Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[CH2:13][C:12]([CH3:15])([CH3:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:16]#[CH:17])[CH:10]=3)[CH2:5]2)[CH2:3][CH2:2]1.[CH2:18]([O:20][C:21](=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=1[F:30])[CH3:19].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:18]([O:20][C:21](=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:17]#[C:16][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH2:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:13][C:12]3([CH3:14])[CH3:15])=[CH:25][C:24]=1[F:30])[CH3:19]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CN(C1CC1)C2
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CN(C2CC2)C3)cc1F
Yield: 47.4 %

Procedure:
Following general procedure F and using 2-cyclopropyl-6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline (Intermediate 27, 0.13 g, 0.571 mmol), 2-fluoro-4-iodo phenyl acetic acid ethyl ester (Reagent C, 0.16 g, 0.52 mmol), triethyl amine (0.8 mL), anhydrous tetrahydrofuiran (2 mL), copper(I)iodide (0.051 g, 0.27 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0.14 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, 0.1 g of the title compound was obtained as an oil. It was further purified by preparative normal phase HPLC on a partisil-10 silica column using 10% ethyl acetate in hexane as the mobile phase (0.055 g, 24%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([Cl:17])[N:5]=[CH:4][N:3]=1.O1CCC[CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].CI>>[Cl:17][C:6]1[C:7]([N:8]([CH3:19])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: C1CCOC1
Reactant: O=C(Nc1c(Cl)ncnc1Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Product: CN(C(=O)c1ccccc1)c1c(Cl)ncnc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of N-(4,6-dichloropyrimidin-5-yl)benzamide (3.0 g, 0.011 mol) in tetrahydrofuran (70 mL, 0.9 mol) was added cesium carbonate (9.8 g, 0.030 mol). The suspension was stirred for 5 minutes and to this was added methyl iodide (1.4 mL, 0.022 mol) (purified on aluminum oxide). After stirring for 1 hour, cesium carbonate (5.0 g, 0.015 mol) and methyl iodide (0.70 mL, 0.011 mol) (purified on alumina) were added. The reaction was stirred for 2 hours, quenched by addition of saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4), filtered, concentrated and trituration in diethyl ether to obtain 2.54 g (80%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=O)[C:5]=2[CH:6]=1.[O:12]1C2C=CC=CC=2C=CN1.N[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([N:9]2[CH:7]=[C:5]3[C:4]([CH:3]=[CH:2][CH:1]=[CH:6]3)=[N:11][C:10]2=[O:12])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1=Cc2ccccc2ON1
Reactant: O=c1[nH]cnc2ccccc12
Reactant: Nc1ccccc1
Product: O=c1nc2ccccc2cn1-c1ccccc1

Procedure:
The quinazolinone inhibitors (e.g., inhibitor compound formula D) of the general structure 16 (Scheme 4, below) are made in two steps from the commercially available benzoxazine 12 (Scheme 4). The benzoxazine is first heated with an aniline (13) to form 3-phenylquinazolinone derivative 14. This intermediate is then reacted with substituted furan-2-carboxaldehyde 15 in the presence of sodium acetate (NaOAc)/acetic acid (AcOH) to provide the desired quinazolinones 16.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:15])[CH:8]=2)=[O:4].[OH-].[K+].Cl>C1COCC1.O>[C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:15])[CH:8]=2)([OH:4])=[O:2]
Reactant: COC(=O)c1cc2ccc(C(=O)NCCc3ccccn3)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCc1ccccn1)c1ccc2cc(C(=O)O)[nH]c2c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 82.6 %

Procedure:
A mixture of 2-(methoxycarbonyl)-N-[2-(2-pyridinyl)-ethyl]indole-6-carboxamide (326 mg, 1.01 mmol) and KOH (68 mg, 1.21 mmol) in THF (20 mL) and H2O (3 mL) was stirred at 20° C. for 15 h then at 65° C. for 3 h, cooled and neutralised with 2N HCl (0.61 mL, 1.2 mmol). The THF was evaporated, the aqueous residue allowed to cool, and the solid filtered off and dried to give 2-carboxy-N-[2-(2-pyridinyl)ethyl]indole-6-carboxamide as a white solid (258 mg, 83%), mp 198-199° C. 1H NMR [(CD3)2SO] δ13.14 (br s, 1H, CO2H), 12.07 (s, 1H, indole NH), 8.59 (t, J=5.6 Hz, 1H, amide NH), 8.54-8.51 (m, 1H, H-6'), 7.95 (s, 1H, H-3 or H-7), 7.71 (td, J=7.7, 1.7 Hz, 1H, H-4'), 7.68 (d, J=8.5 Hz, 1H, H-4), 7.53 (dd, J=8.5, 1.4 Hz, 1H, H-5), 7.29 (d, J=7.8 Hz, 1H, H-3'), 7.23 (ddd, J=7.4, 4.7, 0.8 Hz, 1H, H-5'), 7.13 (d, J=1.2 Hz, 1H, H-3 or H-7), 3.64 (q, J=6.8 Hz, 2H, NHCH2CH2 py), 3.02 (t, J=7.4 Hz, 2H, NHCH2CH2 py); 13C NMR δ166.7 (CONH), 162.5 (CO2H), 159.2 (C-2'), 136.5, 130.6, 130.5, 128.7 (C-2,6,8,9), 149.0, 136.4, 123.1, 121.4, 118.7, 112.2, 107.0 (one peak doubled or not observed, C-3,4,5,7,3',4',5',6'), 39.3, 37.3 (NHCH2CH2 py). Anal. (C17H15N3O3) C,H,N.
Reaction SMILES: Cl.Br[CH:3]([CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]#[N:5].N(CCO)(CCO)CCO>>[C:4]([CH:3]1[CH2:6][N:7]1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:5]
Reactant: CCOC(=O)CNCC(Br)C#N
Agent: Cl
Solvent: OCCN(CCO)CCO
Product: CCOC(=O)CN1CC1C#N
Yield: 34 %

Procedure:
reaction of 2-bromo-3-(carbethoxymethylamino)-propionitrile hydrochloride (prepared by reacting 2,3-dibromopropionitrile with glycine ethyl ester; m.p. 70°-75° C.) with triethanolamine gives ethyl 2-cyano-1-aziridine-acetate; b.p.0.1 : 88°-90° C.; yield 34% of theory;
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]([NH2:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:14][CH:11]([CH3:13])[CH3:12])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 97.8 %

Procedure:
To a solution of 2-fluoronitrobenzene (0.5 mL, 4.7 mmol) in DMSO (10 mL) is added isopropylamine (0.6 mL, 7.1 mmol), followed by Hunig's base (1.2 mL, 7.1 mmol). The reaction flask is sealed and heated to 80° C. overnight. The reaction is then cooled to room temperature and poured over ice H2O and extracted ethyl acetate. The organic layer is washed with H2O, brine, dried (Na2SO4) and concentrated to afford the title compound (828 mg, 97%) as an orange oil.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH3:16]O>>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: NCCCCCCCC(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCCCCCN
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To 15 ml methanol under nitrogen, stirred, at −5° C. was added thionyl chloride (0.80 ml) dropwise. After 5 minutes, 8-aminooctanoic acid (1.592 g, 10 mmol) was added. The reaction was stirred at −5° C. for 1 h, room temperature for 45 minutes, and 40° C. for 2.25 h. After heating, the reaction mixture was concentrated. The residue was taken up in chloroform/water (40 ml/25 ml) and basified to pH 9–10 using 1N NaOH. Layers were shaken, separated and the aqueous layer washed with water (2×30 ml). The combined organics were dried over Na2SO4 and filtered. The filtrate was concentrated in vac and dried to give the product as an oily solid (1.568 g, 90%); 1H NMR (400 MHz, DMSO-d6) δ 1.17–1.33 (m, 8H), 1.43–1.52 (m, 2H), 2.26 (t, J=7.5 Hz, 2H), 2.44–2.49 (m, 2H), 3.55 (s, 3H); IR (film) 3475, 2930, 2850, 1730 cm−1; mass spectrum [EI], m/z 173 M+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:15])[C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5](Cl)=[O:6].O1CCCC1.[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH2:28]>C(N(CC)CC)C>[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH:28][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([F:1])[C:10]([O:11][CH2:12][C:13]#[CH:14])=[C:9]([F:15])[CH:8]=1
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Reactant: CC1CCCCC1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCOc1c(F)cc(C(=O)NC2CCCCC2C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 346 mg of 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride and 1 ml of tetrahydrofuran was added dropwise under ice cooling to a mixture of 5 ml of tetrahydrofuran, 170 mg of 2-methylcyclohexylamine and 182 mg of triethylamine. The mixture obtained was stirred at room temperature for 0.5 hour. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 295 mg of N-(2-methylcyclohexyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 42 of the present invention) represented by the formula:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1>CO.CN(C=O)C.[Pd]>[NH2:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1

Procedure:
Same procedure as above with Z-Trp-NHCH2Ph (616 mg, 1.44 mmol), 10% Pd/C (153 mg) in MeOH/DMF (14.5 mL, 1/1). After purification by flash chromatography on silica gel (3-12% MeOH/CH2Cl2), Trp-NHCH2Ph was isolated as a pale yellow oil (351 mg, 83%). 1H NMR (300 MHz, CDCl3) δ 2.98 (dd, J=14.4 Hz, J=8.7 Hz, 1H, CH2), 3.44 (dd, J=14.4 Hz, J=4.1 Hz, 1H, CH2), 3.80 (dd, J=8.7 Hz, J=4.2 Hz, 1H, CHα), 4.46 (m, 2H, CH2 (Bn)), 7.06 (d, J=2.1 Hz, 1 aromatic H), 7.13-7.36 (m, 7 aromatic H), 7.41 (d, J=8 Hz, 1 aromatic H), 7.61 (m, 1H, NH amide), 7.72 (d, J=7.8 Hz, 1 aromatic H), 8.3 (broad s, 1H, NH indole). 13C NMR (75 MHz, MeOD) δ 30.5 (CH2 Trp), 42.7 (CH2 Ph), 55.4 (CHα), 109.3, 111, 118.1, 118.5, 121.2, 123.5, 126.8, 127, 127.1, 127.4, 128, 128.1, 136.8, 138 (14 aromatic C), 174.6 (CO amide).
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[CH2:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH2:6]1.C(OC([Cl:27])=O)C.[OH-].[K+]>C1(C)C=CC=CC=1>[ClH:27].[CH3:1][NH:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[CH2:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[CH2:6]1
Reactant: C=C1c2ccccc2CC(CCN(C)C)c2ccccc21
Reactant: CCOC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=C1c2ccccc2CC(CCNC)c2ccccc21
Product: Cl

Procedure:
A mixture of 15.2 g. (0.055 mole) of 10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene and 23.6 g. (0.218 mole) of ethylchloroformate in 125 ml. of toluene is refluxed under a nitrogen atmosphere for 18 hours. The excess solvent and reagent is removed by evaporation in vacuo. The resulting oil product is dissolved in a solution of 175 ml. of ethanol, 17 ml. of water and 35 g. (0.625 mole) of potassium hydroxide and refluxed for 10 hours. The solvents are removed in vacuo and the resulting layers are separated between ether and water. The ether is then extracted twice with 2N hydrochloric acid and the resulting aqueous acid is then made basic and extracted with ether. The excess solvent is then dried and evaporated and the resulting oil is dissolved in isopropyl alcohol and treated with hydrochloric gas. The residue is then filtered and recrystallized from isopropyl alcohol to give 10-(2-methylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene hydrochloride, m.p. 176°-177° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:25]([O:27][C:28](=[O:42])[CH2:29][CH2:30][NH:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36](O)=[C:35]([F:40])[CH:34]=1)[CH3:26].C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:25]([O:27][C:28](=[O:42])[CH2:29][CH2:30][NH:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([O:22][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:24])[F:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:35]([F:40])[CH:34]=1)[CH3:26]
Reactant: CCCCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(O)c(F)c1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)OCC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
Combine 1-(4′-trifluoromethyl-biphenyl-4-yl)-heptan-1-ol (0.257 g, 0.76 mmol) and 3-(3-Fluoro-4-hydroxy-benzoylamino)-propionic acid ethyl ester (0.150 g, 0.59 mmol) in toluene (3.0 mL). Add 1,1′(diazocarbonyl)dipiperidine (0.223 g, 0.88 mmol) followed by tributyl-phosphane (0.22 mL, 0.88 mmol) under inert atmosphere. Stir at room temperature for 18 hours. Dilute reaction with ethyl acetate filter and remove solvent under reduced pressure. Purify on silica gel chromatography (0-70% Ethyl acetate/hexanes gradient) to provide 0.305 g of title compound (90%).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:39])=[CH:11][C:12](=[O:38])[N:13]2[CH2:16][CH2:17][CH2:18][C:19]2([C:33]([O:35]CC)=[O:34])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:20]2)=[CH:8][CH:7]=1.[OH-].[Na+]>O>[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:39])=[CH:11][C:12](=[O:38])[N:13]2[CH2:16][CH2:17][CH2:18][C:19]2([C:33]([OH:35])=[O:34])[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][S:27][C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[CH2:21][CH2:20]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)cc(C)c3ccc(OC)cc32)CCN(CCSc2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(C)cc(=O)n(CCCC3(C(=O)O)CCN(CCSc4cccs4)CC3)c2c1
Yield: 88.7 %

Procedure:
To 1 mL of an ethanol solution containing 0.25 g of ethyl 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate, 1 mL of 5 mol/L aqueous sodium hydroxide solution was added and stirred under reflux with heating for 5 hours. 2 mL of water was added, removed ethanol under reduced pressure, adjusted to pH 6.0 with 6 mol/L hydrochloric acid, and the resulting solid was filtered to afford 0.21 g of 4-(3-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylic acid as a pale yellow solid.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[C:10]([OH:21])(=[O:20])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.O1CC[CH2:25]OO1.[CH2:28](O)[CH2:29][CH2:30][CH3:31]>O.C1(C)C=CC=CC=1>[CH2:28]([O:16][C:15]([C:14]1[CH:18]=[C:19]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:21])[O:20][CH2:25]2)=[O:17])[CH2:29][CH2:30][CH3:31]
Reactant: C1COOOC1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: CCCCO
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1ccc2c(c1)COC2=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Oleum (25% SO3, 95 ml) is charged into a reactor (350 ml). Under stirring terephthalic acid (19.0 g; 0.11 mol) is added to the reactor and the mixture is heated to 60° C. After stirring for additional 30 min terephthalic acid (31.0 g; 0.19 mol) is added and the mixture is heated to 100° C. for 1 hour. The mixture is cooled to 25-30°C., trioxane (12.0 g; 0.13 mol) is added in portions and the reaction mixture is heated slowly to 130-135°C. and agitated at this temperature for 1 1/2 hours and for 4 hours at 155° C. The reaction mixture is cooled to 40° C. and over a period of 30 min added to a reactor containing butanol (300 ml) which has been heated to 95-100° C. Toluene (100 ml) and water (100 ml) was added to the formed suspension. The organic phase was separated and concentrated to dryness and redissolved in toluene (100 ml) and heptanes (100 ml) by heating at 75-80° C. The mixture was cooled to 25-30°C. for 30 min and the product was filtered off and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:6]=[C:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].[Cl-:18].[CH3:19][N+:20](=[CH2:22])[CH3:21]>C(#N)C>[ClH:18].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:6]=[C:7]1[CH2:11][CH2:10][CH:9]([CH2:19][N:20]([CH3:22])[CH3:21])[C:8]1=[O:12]
Reactant: C=[N+](C)C
Reactant: COc1ccc(C=C2CCCC2=O)cc1OC
Reactant: [Cl-]
Solvent: CC#N
Product: COc1ccc(C=C2CCC(CN(C)C)C2=O)cc1OC
Product: Cl

Procedure:
0.03 mol of 2-(3,4-dimethoxybenzylidene)cyclopentanone was dissolved in 30 mL anhydrous acetonitrile, treated with 8.4 g (0.09 mol) of N,N-dimethyl-methylene ammonium chloride under refluxing, refluxed for 12 h to yield a solid product which was then suction filtered, dried and recrystallized in acetonitrile/chloroform to yield 2-(3,4-dimethoxybenzylidene)-5-(dimethylaminomethyl)cyclopentanone hydrochloride with a recovery of 69.8%.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:24])[N:4]([CH2:20][CH2:21][CH2:22][CH3:23])[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[C:25](Cl)(=O)[O:26]C1C=CC=CC=1.[CH:35]([C:38]1[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH3:47])[CH3:46])[C:39]=1[NH2:40])([CH3:37])[CH3:36]>O1CCCC1.CN(C)C1C=CN=CC=1.O.CN(C)C=O>[CH2:20]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:2]([NH:1][C:25]([NH:40][C:39]2[C:38]([CH:35]([CH3:37])[CH3:36])=[CH:44][CH:43]=[CH:42][C:41]=2[CH:45]([CH3:47])[CH3:46])=[O:26])[C:3]1=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCn1c(=O)c(N)c(-c2cccc(OC)c2)c2cccnc21
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of 3-amino-1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine (1.70 g, 5.26 mmol) in tetrahydrofuran (14 ml) was added phenyl chlorocarbonate (1.32 ml, 10.5 ml), and the mixture was stirred at 40-50° C. for 3 hours. The mixture was allowed to cool, and thereto was added water, and the mixture was extracted with water. The extract was washed with a 5% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in dimethylformamide (10 ml), and thereto was added a solution of 2,6-diisopropylaniline (1.24 g, 6.31 mmol) and dimethylformamide (5 ml) and 4-dimethylaminopyridine (0.62 g, 5.26 mmol), and the mixture was stirred at room temperature for one hour. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed successively with a 5% aqueous sodium hydrogen carbonate solution and a 5% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (1.75 g, 3.32 mmol) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[CH3:11][C@H:12]1[CH2:17][N:16]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[CH:21][CH:20]=2)[CH2:15][CH2:14][N:13]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:25]([CH3:26])[C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:16]3[CH2:15][CH2:14][N:13]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C@@H:12]([CH3:11])[CH2:17]3)=[CH:24][CH:23]=2)=[O:9])=[N:6][CH:7]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: O=C(Cl)c1ccc(Br)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)cn3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
The acid chloride from step 2 (0.801 g, 3.633 mmol) in DCM (10 mL) was added to a solution of 1,1-dimethylethyl (2S)-2-methyl-4-{[4-(methylamino)phenyl]methyl}-1-piperazinecarboxylate (D3) (0.928 g, 2.906 mmol) in DCM (20 mL). Triethylamine (1.009 mL, 7.266 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with water. The aqueous layer was re-extracted with DCM (×2) and the combined organics were dried and concentrated to give the crude product which was purified by column chromatography. Elution with a 0-50% ethyl acetate/petroleum ether gradient yielded the title compound as a yellow oil (1.432 g). δH (CDCl3, 400 MHz) 8.34 (1H, br.s), 7.72 (1H, br.d), 7.38 (1H, br.d), 7.18 (2H, br.m), 6.98 (2H, br.s), 4.17 (1H, br.s), 3.79 (1H, d), 3.51 (3H, s), 3.46 (1H, d), 3.32 (1H, d), 3.07 (1H, td), 2.68 (1H, d), 2.47 (1H, d), 2.10 (1H, dd), 1.98 (1H, m), 1.45 (9H, s), 1.19 (3H, d). MS (ES): MH+ 503/505.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)C(Cl)=O.[CH3:11][Mg]Br.C([O:16][CH2:17][CH3:18])C>C1COCC1>[Br:1][C:2]1[CH:10]=[C:6]([C:17]([OH:16])([CH3:18])[CH3:11])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: C[Mg]Br
Reactant: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cncc(Br)c1
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-nicotinoyl chloride (900 mg, 4.1 mmol) in THF (18 mL) at −78° C. was added a 3.0 M solution of methylmagnesium bromide in diethyl ether (5.44 mL, 16.3 mmol). The reaction was stirred for 20 minutes and then quenched with saturated aqueous ammonium chloride. The reaction was then brought to room temperature, diluted with brine and ethyl acetate and the layers were separated. The aqueous layer was extracted two additional times with ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 100%) to afford 2-(5-bromo-pyridin-3-yl)-propan-2-ol; MS: (ES+) m/z 216.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:30][C:31]2[CH:32]=[C:33]([CH3:41])[C:34]3[N:35]([C:37]([CH3:40])=[N:38][N:39]=3)[CH:36]=2)[C:9]2[C:10]([C:27](O)=[O:28])=[N:11][N:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[C:13]=2[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([C:17]4[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=4)[C:13]=3[CH:14]([CH3:16])[CH3:15])[C:27](=[O:28])[N:30]2[C:31]2[CH:32]=[C:33]([CH3:41])[C:34]3[N:35]([C:37]([CH3:40])=[N:38][N:39]=3)[CH:36]=2)=[CH:6][CH:7]=1
Reactant: COc1ncc(-n2nc(C(=O)O)c(C(Nc3cc(C)c4nnc(C)n4c3)c3ccc(Cl)cc3)c2C(C)C)c(OC)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ncc(-n2nc3c(c2C(C)C)C(c2ccc(Cl)cc2)N(c2cc(C)c4nnc(C)n4c2)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)amino)methyl)-1-(2,4-dimethoxypyrimidin-5-yl)-5-isopropyl-1H-pyrazole-3-carboxylic acid (Step 67.6) in a mixture CH2Cl2/DMF 20:1 for 30 min at RT. Purification by preparative achiral SFC (diethyl-amino, gradient 11-16% in 6 min_total 11 min). tR: 1.01 min (LC-MS 2); ESI-MS: 559 [M+H]+ (LC-MS 2); Rf=0.40 (CH2Cl2/MeOH 10:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.49 (d, J=6.8 Hz, 3H) 1.16 (d, J=6.8 Hz, 3H) 2.46 (s, 3H) 2.66 (m, 4H) 3.96 (s, 3H) 4.01 (s, 3H) 6.65 (s, 1H) 7.22-7.68 (m, 5H) 8.49 (s, 1H) 8.64 (s, 1H).