Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:11]([C:13]([OH:15])=O)[CH3:12])[CH:5]=1.[NH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@@H:11]([C:13](=[O:15])[NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH3:12])[CH:5]=1
Reactant: COC(=O)c1cccc(O[C@H](C)C(=O)O)c1
Reactant: N#Cc1ccc(N)cc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(O[C@H](C)C(=O)Nc2ccc(C#N)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Cool a solution 3-((R)-1-carboxy-ethoxy)-benzoic acid methyl ester (0.50 g, 1.90 mmol) in pyridine (5 mL), to 0° C., and add 4-aminobenzonitrile (0.28 g, 2.33 mmol) followed by phosphorous oxychloride (0.22 mL, 2.4 mmol). Stir the mixture at 0° C. for 1 h then dilute with water and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography to provide 0.59 g of 3-[(R)-1-(4-cyano-phenylcarbamoyl)-ethoxyl]-benzoic acid methyl ester as an oil.
Reaction SMILES: Cl[CH:2]1[CH:7]([N+:8]([O-:10])=[O:9])[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][C:12]=2[Cl:21])=[CH:5][CH:4]=[N:3]1.[CH:22]([NH2:26])([CH2:24][CH3:25])[CH3:23].CCN(C(C)C)C(C)C>C(#N)C>[CH:22]([NH:26][CH:2]1[CH:7]([N+:8]([O-:10])=[O:9])[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][C:12]=2[Cl:21])=[CH:5][CH:4]=[N:3]1)([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)N
Reactant: O=[N+]([O-])C1C(c2ccc(OC(F)F)cc2Cl)=CC=NC1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)NC1N=CC=C(c2ccc(OC(F)F)cc2Cl)C1[N+](=O)[O-]
Temperature: 25 °C
Yield: 82.3 %

Procedure:
2-Chloro-4-(2-chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridine (0.176 g, 0.53 mmol) was dissolved in acetonitrile (20 mL), followed by the addition of sec butylamine (106 μL, 1.06 mmol) and Hunig's base (184 μL, 1.06 mmol). The reaction was stirred at reflux for 64 h. The solution was cooled to room temperature, extracted with EtOAc/H2O, organic layer was then washed with 1N HCl and made basic with 1N NaOH. The organic layer was washed with brine, dried Na2SO4, filtered and concentrated to yield 0.163 g (83%) of sec-butyl-[4-(chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridin-2-yl]-amine as a yellow oil; MS (AP) 413.0 [(M+H+CH3CN)+, 50].
Reaction SMILES: [NH3:1].[CH3:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5]>CCOCC>[CH3:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)[C:4]([NH2:1])=[O:5]
Reactant: N
Reactant: CN(C(=O)Cl)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: CCOCC
Product: CN(C(N)=O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 24 h

Procedure:
Saturate with NH3 a solution of 6.7 g (20 mmole) N-methyl-N-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]carbamyl chloride in 200 ml Et2O. After 24 hours, wash the Et2O with water, then 1N HCl. Dry, concentrate and recrystallize the solid from ether-hexane to give 5.0 g white solid; m.p. 181°-184°.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:27][N:26]=[C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[N:24]=3)=[CH:19][CH:18]=2)C(=O)OC(C)(C)C)=[CH:5][CH:4]=1.[ClH:43]>C(Cl)Cl>[ClH:43].[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:27][N:26]=[C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[N:24]=3)=[CH:21][CH:22]=2)=[CH:39][CH:40]=1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)OC(C)(C)C)cc2)n1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of tert-butyl 4-(trifluoromethyl)benzyl[4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzyl]carbamate (43 mg, 0.07 mmol) in DCM (3 mL) was added a solution of HCl (4N in dioxane, 3 mL) and the resulting reaction mixture was stirred 3 h at 0° C., then 14 h at rt. Evaporation of the solvent gave the title compound as a white powder used in the next steps without further purification (29 mg, 99%). M−(APCI): 486.0; M+(APCI): 488.2 HPLC (Condition A), Rt: 5.4 min (HPLC purity: 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[N:31]=[CH:30][N:29](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:28]=5)[CH:25]=4)[N:20](C4CCCCO4)[N:19]=3)[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:28]1[C:27]([C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:14]2[CH:13]=[C:12]([C:10]([NH:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:11])[CH:17]=[CH:16][CH:15]=2)=[N:31][CH:30]=[N:29]1
Reactant: O=C(NCc1ccc(F)cc1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1ccc(F)cc1)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 50 °C
Yield: 30.6 %

Procedure:
To a stirred solution of N-[(4-fluorophenyl)methyl](3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.423 g, 0.573 mmol) was added dioxane (4.0 mL) and aqueous 6 N hydrochloric acid (4.0 mL) and the mixture heated at 50° C. for 5.5 h. The mixture was cooled and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0723 g, 31% yield). 1H NMR (CD3OD) δ 8.78 (s, 1H), 8.49 (t, 1H), 8.22 (dt, 1H), 8.13 (d, 1H), 7.94 (dt, 1H), 7.70 (d, 1H), 7.68 (t, 1H), 7.43 (m, 2H), 7.07 (m, 2H), 4.60 (s, 2H). ES-MS (m/z) 413 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:19])[CH:12]=2)[N:7]=1.[NH2:24][C:25]1[S:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[C:14]([C:16](=[O:18])[NH:24][C:25]2[S:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:19])[CH:12]=2)[N:7]=1
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: Cc1ccc2nc(OCc3ccccc3Cl)cc(C(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(NC(=O)c2cc(OCc3ccccc3Cl)nc3ccc(C)cc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
To a stirred solution of 2-(2-chlorobenzyloxy)-4-carboxy-6-methylquinoline (Method 7; 0.350 g, 1.067 mmol) and ethyl 2-aminothiazole-5-carboxylate (0.184 g, 1.067 mmol) in dimethyl formamide (DMF, 6 ml) was added 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.307 g, 1.601 mmol) and 4-dimethylaminopyridine (0.391 g, 3.202 mmol). The reaction mixture was stirred overnight at room temperature, and then diluted with ethyl acetate (20 ml). The mixture was washed with water (20 ml), and the aqueous washings extracted with ethyl acetate (3×15 ml); the organic phases were combined and concentrated in vacuo. Flash chromatography on silica gel, eluting with a gradient of 2–20% ethyl acetate in iso-hexane, gave the title compound as a colourless solid (0.100 g, 19%). NMR: 1.30 (3H, t), 2.40 (3H, s), 4.30 (2H, q), 6.65 (2H, d), 7.20 (2H, m), 7.55 (2H, m), 7.65 (1H, m), 7.75 (1H, d), 7.95 (1H, s), 8.10 (2H, m), 8.15 (1H, s); m/z 482 (M+H)+, 480 (M−H)+,
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C1(C)C=CC=CC=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Br:8][C:4]1[N:3]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([F:16])[CH:18]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: OB(O)c1cncc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1cncc(-c2cccc(Br)n2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Added to a solution of 2.00 g (8.44 mmol) of 2,6-dibromo-pyridine in 80 ml of a 4/1 mixture of toluene and ethanol, are 1.18 g (8.44 mmol) of 5-fluoropyridine-3-boronic acid, 0.48 g (0.42 mmol) of Pd(PPh3)4 and 25 ml of a 1M aqueous solution of sodium carbonate. The mixture is stirred at 90° C. for 2 hours.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][O:11][CH3:12].[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>ClCCl>[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:10]([O:11][CH3:12])[CH3:9])=[O:17]
Reactant: CNOC
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccc1F
Reaction time: 0.17 h
Yield: 674.6 %

Procedure:
Triethylamine (5.32 mL, 37.84 mmol) was added dropwise to a solution of N,O-dimethylhydroxylamine hydrochloride (2.768 g, 28.38 mmol) in anhydrous dichloromethane (45 mL) at 0° C. After stirring for 10 min, 2-fluorobenzoyl chloride (0.303 mL, 2.52 mmol) in anhydrous dichloromethane (15 mL) was added dropwise. The reaction mixture was returned to room temperature and stirred for 5 h. The reaction mixture was quenched with water (60 mL) and the products were extracted with dichloromethane (2×60 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 93:7 to 60:40) afforded 2-Fluoro-N-methoxy-N-methyl-benzamide (3.116, 17 mmol) in a 90% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCCCCC(=O)O
Product: O=C(O)CCCCCNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
6-Aminohexanoic acid (2.62 g, 0.02 mol) was treated with 4-chlorobenzenesulphonyl chloride (4.22 g, 0.02 mol) by the method described in Example 4 to give the title compound which was recrystallised from ethylacetate-ether (1.92 g, m.p. 126°-7° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C=CC=CC=1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH:38]=O>C1(C)C=CC=CC=1>[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH:38]=[CH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C=Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a suspension of tert-butyl triphenylphosphoranediylacetate (8.82 g, 23.4 mmol) in toluene (15 mL) was added a solution of 2-naphthaldehyde (2.82 g, 18.0 mmol) in toluene (15 mL). The mixture was stirred at room temperature for 18 hr and filtered. The filtrate was concentrated, subjected to silica gel column chromatography (ethyl acetate/hexane=1/30) and recrystallized (acetonitrile/water=1/2) to give the title compound as a colorless paste (4.1 g, yield 91%), melting point: 74-75° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([NH2:21])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:21][CH2:19][CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CCN
Product: CCNc1c(C(=O)OCC)cnc2c(OC)cccc12

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with ethylamine following general procedure B to afford 4-ethylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (220 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (180 mg) following general procedure E. The above ethylamide (0.65 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1,3-diethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (20 mg). LCMS: m/z 300 [M+1]+. LCMS: m/z 300 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.48 (s, 1H), 7.87 (d, 1H), 7.56 (t, 1H), 7.22 (d, 1H), 4.42 (q, 2H), 4.16 (q, 2H), 4.12 (s, 3H), 1.73 (t, 3H), and 1.33 (t, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(N[C@@H]4CCCNC4)ncnc32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC[C@@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 50.4 %

Procedure:
To a solution of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-piperidin-3-yl]-9H-purin-6-amine (20 mg, 0.046 mmol, 1 eq.) in 2 mL of dichloromethane was added methanesulfonyl chloride (0.007 mL, 0.091 mmol, 2 eq.) and triethylamine (0.02 mL, 0.137 mmol, 3 eq.). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 12 mg (51%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-[(3R)-1-methanesulfonylpiperidin-3-yl]-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.81-2.18 (m, 4 H) 2.77-2.94 (m, 3 H) 3.07-3.29 (m, 2 H) 3.42 (br. s., 1 H) 3.82 (d, J=9.89 Hz, 1 H) 4.68 (br. s., 1 H) 6.13 (br. s., 1 H) 7.12-7.65 (m, 8 H) 8.48 (s, 1 H), [M+H]+ 517.8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4](Cl)[CH:3]=1.[CH3:12][NH2:13]>[Cu]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([NH:13][CH3:12])[CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1Cl
Reactant: CN
Agent: [Cu]
Product: CNc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4'-fluoro-2'-chloroacetophenone (40 g), methylamine (33% w/w solution in industrial methylated spirit, 60 ml), industrial methylated spirit (40 ml) and copper powder (0.5 g) was stirred at 80° in a sealed pressure vessel for 3 hours. After cooling to ambient temperature, the reaction mixture was transferred to a conical flask. The reaction vessel was washed out with industrial methylated spirit (2×30 ml) and the washings added to the reaction mixture. Sodium sulphide nonahydrate (2.3 g) in water (23 ml) was added and the mixture heated at 50° for 10 minutes. The mixture was filtered through diatomaceous earth (sold under the trade name CELITE). Solvent was removed from the filtrate under reduced pressure at 40° and hydrochloric acid (5M, 160 ml) was added to the residue. The mixture was stirred for approximately 2 hours and then extracted with dichloromethane (100 ml, then 2×60 ml). The combined extracts were dried over magnesium sulphate and evaporated to give the novel compound 4'-fluoro-2'-(methylamino)acetophenone as an oil which solidified on storing at ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH3:16])[C:12]([OH:14])=O.Cl.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[OH:28]>>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([CH2:19][NH:18][C:12](=[O:14])[CH:11]([C:3]2[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:15][CH3:16])=[C:21]([OH:28])[CH:22]=1)#[N:25]
Reactant: COc1cc(F)c(C(OC)C(=O)O)c(F)c1
Reactant: N#Cc1ccc(CN)c(O)c1
Agent: Cl
Product: COc1cc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2O)c(F)c1

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-methoxy-acetic acid (example 66.1) was coupled with 4-aminomethyl-3-hydroxy-benzonitrile hydrochloride (example 110.2) according to general procedure C to give (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Colorless foam. MS 361.1 ([M−H]−)
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])[CH3:3].[H-].[Na+].[CH3:21]I.[OH-].[Na+]>CC(N(C)C)=O.C1COCC1>[C:2]([O:5][C:6]([N:8]([CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15]1)[CH3:21])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCC1CCC(C(=O)O)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CN(C[C@H]1CC[C@H](C(=O)O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 20 g (77.7 mmol) of BOC-tranexamic acid in 162 mL of DMA and 320 mL of THF was cooled to 0° C. and treated with 7.46 g (170.99 mmol, 2.2 eq) of NaH (55% in oil) over 30 min. The mixture was warmed to RT, cooled to 0° C. again and treated with 77.42 mL (1243 mmol, 16 eq) of CH3I and warmed to RT overnight. 230 mL (2487.1 mmol, 32 eq) of aqueous 32% NaOH were added at 0° C., the solution was stirred for 1 h at RT and partitioned between Et2O (×3)/H2O. The organic phase was evaporated to remove the DMA. The residue was dissolved in 100 mL of dioxane and treated with 233 mL (233 mmol) of aqueous 1M NaOH at RT, and the solution was stirred overnight. The reaction was partitioned between Et2O (×3)/H2O, the aqueous phase was acidified with aqueous 10% KHSO4 and partitioned between Et2O (×3), washed once with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 19.2 g (87%) of trans-4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexane-carboxylic acid, MS: 270 (M−H−).
Reaction SMILES: C([N:5](S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])C(C)C.C1(S(N[C@H](C(O)=O)CC2C=CC=CC=2)(=O)=O)C=CC=CC=1>>[NH2:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1
Product: NCCCC[C@H](N)C(=O)O

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine (385 mg, 1.0 mmol, example 5, step C) as described in general procedure Bc using Nα-benzenesulfonyl-L-phenylalanine (335 mg, 1.1 mmol) which was prepared in step A of example 8. The final product was purified by preparative HPLC to yield 550 mg (85%) of Nα-(4-nitrobenzenesulfonyl)-Nα-isobutyl-Nε-(N′α-benzenesulfonyl)-L-phenylalanyl)-L-lysine. The latter derivative (200 mg) was hydrogenolysed following the indications of general procedure E. Purification by HPLC gave the desired material (129 mg, 65%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6]C(=O)OC(C)(C)C)[CH2:2]1.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.[ClH:23].O1CCOCC1>C(Cl)(Cl)Cl>[ClH:23].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:1]2[CH2:5][CH2:4][C@@H:3]([NH2:6])[CH2:2]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: N[C@@H]1CCN(Cc2ccc(F)cc2)C1

Procedure:
To a chloroform solution (2 mL) of tert-butyl (R)-pyrrolidin-3-yl-carbamate (500 mg, 2.68 mmol), 4-fluorobenzyl bromide (329 μL, 2.68 mmol) was added and the resultant solution was stirred at room temperature for 1 day. Subsequently, 4 M hydrogen chloride/1,4-dioxane solution (2 mL) was added to the reaction solution and the resultant mixture was stirred for 1 day. After completion of the reaction, solidified product was collected by filtration and dried under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[O:20][C:19]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[N:18][N:17]=2)=[N:4][C:5]([O:14][CH3:15])=[C:6]([C:10]([F:13])([F:12])[F:11])[C:7]=1[CH:8]=[CH2:9].[CH3:28]C1(C)C(C)(C)OB(C(C)=C)O1>>[NH2:1][C:2]1[C:3]([C:16]2[O:20][C:19]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[N:18][N:17]=2)=[N:4][C:5]([O:14][CH3:15])=[C:6]([C:10]([F:12])([F:13])[F:11])[C:7]=1[C:8]([CH3:28])=[CH2:9]
Reactant: C=Cc1c(N)c(-c2nnc([C@](C)(O)C(F)(F)F)o2)nc(OC)c1C(F)(F)F
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Product: C=C(C)c1c(N)c(-c2nnc([C@](C)(O)C(F)(F)F)o2)nc(OC)c1C(F)(F)F

Procedure:
The title compound was prepared analogously to (S)-2-(5-(3-Amino-6-methoxy-5-(trifluoromethyl)-4-vinylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol (Example 14.0 step 1) by replacing 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane with 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane;
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:8]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:7]2[CH:8]=[C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:4]=[N:5][CH:6]=[C:7]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)[CH:8]=4)[CH2:23][CH2:22]3)[CH:4]=[N:5][CH:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cncc(CN3CCCN(Cc4cncc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC

Procedure:
3-Chloromethyl-5-(3,4,5-trimethoxyphenyl)pyridine (70 mg) and homopiperazine (12 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base. Yield: 56 mg (76%). 1H-NMR (400 MHz, CDCl3) δ: 1.85 (br, 2H), 2.73 (br, 4H), 2.79 (t, 4H, J=5.9 Hz), 3.73 (s, 4H), 3.90 (s, 6H), 3.94 (s, 12H), 6.76 (s, 4H), 7.82 (s, 2H), 8.53 (d, 2H, J=2.0 Hz), 8.68 (d, 2H, J=2.1 Hz). m/z (EI): 614 [M+].