Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[F:13].[C:15](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:15])=[CH:8][C:7]=1[F:13]
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNc1ccc(C(=O)OC)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Add formaldehyde (0.15 g) to a mixture of 2-fluoro-4-amino benzoic acid methyl ester (0.62 g), acetic acid (2.1 mL) and 1,2 dichloroethane (20 mL). Stir at room temperature overnight. Add sodium triacetoxyborohydride (1.15 g) and stir at room temperature for 2 hours. Quench by pouring the reaction mixture into a mixture of saturated aqueous sodium bicarbonate and ethyl acetate. Separate the layers, wash the organic phase with water, dry the remaining organic phase over sodium sulfate and then concentrate under reduced pressure. The residue is purified by chromatography eluting with ethyl acetate:hexane (1:4) to provide 2-fluoro-4-methylamino benzoic acid methyl ester (0.10 g, 15%) as an oil.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].O=[CH:10][CH2:11][CH2:12][C:13]([O:15]CC(C)C)=O>>[O:8]=[C:5]1[CH2:6][N:7]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[N:4]1[CH2:2][CH3:3]
Reactant: CC(C)COC(=O)CCC=O
Reactant: CCNC(=O)CN
Agent: Cl
Product: CCN1C(=O)CN2C(=O)CCC12

Procedure:
Glycine ethylamide hydrochloride (2.1 g, 15.1 mmol) and isobutyl 4-oxobutanoate (2 g, 12.6 mmol) were reacted together according the procedure of Example 2 to give the title compound, 0.5 g (23.5%) as a viscous oil. Rf=0.51 (silica gel plates, eluent dichloromethane-methanol 9:1) NMR (CDCl3): deltaH =5.27 (t, J=6 Hz, 1H, N--CH--N); 4.20 and 3.45 (ABq, J=17 Hz, 2H, N--CH2 --CO); 3.25 (q, J=7 Hz, 2H, NCH2CH3); 2.70-1.75 (c.a., 4H, COCH2CH2CH); 1.12 (t, J=7 Hz, 3H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=168 (M+), 112 (M--C3H4O)+, 97 (M--C4H7O)+.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[Cl:19][CH2:20][C:21]1[C:22]([NH:34][CH2:35][CH3:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH2:32][CH3:33])=[CH:26][CH:25]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:19].[ClH:18].[CH2:32]([O:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([NH:34][CH2:35][CH3:36])[C:21]([CH2:20][C:6]1[C:7]3[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=3)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=1[OH:17])=[CH:30]2)[CH3:33]
Reactant: CCNc1nc2ccc(OCC)cc2cc1CCl
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1nc2ccc(OCC)cc2cc1Cc1c(O)nc(CC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 10 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (140 mg, 0.60 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-ethoxy-N-ethylquinolin-2-amine hydrochloride SLA 41042 (181 mg, 0.60 mmol) at RT followed by a 2 N aq. LiOH solution (0.60 mL, 1.20 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided after evaporation 33 mg of 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.05 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((6-ethoxy-2-(ethylamino)quinolin-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 41 as a yellow solid (31.4 mg, 10% yield).
Reaction SMILES: C(C1C=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[CH:10][NH:9][C:6]2=[N:7]C=1)#N.FC1C=[C:41](C=CC=1F)[CH2:42][N:43]1C=CC=C(C(NCC2C=C(B(O)O)C=CC=2)=O)C1=O.[B].N1C=CN=C2NC=CC=12>>[N:43]1[CH:42]=[CH:41][N:7]=[C:6]2[NH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=3)[CH2:15][NH:16][C:17]([C:19]3[C:20](=[O:34])[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])[C:5]=12
Reactant: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Reactant: O=C(NCc1cccc(B(O)O)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: [B]
Agent: c1cnc2[nH]ccc2n1
Product: O=C(NCc1cccc(-c2c[nH]c3nccnc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5H-pyrrolo[2,3-b]pyrazin-7-yl)-benzylamide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenylboronic acid as activated boron species and 5H-Pyrrolo[2,3-b]pyrazine as substituted bicyclic heterocycle, to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.287 (s, 1H) 10.040 (t, J=5.7 Hz, 1H) 8.448 (d, J=2.4 Hz, 1H) 8.410-8.374 (m, 1H) 8.386 (d, J=2.9 Hz, 1H) 8.286 (d, J=2.4 Hz, 1H) 8.224 (dd, J=7.0, 2.3 Hz, 1H) 8.182 (s, 1H) 8.104 (d, J=7.9 Hz, 1H) 7.462-7.337 (m, 3H) 7.170 (d, J=7.9 Hz, 1H) 7.190-7.125 (m, 1H) 6.592 (t, J=7.1 Hz, 1H) 5.192 (s, 2H) 4.556 (d, J=5.8 Hz, 2H); MS m/z=472.29 M+H.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16].N1C=CC=CC=1.[Si](Cl)(Cl)(Cl)Cl>O>[CH3:16][CH:15]([NH:18][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([S:2][CH3:1])=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13])[CH3:17]
Reactant: CC(C)N
Reactant: CSc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CSc1ccc(C(=O)NC(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A solution of 4-methylthio-2-nitrobenzoic acid (3.07 g, 0.01439 mol) [Lit. Ref. DE 2421541], isopropylamine (1.47 ml, 0.01728 mol) and pyridine (100 ml) was cooled in an ice bath. Silicon tetrachloride (2.01 ml, 0.01728 mol) was added dropwise under nitrogen over 15 mins. After stirring at room temperature for 2 hr the solution was refluxed for 7 hr, then allowed to cool to room temperature. The solution was added to water and concentrated in vacuo. The precipitate was dissolved in dichloromethane and washed twice with 1N hydrochloric acid (150 ml), dried and concentrated in vacuo to afford 2.82 g of amorphous yellow solid. δ(1H NMR, CDCl3, ppm): 1.10 (6H, d), 2.50 (3H, s), 4.2 (1H, m), 5.50 (1H, s), 7.35 (2H, m), 7.75 (1H, s).
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH:30]4[CH2:32][CH2:31]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH:30]1([C:26]2[CH:27]=[C:28]([CH3:29])[C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:15]([C:12]4[CH:11]=[CH:10][C:9]([N:2]5[CH2:3][CH2:4][CH2:5][S:1]5(=[O:7])=[O:6])=[CH:14][N:13]=4)=[O:16])[CH2:22][CH2:21]3)=[N:24][CH:25]=2)[CH2:31][CH2:32]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Reactant: O=S1(=O)CCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cn2)CC1
Yield: 40.8 %

Procedure:
Using isothiazolidine 1,1-dioxide (94 mg) and (5-bromopyridin-2-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (310 mg) described in Preparation Example 135 and by the reaction and treatment in the same manner as in Example 1, the title compound (139 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][N:13]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:12]2[CH:17]=[C:16]([CH:15]=[CH:14][N:13]=2)[C:18]#[N:19])[CH2:4][CH2:3]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC(Oc2cc(C#N)ccn2)CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
1-Methylpiperidin-4-ol (0.457 g, 3.97 mmol) was dissolved in 5 mL of DMSO under argon and NaH (0.173 g, 3.97 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 h and 30 min at 60° C. The mixture was allowed to cool and 2-chloro-4 pyridinecarbonitrile (0.500 g, 3.97 mmol) was added. The mixture was stirred for 2 h at ambient temperature and subsequently poured into 100 mL of water, extracted three times with EtOAc. The combined organic layer washed with water, dried over Na2SO4 and evaporated. The crude product was purified by preparative HPLC (Kromasil C8 50×250 mm, CH3CN/0, 2% HOAc 5/95-50/50). The product was freeze dried from water. Yield: 0.250 g (32%). 1H NMR (500 MHz, CD3OD) δ8.32 (d, 1H), 7.19 (dd, 1H), 7.12 (bs, 1H), 5.14 (m, 1H), 2.75 (m, 2H), 2.38 (m, 2H), 2.32 (s, 3H), 2.06 (m, 2H), 1.84 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[Na+].[Na+]>>[C:41]([O:40][C:38]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:25]([NH:1][C@H:2]1[CH2:8][S:7][C@H:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCOC(=O)C(Br)CCCCCCNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2ccccc2)SC[C@H](N)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)C(CCCCCCNC(=O)OC(C)(C)C)N[C@H]1CS[C@H](c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
By following the same procedure as described in Example 4, a condensation reaction was carried out between 400 mg of t-butyl rel-α-[6(R)-amino-5-oxo-2(R)-phenylperhydro-1,4-thiazepin-4-yl]acetate and 1.08 g of ethyl 2-bromo-8-t-butoxycarbonylaminooctanoate in the presence of 0.76 g of sodium carbonate to give two diastereoisomers. These isomers were separated by column chromatography through silica gel, using a mixture of methylene chloride and ethyl acetate in the ratio 10:1 by volume as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:11][NH2:12].Cl.C(N(CC)CC)C.[CH3:21][C:22]([O:25][C:26](ON=C(C1C=CC=CC=1)C#N)=[O:27])([CH3:24])[CH3:23]>O.O1CCCC1>[C:22]([O:25][C:26]([C:4]1[C:3]([CH2:11][NH2:12])=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])=[O:27])([CH3:24])([CH3:23])[CH3:21]
Reactant: NCc1cc(C(=O)O)ccc1Cl
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1c(C(=O)O)ccc(Cl)c1CN
Temperature: 0 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A suspension of 4-chloro-3-aminomethylbenzoic acid.HCl (6.7 g, 30 mmol) and triethylamine (9.3 g, 92 mmol) in 50 ml of H2O, was added to a solution of Boc-ON (9.2 g, 38 mmol) in 50 ml of tetrahydrofuran cooled to 0° C. The reaction mixture was stirred at room temperature overnight, and the volatile compounds were removed by concentration under reduced pressure. The residue was diluted with H2O, washed with ether, acidified to pH 3 with 1N HCl, and extracted with ethyl acetate. The extracts were washed with H2O, brine, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. This material was triturated with ether-hexane to provide the title compound (7.4 g, 87%) as a white powder. mp 159° C. (dec); 1H NMR (D6 -DMSO) 13.20 (br s, 1H), 7.90 (s, 1H), 7.80 (dd, 1H), 7.60 (br s, 1H), 7.55 (d, 1H), 4.20 (br d, 2H), 1.40 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[SH2:29].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)=O>C(Cl)Cl>[SH:29][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1=C(C)NC(CCl)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 70.4 %

Procedure:
A solution of 2-chloromethyl-3,5-dicarboethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (1 g) and tetrabutylammonium hydrogen sulfide (0.7 g) in methylene chloride (10 ml) is stirred at -10° C., for 20 minutes, neutralized with a drop of AcOH, evaporated under vacuum and the residue recrystallized from Et2O to give 0.7 g of 2-mercaptomethyl-3,5-dicarboetoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, m.p. 145°-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([NH:12][C:13]2[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[N:17][CH:18]=2)[CH2:7]1.[OH-].[Na+].Cl>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([NH:12][C:13]2[N:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[N:17][CH:18]=2)[CH2:7]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(Cc3cccc(Cl)c3)C2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1cnc(N[C@@H]2CCCN(Cc3cccc(Cl)c3)C2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
The mixture of ethyl (2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate (235 mg, 0.59 mmol) and 1N-NaOH (1.2 mL) in EtOH (2 mL) was stirred at ambient temperature for 1 hr and the mixture was allowed to stand for 18 hrs. The reaction mixture was adjusted to PH 5.0 with 1 mol/L hydrochloric acid and evaporated in vacuo to give (2E)-3-(5-{[(3R)-1-(3-chlorobenzyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylic acid (218 mg, 100%).
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O:20]CC2C=CC=C(C(F)(F)F)C=2)=[O:19])[CH2:3]1.[Li+:32].[OH-]>>[F:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[C@@H:4]([C:18]([O-:20])=[O:19])[CH2:3]1.[Li+:32]
Reactant: O=C(OCc1cccc(C(F)(F)F)c1)[C@H]1C[C@H](F)CN1Cc1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C([O-])[C@H]1C[C@H](F)CN1Cc1cccc(C(F)(F)F)c1

Procedure:
The title compound (D16) (60 mg) was prepared according to the general procedure for esters hydrolysis starting from (2R,4S)-3-(trifluoromethyl)benzyl 4-fluoro-1-(4-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D9) (110 mg). (LiOH: 2 eq; Reaction time: 18 hrs)
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[C:11](N)=[CH:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:8][N:7]=1.[BrH:20]>O>[Br:5][C:6]1[C:11]([Br:20])=[CH:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:8][N:7]=1
Reactant: Br
Reactant: Nc1cc(-c2ccc(Cl)cc2)cnc1Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccc(-c2cnc(Br)c(Br)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.33 g (4.85 mmol) of sodium nitrite in 1.9 mL of water was added at 0° C. with vigorous stirring to a suspension of 1.25 g (4.41 mmol) of 2-bromo-5-(4-chlorophenyl)pyridin-3-ylamine in 9.90 mL (88.16 mmol) of 48% aqueous HBr and 9.90 mL of water and stirred for a further 10 minutes at 0° C. Subsequently a solution of 0.95 g (6.61 mmol) of CuBr in 3.47 mL of 48% aqueous HBr was added and the mixture was stirred for I hour at 60° C. The reaction mixture was diluted with water and exhaustively extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, and evaporated down in vacuo. The residue was purified by column chromatography (silica gel, PE/DCM 1:1). Yield: 1.00 g (65% of theoretical); C11H6Br2ClN (M=347.433); calc.: molpeak (M+H)+:346/348/350/352 (2BrCl); found: molpeak (M+H)+: 346/348/350/352 (2BrCl).
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]OCC(C1C=CC=C(OC)C=1)(F)F>>[F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][O:5][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Br:13]
Reactant: OCCC(F)(F)c1ccccc1
Reactant: COc1cccc(C(F)(F)COCCCCCCBr)c1
Product: FC(F)(CCOCCCCCCBr)c1ccccc1

Procedure:
Obtained from Intermediate 77 (0.41 g, 0.83 mmol) by the procedure described in Intermediate 69. The resulting oil was purified by column chromatography with silica gel eluting with n-hexane/ethyl acetate (from pure n-hexane to 9:1) to give the title compound (0.85 g of 66% purity, 64%) as oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[N:5]=[CH:4]1)C.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1>C(#N)C>[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH:21][S:8]([C:6]2[N:5]=[CH:4][N:3]([CH3:1])[CH:7]=2)(=[O:10])=[O:9])[CH2:14][CH2:13]1
Reactant: CCn1cnc(S(=O)(=O)Cl)c1
Reactant: NCCCN1CCOCC1
Solvent: CC#N
Product: Cn1cnc(S(=O)(=O)NCCCN2CCOCC2)c1

Procedure:
Analogously to Example 7, 10 g (51 mmol) of 1-ethyl-4-imidazolesulfonyl chloride from Example C-2 are reacted with 7.5 ml (51 mmol) of 3-morpholinopropylamine in 200 ml of acetonitrile and the mixture is correspondingly worked up. The hydrochloride thus obtained is dissolved in methanol and converted into the free base by means of an equivalent amount of methanolic sodium methylate solution. The oil remaining after evaporating in vacuo crystallizes after addition of an equimolar amount of ethanolic fumaric acid as the hydrogenfumarate of melting point 148°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C([Mg]Br)=C.[CH2:21]1[CH2:25][O:24]CC1.[NH4+].[Cl-]>CCOCC>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)([CH:21]2[CH2:25][O:24]2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)C1CO1
Reaction time: 0.33 h

Procedure:
To a solution of 6 g of 4,4'-dichlorobenzophenone in 200 mL of ether was added 30 mL of 1.4M vinylmagnesium bromide/THF at 0°. After being stirred at 25° for 20 minutes, the mixture was poured onto aqueous NH4Cl, partitioned, washed with brine, dried (MgSO4), filtered, and concentrated. The crude adduct was allowed to stand in 50 mL of methylene chloride with 5.8 g of m-chloroperbenzoic acid for 3 days at 25°. The mixture was diluted with CH2Cl2, washed with aqueous NaHSO3, aqueous NaHCO3, brine, dried (Na2SO4), concentrated, and chromatographed (150 mL SiO2 /30% CH2Cl2 in hexane) to provide 2.9 g of the title compound (after washing the concentrated fractions with pentane), m.p. 87°-88°.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12]>COCCOC.CN(C)C=O.O>[Cl:18][C:16]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[C:9]([O:4][CH2:3][CH:2]([F:5])[F:1])[N:17]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)nc1OCC(F)F
Reaction time: 1 h
Yield: 97.5 %

Procedure:
2,2-Difluoroethanol (3.51 mL, 55.5 mmol) was added dropwise over 30 minutes to a suspension of NaH (2.22 g, 60% w/w dispersion in oil) in 1,2-dimethoxyethane (40.0 mL) at 14° C. and stirred for 1 hour. A portion of this solution (25 mL, 35 mmol) was added dropwise over 10 minutes to a solution of 2,6-dichloro-nicotinamide (5.30 g, 27.7 mmol) in dimethylformamide (40 mL) at 14° C. The resultant suspension was stirred for an additional 1 hour at 14° C., diluted with water (600 mL) and extracted with EtOAc (3×400 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated to give title compound as a light orange solid (6.39 g, 97%). This was used without further purification.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[N+:16]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.CO.[Pd]>[NH2:16][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:8]=1[NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:12]#[N:13]
Reactant: N#Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NC2CCCCC2)c(N)c1
Yield: 99.2 %

Procedure:
A solution of compound 3 (1.23 g, 5.01 mmol) in ethyl acetate (30 mL) and methanol (10 mL) was hydrogenated over 10% palladium on carbon (0.11 g) at 20 psi for 1 h. The reaction mixture was filtered and concentrated on a rotary evaporator to give compound 4 (1.07 g, 99%) as a red-brown solid. ESI-MS m/e 216.3 (M+1).