6b =4.2 Hz, H-6B), 4.25-4.01 (m, 5H, Hd, He, H-5, H-6'a, H-6'b), 3.85-3.78 (m, 2H, H-4, H-5'), 3.42 (dd, 1H, H-2'). Calc'd for C27H37ClO16 (653.025) C, 49.66; H, 5.71, Cl, 5.43. Found C, 49.68, H, 5.68, Cl, 5.73.
Reaction SMILES: [CH2:1]([C:4]1[C:9](=[O:10])[C:8]([CH3:11])=[C:7]([C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])[C:6](=[O:19])[C:5]=1[CH3:20])[CH:2]=[CH2:3].[Cl:21][CH2:22][CH2:23][N:24]([CH2:32][CH2:33][Cl:34])[C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1>>[CH2:1]([C:4]1[C:9](=[O:10])[C:8]([CH3:11])=[C:7]([C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([O:16][C:28]2[CH:27]=[CH:26][C:25]([N:24]([CH2:23][CH2:22][Cl:21])[CH2:32][CH2:33][Cl:34])=[CH:30][CH:29]=2)=[O:15])[C:6](=[O:19])[C:5]=1[CH3:20])[CH:2]=[CH2:3]
Reactant: Oc1ccc(N(CCCl)CCCl)cc1
Reactant: C=CCC1=C(C)C(=O)C(C(C)(C)CC(=O)O)=C(C)C1=O
Product: C=CCC1=C(C)C(=O)C(C(C)(C)CC(=O)Oc2ccc(N(CCCl)CCCl)cc2)=C(C)C1=O
Yield: 26 %

Procedure:
Using an analogous procedure to that described in Example 5, 3-(3-allyl-2,5-dimethyl-1,4-benzoquinonyl)-3-methylbutyric acid was reacted with 4-[bis(2-chloroethyl)amino]phenol to give 4-[bis(2-chloroethyl)amino]phenyl 3-(3-allyl-2,5-dimethyl-1,4-benzoquinonyl)-3-methylbutyrate as an oil in 26% yield; NMR Spectrum: (CDCl3) 1.52 (s, 6H), 1.96 (s, 3H), 2.17 (s, 3H), 3.15 (d, 2H), 3.2 (s, 2H), 3.56-3.72 (m, 8H), 4.99 (m, 2H), 5.72 (m, 1H), 6.58-6.88 (m, 4H); Mass Spectrum: (M+H+) 496,494,492.
Reaction SMILES: I[C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C([O:28][B:29]([O:33]CC)[O:30]CC)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:14]([O:13][C:12]([NH:11][C:10]1[C:9]([S:19][CH3:20])=[N:8][N:7]2[C:2]([O:28][B:29]([OH:33])[OH:30])=[CH:3][CH:4]=[CH:5][C:6]=12)=[O:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOB(OCC)OCC
Reactant: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1nn2c(OB(O)O)cccc2c1NC(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
After dissolving tert-butyl N-(7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl)carbamate (200 mg) in tetrahydrofuran (2 mL), the mixture was cooled to −78° C. and n-butyllithium (1.6 M; 0.66 mL) was added dropwise. The mixture was stirred for 1 hour at the same temperature, triethoxyborane (109 μL) was added and the temperature was increased to room temperature. Saturated aqueous ammonium chloride was added to the obtained reaction mixture, and extraction was performed with ethyl acetate. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (106 mg) as grayish white crystals.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:22])[CH:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-])=O)[CH:10]=2)[NH:5][C:4](=[O:23])[CH2:3]1.[H][H].C>>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:22])[CH:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH2:19])[CH:10]=2)[NH:5][C:4](=[O:23])[CH2:3]1
Reactant: [H][H]
Reactant: Cc1cc(Nc2ccccc2[N+](=O)[O-])cc2c1NC(=O)CC2C
Product: Cc1cc(Nc2ccccc2N)cc2c1NC(=O)CC2C

Procedure:
This compound, m.p. 195°-199°, was prepared similarly to Preparation 17 using 3,4-dihydro-4,8-dimethyl-6-[(N-2-nitrophenyl)-amino]-2-(1H)-quinolone, hydrogen and palladised charcoal as starting materials. The product was characterised spectroscopically and used directly in Examples 13, 15 and 16 without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[CH2:18]([CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23]Br)[CH2:19][CH2:20][CH3:21].[NH4+].[Cl-]>CO>[CH2:18]([CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][N:7]1[N:6]=[C:5]2[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]2=[N:8]1)[CH2:19][CH2:20][CH3:21]
Reactant: Fc1cc2nn[nH]c2cc1F
Reactant: CCCCCCC(CBr)CCCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CCCCCCC(CCCC)Cn1nc2cc(F)c(F)cc2n1

Procedure:
5,6-difluoro-1H-benzo[d][1,2,3]triazole (8.04 g, 1.0 eq), potassium tert-butoxide (5.87 g, 1.01 eq), and 2-butyloctylbromide (13.04 g, 1.01 eq) were dissolved in 130 mL of methanol. The reaction was heated to reflux for 17 h. The reaction mixture was then poured into saturated NH4Cl solution, and extracted with ethyl acetate. The organic layer was washed with water (2×), dried (Na2SO4), filtered, concentrated in vacuo, and purified by column chromatography on silica gel using 10:1 hexanes:ethyl acetate as the eluent. Yield: 2.88 g (17%). Colorless oil. 1H NMR (CDCl3, 400 MHz, δ): 7.59 (t, 3JTHF=8.4 Hz, 2H), 4.58 (d, 3JHH=6.8 Hz, 2H), 2.22 (m, 1H), 1.28 (m, 16H), 0.86 (t, 3JHF=5.6 Hz, 6H).
Reaction SMILES: [ClH:1].Cl.[OH:3][C:4]1[C:5]([CH2:19]O)=[N+:6]([O-])[C:7]([CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][CH:9]=1>[Pd].CO>[ClH:1].[ClH:1].[OH:3][C:4]1[C:5]([CH3:19])=[N:6][C:7]([CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:8][CH:9]=1
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(CO)[n+]1[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1nc(C(O)CNC(C)(C)C)ccc1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into a 500 ml. Parr bottle there was introduced 13.4 g. (0.04 mole) of 3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)-2-hydroxymethylpyridine N-oxide dihydrochloride and 6.5 g. of 5% palladium on carbon catalyst in 150 ml. of methanol. Under a hydrogen pressure of 43 psi the mixture was shaken at room temperature for two days. The catalyst was removed by filtration under a nitrogen atmosphere followed by removal of the solvent in vacuo to give an oil which was triturated with isopropanol to induce crystallization. Filtration of the resulting solid affored 3-hydroxy-6-(1-hydroxy-2-tert-butylaminoethyl)-2-methylpyridine dihydrochloride, 10.0 g. (85%) m.p. 226°-228.5° C. (dec.); NMR (DMSO d6) delta 7.80 (q, 2H, pyridyl H), 5.40 (br m, 1H); 3.30 (br m, 2H), 2.60 (s, 3H, 2-CH3) and 1.35 (s, 9H, t-Bn).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:27]=[C:28]([O:32][CH3:33])[CH:29]=[CH:30][CH:31]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4cccnc4Cl)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12l and 3-bromoanisole
Reaction SMILES: [NH3:1].Cl[C:3]1[C:8]([Cl:9])=[C:7]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[N:6]=[C:5]([CH:17]2[CH2:19][CH2:18]2)[N:4]=1>C(O)C>[Cl:9][C:8]1[C:3]([NH2:1])=[N:4][C:5]([CH:17]2[CH2:19][CH2:18]2)=[N:6][C:7]=1[CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: CCOC(OCC)c1nc(C2CC2)nc(Cl)c1Cl
Reactant: N
Solvent: CCO
Product: CCOC(OCC)c1nc(C2CC2)nc(N)c1Cl
Temperature: 75 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Ethanol (190 mL) was saturated with ammonia. 4,5-Dichloro-2-cyclopropyl-6-(diethoxymethyl)pyrimidine (i.e. the product of Example 5) (25.2 g, 86.5 mmol) was added, and the mixture sealed in a pressure vessel (Parr Instrument Co., Moline, Ill.). The mixture was warmed to 75° C., and the pressure was maintained at 40 psi (276 kPa). After 8 h at this temperature and pressure the mixture was allowed to cool to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and then filtered. The filtrate was evaporated under reduced pressure, and the residue was taken up in hexanes to crystallize the product as an off-white solid (19.97 g, 85% yield). The product recrystallized from hexanes had a melting point of 104.5-109.5° C.
Reaction SMILES: [Mg].C(Br)C.[C:5]1([C@H:11]([CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I:21]I.Cl>O1CCCC1>[C:5]1([C@H:11]([CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([I:21])=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: II
Reactant: C[C@H](Cc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CCBr
Solvent: C1CCOC1
Product: C[C@H](Cc1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
35 ml of tetrahydrofuran (THF) was added to 11.6 g (0.48 mol) of magnesium, and a solution having 23.6 g (0.22 mol) of ethyl bromide dissolved in 70 ml of THF was dropwise added thereto over a period of 1 hour at room temperature with stirring, followed by stirring for 1 hour. A solution having 50.0 g (0.22 mol) of (R)-2-phenyl-1-(4-chlorophenyl)propane dissolved in 50 ml of THF was dropwise added thereto over a period of 30 minutes at room temperature, followed by stirring under reflux for 5 hours. After the mixture was cooled to room temperature, 250 ml of THF was added thereto, and the mixture was further cooled to −30° C. A solution having 112 g (0.44 mol) of iodine dissolved in 300 ml of THF was dropwise added thereto at −30° C. over a period of 30 minutes, followed by stirring for 1 hour. The temperature was raised to 0° C., and 120 ml of 4M hydrochloric acid was dropwise added thereto, followed by stirring for 10 minutes. After extraction with toluene from the reaction liquid, washing with water and drying were carried out to obtain 69.8 g of (R)-2-phenyl-1-(4-iodophenyl)propane (GC purity: 95.2%, 0.22 mol).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[N:8]([C:16](=[O:27])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](O)=[O:25])[CH:19]=1)[CH2:7][CH2:6]2.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:41][N:42]([CH3:47])[CH2:43][CH2:44][NH:45][CH3:46]>ClCCl.C1COCC1.CN(C=O)C>[CH3:41][N:42]([CH3:47])[CH2:43][CH2:44][N:45]([CH3:46])[C:24]([C:20]1[CH:19]=[C:18]([NH:17][C:16]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([S:2][CH3:1])=[C:11]([C:12]([F:13])([F:15])[F:14])[CH:10]=3)[CH2:6][CH2:7]2)=[O:27])[CH:23]=[CH:22][CH:21]=1)=[O:25]
Reactant: CSc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(C(=O)O)c1)CC2
Reactant: CNCCN(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(C(=O)N(C)CCN(C)C)c1)CC2
Reaction time: 1 h
Yield: 83.2 %

Procedure:
The carboxylic acid from Example 12 (0.5 g, 1.25 mmol) in dichloromethane (10 ml) was treated with oxalyl chloride (0.3 ml, 3.4 mol) and DMF (catalytic). Solution was stirred for 1 h and evaporated to dryness. The residue in dry THF (5 ml) was added to a stirred solution of triethylamine (0.3 ml, 4 mmol) and N,N,N'-trimethylethylenediamine (0.5 ml, 4.5 mmol) in dry THF (10 ml). Following 3 hours at room temperature, the solution was partitioned (H2O/EtOAc). Drying and removal of the organic layers followed by recrystallisation (EtOAc/60°-80° petrol) afforded the title compound (0.5 g, 83%) as a white solid. M.pt. 140°-141° C.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[C:12]1([O:18]C2C=CC=CC=2)C=CC=[CH:14][CH:13]=1.CCCC(C)C>C(#N)C>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:5]=1[N:6]=[CH:14][CH:13]=[C:12]2[OH:18]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccccc1OC(F)F
Solvent: CC#N
Solvent: CCCC(C)C
Product: Oc1ccnc2c(OC(F)F)cccc12

Procedure:
2-difluoromethoxyaniline (7.63 g) and the product from step a) were stirred in acetonitrile (100 ml) overnight. The solvent was removed by evaporation and the solid triturated with 4:1 isohexane/diethyl ether (200 ml) before filtering to give a light green solid. The solid was added portionwise to refluxing diphenylether (120 ml) and continued heating for a further 10 minutes before cooling. The solution was poured into isohexane (600 ml) and the solid filtered off to give the title compound (12.0 g).
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[C:12](OC)=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:1])[F:19])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:22][CH:23]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1c(N)ccc2c1CCC(NCC(F)F)CC2
Product: NC(=O)[C@@H]1[C@H](Nc2nc(Nc3ccc4c(c3)CCC(NCC(F)F)CC4)ncc2Cl)[C@H]2C=C[C@@H]1C2
Yield: 29 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield (1S,2S,3R,4R)-3-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (28.05 mg, 29% yield) as an off white amorphous solid. 1H-NMR (CDCl3) δ 8.16 (d, J=8.2 Hz, 1H), 7.89 (s, 1H), 7.39 (s, 1H), 6.96 (m, 1H), 6.87 (d, J=8.3 Hz, 1H), 6.37 (br s, 1H), 6.32 (br s, 1H), 5.83 (m, 1H), 5.59 (br s, 1H), 5.37 (br s, 1H), 4.36 (m, 1H), 3.72 (s, 3H), 3.22 (m, 1H), 3.03 (m, 3H), 2.95 (s, 1H), 2.83 (m, 2H), 2.66 (m, 1H), 2.50 (m, 1H), 2.24 (d, J=9.4 Hz, 1H), 2.09 (m, 2H), 1.63 (d, J=9.0 Hz, 1H), 1.30 (m, 2H). LC/MS (ESI+)=553 (M+H). MP=127.5-128.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>>[N+:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Cl:1])[C:6]#[N:7])([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccc(Cl)cc1
Product: N#Cc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
4-chloro-benzonitrile was reacted with nitric acid to obtain 3-nitro-4-chloro-benzonitrile melting at 100°-101° C. which was reacted with N-hydroxy-phthalimide to obtain 0-(4-cyano-2-nitrophenoxy)-phthalimide melting at 233°-234° C. The latter was reacted to obtain 0-(4-cyano-2-nitro-phenyl)-hydroxylamine melting at 154°-155° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@H:31]([NH2:36])[CH2:32][C:33]([OH:35])=[O:34])=[CH:22]1.C([BH3-])#N.[Na+]>CO.C1COCC1.C(OCC)(=O)C>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@H:31]([NH:36][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:32][C:33]([OH:35])=[O:34])=[CH:22]1
Reactant: N[C@H](CC(=O)O)Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCN[C@H](CC(=O)O)Cc1c[nH]c2ccccc12)CCc1ccccc1

Procedure:
Combine N-t-butoxycarbonyl-N-(2-oxo-ethyl)-2-phenyl-ethylamine (5.10 g, 19.16 mmol) and (S)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((S)-tryptophan methyl ester hydrochloride salt) (4.90 g, 19.23 mmol) in methanol (50 mL) and stir for 10 minutes. Add sodium cyanoborohydride in solution (19.0 mL, 1M in THF, 19.0 mmol) and stir under an inert atmosphere for 18 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel eluting with 50% ethyl acetate/hexane to give the title compound.