Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:12]([C:15]1[N-:19][N:18]=[N:17][N:16]=1)(O)=[O:13].[K+].[NH2:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)=[O:31])[CH2:26][CH2:25]1.N1C=CC=CC=1>CC#N>[N:16]1[NH:17][N:18]=[N:19][C:15]=1[C:12]([NH:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[C:38]([Cl:40])[CH:37]=[C:36]([Cl:41])[CH:35]=2)=[O:31])[CH2:26][CH2:25]1)=[O:13]
Reactant: NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)c1nnn[n-]1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)c1nn[nH]n1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Under nitrogen, oxalyl chloride (58 μl, 0.657 mmol) was dissolved in MeCN (0.5 ml) and cooled to −20° C. DMF (25 μl, 0.329 mmol) was added and the reaction mixture was stirred for 15 minutes. Potassium 5-carboxytetrazol-1-ide (50 mg, 0.329 mmol) was added and the reaction mixture was stirred for a further 20 minutes. A suspension of 3,5-dichlorobenzyl 4-(2-aminoethyl)piperidine-1-carboxylate (Example 3, step 1) (109 mg, 0.329 mmol) and pyridine (32 μl, 0.394 mmol) in MeCN (2 ml) was added and after warming to RT, the reaction mixture was heated at reflux for 1 hr then was allowed to cool. The mixture was evaporated under reduced pressure and the crude product was purified by preparative LC-MS. The product fractions were evaporated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was separated, dried over MgSO4 (anh), filtered and evaporated under reduced pressure to afford the title product.
Reaction SMILES: [H-].[Na+:2].[C:3]([O:6][CH2:7][CH3:8])(=[O:5])[CH3:4].[CH:9](OCC)=[O:10]>C(OC(C)C)(C)C>[CH2:7]([O:6][C:3](=[O:5])/[CH:4]=[CH:9]\[O-:10])[CH3:8].[Na+:2]
Reactant: CCOC=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Product: CCOC(=O)/C=C\[O-]
Temperature: 45 °C
Reaction time: 8 h

Procedure:
Sodium hydride (21.79 g, 545 mmol) was suspended in isopropyl ether (378 mL) in a 3-neck flask equipped with a thermometer adapter, addition funnel and a capped neck. Ethyl acetate (44.4 mL, 454 mmol) was added slowly via syringe through the capped neck. An internal temperature of 45° C. was maintained. Ethyl formate (78 mL, 962 mmol) was added via the addition funnel slowly, maintaining the temperature at 42° C. The reaction was allowed to stir overnight, at which point solid had crashed out. This solid was filtered and washed with ethyl ether (2×100 mL) and hexanes (200 mL) and the solid was dried to give the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:29]=[C:30]([O:34][CH3:35])[CH:31]=[CH:32][CH:33]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: COc1cccc(Br)c1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4cccc(F)c4OC)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12h and 3-bromoanisole
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C1COCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCCC1

Procedure:
A solution of piperidine (5.64 g, 66 mmol), diisopropylethyl amine (1 3.64 mL, 78 mmol), and p-fluorobenzenesulfonyl chloride (13.64 mL, 78 mmol) in THF at 0° C. was stirred for 2 hours at ambient temperature. The solvent was removed in vacuo and the crude reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with aqueous HCl, and brine. It was dried over sodium sulfate, and filtered. Removal of the solvent gave near quantitative yield of the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:24]([O:23][C:13](=[O:22])[CH:14]=[C:15]([C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:25]
Reactant: COc1cc(Br)c2cc[nH]c2c1
Reactant: CCOC(=O)C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C=C(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-6-methoxy-indole CXIV (920 mg, 4.1 mmol), ethyl cinnamate (1.03 ml, 6.1 mmol), TEA (850 μl, 6.1 mmol), Pd(OAc)2 (46 mg, 0.20 mmol) and (o-Tol)3P (120 mg, 0.41 mmol) was heated in a sealed vial to 100° C. for 27 hours; The reaction mixture was cooled to room temperature, diluted with DCM, and the mixture was filtered through celite. The filtrate was concentrated and purified via flash chromatography (hexane/EtOAc) to afford 3-(6-methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester CXVI as a yellow-brown waxy solid (440 mg, 34% yield).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.[CH:8]([C:10]1[S:14][C:13](B(O)O)=[CH:12][CH:11]=1)=[O:9].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.CCO>[Cl:7][C:4]1[S:3][C:2]([C:13]2[S:14][C:10]([CH:8]=[O:9])=[CH:11][CH:12]=2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(Br)s1
Reactant: O=Cc1ccc(B(O)O)s1
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
Product: O=Cc1ccc(-c2ccc(Cl)s2)s1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
In a flask are placed 2-bromo-5-chlorothiophene (0.55 mL, 5.0 mmol) and Pd(PPh3)4 (0.17 g, 0.15 mmol), and the flask is vacuum purged and nitrogen filled (3×). THF (10 mL) is added by syringe and stirred 10 min. In a separate flask is placed 5-formyl-2-thiopheneboronic acid (0.94 g, 6.0 mmol) and EtOH (2 mL) and stirred until dissolved. This mixture is added by syringe to the first flask followed by vacuum purge and nitrogen fill (3×). A solution of Na2CO3 (2M, 5.0 mL, 10.0 mmol) is added by syringe followed by vacuum purge and nitrogen fill (3×). The reaction mixture is heated at 85° C. for 20 h. The reaction is cooled to rt and diluted with water. The aqueous solution is extracted with ether (3×). The combined ether layers are washed with water (3×) then brine (2×). The ether is dried over MgSO4, filtered, and concentrated. The crude product is purified over silica gel (5% EtOAc-heptane) to provide 5′-chloro-2,2′-bithiophene-5-carboxaldehyde as an orange solid (0.27 g, 24%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]([CH3:27])[CH3:26])[C:15]2[C:20]([NH:21][CH:22](C)[CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:25]([CH3:26])[CH3:27])[C:15]2[C:20]([NH:21][CH2:22][CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Nc1cccnc1N(C(C)C)C1CCN(Cc2ccccc2)CC1
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1cccnc1N(C(C)C)C1CCN(Cc2ccccc2)CC1
Reaction time: 15 h

Procedure:
1-benzyl-4-[N-isopropyl-N-(3-amino-2-pyridinyl)amino]piperidine (EXAMPLE 101, after titanium chloride reduction of nitro group; 1.92 g) is dissolved in 15 ml of methanol and cooled to 0°. Then 0.5 ml of acetaldehyde and 0.56 g of sodium cyanoborohydride are added. The reaction is allowed to warm slowly to 20°-25° and stirred for 15 hr. Then it is poured into sodium hydroxide (1N) and extracted with chloroform. The extracts are dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash column chromatography (20% ethyl acetate/hexane) gives the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[C:22][C:23]4[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=4)[CH:19]=3)[S:14][C:13]([CH3:35])([CH3:34])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[C:22][C:23]4[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:32][CH:33]=4)[CH:19]=3)[S:14][C:13]([CH3:35])([CH3:34])[CH:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)C=C(c2ccc(C(C)(C)C)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc2S1
Temperature: 45 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of ethyl 4-[[4-(4-tert-butylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 229, 65.0 mg, 0.135 mmol) in 2.0 mL THF and 2.0 mL EtOH was added NaOH (80.0 mg, 2.0 mmol, 2.0 mL of a 1M aqueous solution). The resulting solution was heated to 45° C. and stirred overnight. Upon cooling to room temperature the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 33.0 mg (54%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.01 (2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.45 (4H, m), 7.24 (3H, m), 5.93 (1H, s), 1.47 (6H, s), 1.34 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:29])=[C:4]([N:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])[C@@H:12]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.NC1C=CC=CC=1.[CH:37]1([N:40]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=2)[C:41]2[C:46]3=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:45]3[N:44]=[C:43](S(C)(=O)=O)[N:42]=2)[CH2:39][CH2:38]1>>[Si:22]([O:21][C@@H:12]1[C@@H:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH2:14][CH2:15][N:10]([C:4]2[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([NH:1][C:43]3[N:42]=[C:41]([N:40]([CH:37]4[CH2:39][CH2:38]4)[CH2:56][C:57]4[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=4)[C:46]4=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:45]4[N:44]=3)[C:3]=2[Cl:29])[CH2:11]1)([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:23])[CH3:24]
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: COC(=O)N[C@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: Nc1ccccc1
Product: COC(=O)N[C@H]1CCN(c2cc(C#N)cc(Nc3nc(N(Cc4ccc(OC)cc4)C4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
methyl ((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate was prepared starting from methyl ((3S,4S)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)carbamate (127 mg, 0.289 mmol) according to general procedure for the coupling of aniline to 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile, method described for Example 7. Methyl ((3S,4S)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (180 mg) was obtained as a white solid.
Reaction SMILES: O[C:2]([CH3:11])([CH2:7][CH2:8][CH:9]=[CH2:10])[CH2:3][C:4](O)=[O:5].C([O-])(=O)C.[K+].C1(C)C=CC=CC=1>C(OC(=O)C)(=O)C>[CH3:11][C:2]1[C@H:3]2[C@H:9]([CH2:10][C:4]2=[O:5])[CH2:8][CH:7]=1
Reactant: C=CCCC(C)(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC1=CC[C@H]2CC(=O)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Hydroxy-3-methylhept-6-enoic acid (5.24 g, 36.4 mmol) was dissolved in acetic anhydride (40 mL). To the solution, potassium acetate (12.52 g, 127 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was heated to reflux and stirred for 4 hours. To the reaction solution, ice water and toluene were then added, and this mixture was stirred overnight at room temperature. The mixture was separated into aqueous and organic layers by the addition of diethyl ether and saturated saline. Then, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain the compound of interest as a pale yellow oil substance (1.10 g, 17%, diastereomeric mixture).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:6](=[CH:10][C:11]([CH3:19])=[C:12]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH:13]=1)[NH:7][CH2:8][CH3:9])[CH3:2].C(N(C(C)C)C(C)C)C.[CH2:30]([O:32][C:33](=[O:38])[CH2:34][C:35](Cl)=[O:36])[CH3:31]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:6](=[CH:10][C:11]([CH3:19])=[C:12]([C:14](=[O:18])[CH2:15][CH2:16][CH3:17])[CH:13]=1)[N:7]([CH2:8][CH3:9])[C:35](=[O:36])[CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:38])[CH3:2]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCCC(=O)c1cc(C(=O)OCC)c(NCC)cc1C
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)c1cc(C(=O)OCC)c(N(CC)C(=O)CC(=O)OCC)cc1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
13.86 g of the above anthranilic acid ethyl ester are dissolved in 140 ml of absolute toluene and 6.45 g of ethyl diisopropylamine are added. A solution of 7.6 g of chlorocarbonylacetic acid ethyl ester in 75 ml of absolute toluene is added dropwise at room temperature to this solution over a period of 30 minutes. After stirring for 10 hours at room temperature, a further 7.6 g of chlorocarbonylacetic acid ethyl ester in toluene are added dropwise in the course of 15 minutes and the mixture is stirred for a further 15 hours at room temperature. The reaction mixture is washed with water, sodium bicarbonate solution and water, dried over anhydrous sodium sulphate, filtered and concentrated to dryness by evaporation in vacuo. In this manner N-ethyl-5-butyryl-4-methyl-N-(1'-oxo-2'-ethoxycarbonylethyl)-anthranilic acid ethyl ester is obtained in the form of a pale yellow oil, which is further processed without further purification.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:21]([CH:23]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[CH2:24][C:25]([O:27]C)=[O:26])#[N:22]>>[C:21]([CH:23]([C:29]1[CH:34]=[CH:33][C:32]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]/[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)=[CH:31][CH:30]=1)[CH2:24][C:25]([OH:27])=[O:26])#[N:22]
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Reactant: CO/N=C(/COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(/COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1ccccc1
Yield: 30.1 %

Procedure:
Compound 98 was synthesized from (4-{[(2E)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.55 g, 2.03 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.46 g, 2.22 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 30.1%); Purity: 93.18%.
Reaction SMILES: C(OC(N[C@@H](CCC)C(OC)(OC)C(O)=O)=O)(C)(C)C.[OH-].[K+].[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:44][CH2:45][CH3:46])[C:32]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])[C:33]([O:35]CC)=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24].Cl>O.CCO.ClCCl>[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH2:44][CH2:45][CH3:46])[C:32]([O:38][CH2:39][CH3:40])([O:41][CH2:42][CH3:43])[C:33]([OH:35])=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(OCC)(OCC)C(=O)OCC
Agent: CCC[C@H](NC(=O)OC(C)(C)C)C(OC)(OC)C(=O)O
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(OCC)(OCC)C(=O)O
Temperature: 25 °C
Reaction time: 23 h
Yield: 80.2 %

Procedure:
Step 2—preparation of (S)-3-(tert-butoxycarbonylamino)-2,2-dimethoxyhexanoic acid: A solution of KOH (6.95 g, 123.9 mmol) in 100 mL water was added to a solution of Ethyl(S)-3-(tert-butoxycarbonylamino)-2,2-diethoxyhexanoate (8.6 g, 24.6 mmol) in 100 mL EtOH. Further 100 mL EtOH were added to obtain a clear solution and the mixture was stirred at room temperature for 23 hours. Dichloromethane (200 mL) and water (200 mL) were added, and the pH of the mixture was adjusted with conc. HCl from 12.5 to 2.5. The phases were separated, and the aqueous phase was extracted twice with dichloromethane (100 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed in vacuo to yield 6.3 g (S)-3-(tert-butoxycarbonylamino)-2,2-diethoxyhexanoic acid (80% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9](Cl)[C:8]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][CH:6]=1)[CH3:2].[CH2:18]([Zn]CC)[CH3:19]>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([CH2:18][CH3:19])[C:8]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(N(CC)CC)c(Cl)c1
Reactant: CC[Zn]CC
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(N(CC)CC)c(CC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-chloro-6-diethylamino-nicotinic acid ethyl ester (2.96 g, 11.5 mmol) in dioxane (50 mL), Pd(dppf) (470 mg, 0.576 mmol) is added under argon. To this mixture, diethyl zinc (8.53 g, 69.1 mmol, as a 1.1 M solution in toluene) is added dropwise. The mixture is stirred at 75° C. for 16 h before another portion of Pd(dppf) 94 mg, 0.115 mmol) and diethyl zinc (1.42 g, 11.5 mmol, as a 1.1 M solution in toluene) is added. Stirring is continued at 75° C. for 24 h. The reaction mixture is cooled to rt and carefully quenched with water. The mixture is filtered over celite and the filtrate is extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC (heptane:EA 9:1) to give 6-diethylamino-5-ethyl-nicotinic acid ethyl ester (2.40 g) as a colourless oil; LC-MS: tR=0.78 min, [M+1]+=251.19; 1H NMR (CDCl3): δ 1.15 (t, J=7.0 Hz, 6H), 1.27 (t, J=7.3 Hz, 3H), 1.40 (t, J=7.3 Hz, 3H), 2.65 (q, J=7.5 Hz, 2H), 3.36 (q, J=7.0 Hz, 4H), 4.37 (q, J=7.0 Hz, 2H), 7.99 (d, J=2.3 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]([F:52])=[C:29]([C:31]2[CH:32]=[N:33][C:34]([N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[C:43]([C:46]([O:48][CH3:49])=[O:47])[CH:44]=4)[C:39]([CH2:50][OH:51])=[CH:38]3)=[N:35][CH:36]=2)[CH:30]=1)[CH3:24]>ClCCl>[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]([F:52])=[C:29]([C:31]2[CH:36]=[N:35][C:34]([N:37]3[C:45]4[C:40](=[CH:41][CH:42]=[C:43]([C:46]([O:48][CH3:49])=[O:47])[CH:44]=4)[C:39]([CH:50]=[O:51])=[CH:38]3)=[N:33][CH:32]=2)[CH:30]=1)[CH3:24]
Reactant: CCc1ccc(F)c(-c2cnc(-n3cc(CO)c4ccc(C(=O)OC)cc43)nc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCc1ccc(F)c(-c2cnc(-n3cc(C=O)c4ccc(C(=O)OC)cc43)nc2)c1
Reaction time: 3 h

Procedure:
Dess-Martin periodinane (0.541 g, 1.27 mmol) was added at 0° C. to a solution of 331b) (0.345 g, 0.85 mmol) in dichloromethane (25 mL). The resulting mixture was stirred at this temperature for 3 h and then filtered through celite. The filter was rinsed with dichloromethane (2×30 mL) and the filtrate was washed with saturated sodium hydrogen carbonate solution (3×20 mL) and brine (20 mL), dried over sodium sulfate and concentrated. Light yellow solid. Yield: 0.32 g (93% of theory)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1F.C(N(C(C)C)CC)(C)C.C(Cl)Cl>C(OCC)(=O)C.O>[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C

Procedure:
To a solution of 19.9 g of morpholine, 28.7 g of 3,4-difluoronitrobenzene, and 14.8 g of diisopropyl ethylamine in 100 mL of ethyl acetate was heated at reflux under nitrogen for 4 h. The mixture was allowed to cool to room temperature overnight, then 100 mL of ethyl acetate, 150 mL of methylene chloride, and 150 mL of water were added, and the aqueous layer extracted with 2×50 mL of methylene chloride and 50 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) to give a yellow solid. This was recrystallized from acetone-water to give a yellow solid, mp=112°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[N:6]([CH2:13][C:14]([OH:16])=[O:15])[C:5]2=[O:17].[C:18]([O-])(O)=O.[Na+]>CO.OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[N:6]([CH2:13][C:14]([O:16][CH3:18])=[O:15])[C:5]2=[O:17]
Reactant: O=C([O-])O
Reactant: O=C(O)CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CN1C(=O)c2cc(Cl)c(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of 2-(5,6-dichloro-1,3-dioxoisoindolin-2-yl)acetic acid (2.33 g, 8.50 mmol) in MeOH (35 ml), conc. H2SO4 (3 ml) was added at 0° C. The reaction was warmed at room temperature and stirred for 16 hours. The mixture was poured into an ice/water mixture and neutralized with aqueous NaHCO3. The resulting precipitate was recovered by filtration, washed with water and dried affording methyl 2-(5,6-dichloro-1,3-dioxoisoindolin-2-yl)acetate (2.42 g, 8.40 mmol, 99% yield). MS/ESI+ 288.0 [MH]+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:23])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[O:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:23])[CH2:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:17]([CH2:18][NH:30][CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[CH:16]=1
Reactant: NC1CCOCC1
Reactant: O=Cc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: OC(COc1cccc(CNC2CCOCC2)c1)CN1CCc2ccccc2C1
Temperature: 60 °C
Yield: 17 %

Procedure:
To a solution of 3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropoxy)benzaldehyde (200 mg, 0.64 mmol) in DCM (15 mL) was added tetrahydro-2H-pyran-4-amine (97 mg, 0.96 mmol). The solution was heated at 60° C. for 0.5 h. Then, NaBH(OAc)3 (204 mg, 0.96 mmol) was added into the reaction mixture and heated at 60° C. for another 1 h. The reaction mixture was quenched by adding 1N HCl aqueous solution and diluted with DCM then washed with NaHCO3 aqueous solution. The separated organic layer was concentrated and the crude product was purified by preparative HPLC purification. (40 mg, yield 17%) MS (ESI+) e/z: 397.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.36 (t, J=8.0 Hz, 1H), 7.19-7.15 (m, 3H), 7.11-7.02 (m, 4H), 4.39-4.33 (m, 1H), 4.16 (s, 2H), 4.08-4.00 (m, 6H), 3.49-3.40 (m, 3H), 3.25-3.20 (m, 2H), 3.15-3.03 (m, 4H), 2.12-2.02 (m, 2H), 1.71-1.60 (m, 2H).