Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1.Cl>[C:4]([C:3]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:2]=1[O:1][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccccc2)c(OCCCC(=O)O)c1
Reaction time: 20 h

Procedure:
A 100 mL mini-block tube equipped with a magnetic stir bar was charged with 4.56 g (20.0 mmol) of 2-hydroxy-4-methoxybenzophenone, 2.70 mL (3.68 g, 18.9 mmol) of ethyl 4-bromobutyrate and 40 mL of dimethylformainide (DMF). Potassium carbonate (2.96 g, 21.4 mmol) was added to the clear solution. The reaction mixture was heated to 80 C. After stirring for 20 hr at 25 C, the clear reaction mixture was diluted with water. The resulting solid was isolated by filtration. This solid was taken up in 30 mL of tetrahydrofuran (THF) and treated with 3.10 g (24.0 mmol) of potassium trimethylsilanoate. The orange solution was stirred for 20 hr at 25 C, diluted with aqueous 4% hydrochloric acid to pH 7.5 and washed with MTBE. The organic phase was extracted with aqueous 3% sodium bicarbonate solution. The combined aqueous phases were acidified to pH 2 with aqueous 4% hydrochloric acid and extracted with 60 mL of MTBE. This organic phase was washed with brine (1×40 mL), dried over sodium sulfate and concentrated. The resulting solid was purified by trituration using MTBE/hexanes. More of the product was isolated from the mother liquor. LC-MS analysis: m+1 peak confirmed (315). 1H NMR Analysis: (d6-DMSO): δ 12.0, bs, 1H (COOH); δ 7.6, d, 2H, (phenyl H's, o to CO); δ 7.56, t, 1H (phenyl H, p to CO); δ 7.44, t, 2H (phenyl H's, m to CO); δ 7.35, d, 1H (aryl H, o to CO); δ 6.64, m, 2H (aryl H's, m to CO); δ 3.88, t, 2H, (CH2 α to O); δ 3.82, s, 3H, (CH3O); δ 1.84, t, 2H (CH2 α to COOH); δ1.53, p, 2H (middle CH2 in chain). 13C NMR (d6-DMSO): 195.08, 173.91, 163.17, 158.33, 138.84, 132.37, 131.37, 128.67, 128.24, 120.87, 105.87, 99.02, 66.89, 55.53, 29.45, 23.79.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH3:11][O:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)=[O:16].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:11][O:12][C:13]1[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=1[C:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: COc1ccccc1C(=O)c1ccc(C(=O)O)cc1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)c1ccc(C(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.308 g (1.2 mmol) of 4-(2-methoxybenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][CH2:10][CH2:11][C:12]#[N:13].C[O-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[C:20]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:19]=1>CO.C(#N)C>[Cl:17][C:18]1[N:23]=[C:22]([NH:13][CH2:12][CH2:11][C:10]#[N:9])[CH:21]=[C:20]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:19]=1
Reactant: N#CCCN
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Agent: C[O-]
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: N#CCCNc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 3-aminopropanenitrile fumarate (147 mg, 0.74 mmol) and sodium methoxide (1.1 mL, 0.54 mmol) in MeOH (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (64 mg, 0.25 mmol) in acetonitrile (2 mL). The mixture stirred at rt over night. The mixture was heated to 50° C. for 20 h. The reaction mixture was concentrated in vacuo and the crude was partitioned between EtOAc and 1M NaOH. The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound, 29 mg (40%).
Reaction SMILES: Br.[NH2:2][C:3]1[N:8]=[CH:7][N:6]2[CH:9]=[C:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[N:11]=[C:5]2[CH:4]=1.CN(C=O)C.[CH3:24][O:25][C:26](=[O:29])[CH2:27]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.CO>[CH3:24][O:25][C:26](=[O:29])[CH2:27][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:10]2[N:11]=[C:7]3[N:8]=[C:3]([NH2:2])[CH:4]=[CH:5][N:6]3[CH:9]=2)[CH:13]=1
Reactant: COC(=O)CBr
Reactant: Nc1cc2nc(-c3cccc(O)c3)cn2cn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)COc1cccc(-c2cn3ccc(N)nc3n2)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
3-(7-Aminoimidazo[1,2-c]pyrimidin-2-yl)phenol hydrobromide (100 mg, 0.33 mmol) was combined with DMF (0.2 ml) to give a light brown suspension. Methyl-2-bromoacetate (55 mg, 0.36 mmol) and Cs2CO3 (424 mg, 1.3 mmol) were added, and the reaction mixture was stirred 2 h in a sealed tube at 65° C. The reaction mixture was directly put on a column and the product was isolated by flash chromatography (SiO2—NH2 cartridge; eluent: CH2Cl2/MeOH 95:05) to yield the title compound (57 mg, 58%) as a light yellow solid. MS (m/z)=299.1 [M+H+].
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C>[N:5]1[C:4]2[CH:8]=[CH:9][NH:10][C:3]=2[C:2]([NH:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:7][CH:6]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cccc(Nc2ncnc3cc[nH]c23)c1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 55.8 %

Procedure:
A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (2.78 g), ethyl 3-aminobenzoate (4.49 g) and 1-methyl-2-pyrrolidone (20 mL) was stirred at 120° C. for 1.5 hrs. To the reaction mixture were added ethyl acetate, water and saturated aqueous sodium hydrogen carbonate solution. The insoluble material was filtered off, and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate, and the mixed ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The filtered insoluble material was suspended in methanol and ethyl acetate and saturated brine were added. The ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixed ethyl acetate layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate) and crystallized from methanol-acetone-diisopropyl ether to give the title compound (2.85 g) as a pale-brown powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH2:13])=[CH:10][CH:11]=2)[N:6]=1.C(N(CC)CC)C.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:26](=[O:27])[CH2:25][O:24][C:21](=[O:23])[CH3:22])=[CH:10][CH:11]=2)[N:6]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: NCc1ccc(-c2csc(N)n2)s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)NCc1ccc(-c2csc(N)n2)s1
Temperature: 25 °C

Procedure:
To a suspension of 2-amino-4-(5-aminomethyl-2-thienyl) thiazole in 150 ml of chloroform is added 10 ml of triethylamine, and 3.1 g of acetoxyacetylchloride is added dropwise with stirring at room temperature (10°-35° C.). The whole mixture is stirred at room temperature for an hour, and then washed with water. The organic layer is separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is recrystallized from ethanol to give 2-amino-4-(5-acetoxyacetylaminomethyl-2-thienyl) thiazole, melting at 149°-150° C. The corresponding maleate melts at 153°-154° C. with decomposition.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4([CH2:41][CH3:42])[CH2:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[C:33]4=[O:40])[CH:27]=3)[CH:18]=2)[C:12]([CH3:15])=[N:13][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:52]>>[ClH:52].[ClH:52].[NH2:7][CH2:8][CH2:9][C:10]1[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4([CH2:41][CH3:42])[CH2:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[C:33]4=[O:40])[CH:27]=3)[CH:18]=2)[C:12]([CH3:15])=[N:13][CH:14]=1
Reactant: CCC1(c2cccc(Oc3cc(Cn4c(CCNC(=O)OC(C)(C)C)cnc4C)ccc3C#N)c2)CCCCN(C)C1=O
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1(c2cccc(Oc3cc(Cn4c(CCN)cnc4C)ccc3C#N)c2)CCCCN(C)C1=O
Product: Cl
Reaction time: 0.5 h

Procedure:
To a solution of [2-(3-{4-cyano-3-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzyl}-2-methyl-3H-imidazol-4-yl)-ethyl]-carbamic acid tert-butyl ester (as described in Step B above) (0.2 g, 0.41 mmol) in CH2Cl2 (6.0 mL) was added TFA (3.0 mL) and the solution was stirred for 0.5 hr. The solvents were removed in vacuo and the crude product was purified by preparative HPLC. Conversion to the HCl salt yielded the title compound.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[CH2:13]([N:20]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C@H:26]1([NH:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH2:46])[CH:42]=3)[N:37]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>>[CH2:13]([N:20]1[CH2:24][CH2:23][CH:22]([NH:25][C:1]([NH:46][C:41]2[CH:42]=[C:43]3[C:38](=[CH:39][CH:40]=2)[N:37]=[C:36]([NH:35][C@H:26]2[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27]2)[CH:45]=[CH:44]3)=[O:12])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)NC1CCN(Cc2ccccc2)C1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, rac-1-benzyl-3-aminopyrrolidine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=478.6 (M+H+).
Reaction SMILES: [CH3:1][S:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH3:19])[C@H:6]([OH:20])[C@@H:5]1[OH:21].[C:22](O)(=O)C.[Br:26]C>C(OCC)C>[Br-:26].[CH3:1][S+:2]([CH3:22])[CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[CH3:19])[C@H:6]([OH:20])[C@@H:5]1[OH:21]
Reactant: CBr
Reactant: CC(=O)O
Reactant: CSC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCOCC
Product: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](C[S+](C)C)[C@@H](O)[C@H]1O
Product: [Br-]
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Compound 20a (78 mg, 0.25 mmol) in a 2:1 mixture (4 mL) of formic and acetic acid was treated with a 2M solution of bromomethane in diethyl ether (5 mL) and stirred for 6 days in darkness at room temperature. Solvents were removed in vacuo and a solution of the residue in water (10 mL) was extracted with (3×10 mL) ether. The aqueous layer was concentrated to dryness. The resulting product was dissolved in MeOH (10 mL), filtered and treated with diethyl ether to precipitate out the salt. The salt was filtered, washed with ether, and dried in vacuo to give white solid: yield 79 mg (78%); MS m/z 326 (M)+; 1HNMR (D2O) δ 8.24 (s, 1H, H-2), 6.03 (d, 1H, H-1′, J1′,2′=5.4 Hz), 5.29 (t, 1H, H-2′, J2′,3′=5.7 Hz), 4.80 (t, 1H, H-3′, J3′,4′=4.8 Hz), 4.52-4.60 (m, 1H, H-4′), 4.11-4.20 (m, 1H, 5′-CH2), 3.81-3.90 (m, 1H, 5′-CH2), 2.92 and 2.89 (2s, 6H, S—(CH3)2), 2.67 (s, 3H, 8-CH3).
Reaction SMILES: [C:1](=[O:4])([O-])O.[Na+].[CH3:6][OH:7].[N:8]1[C:15](Cl)=[N:14][C:12](Cl)=[N:11][C:9]=1[Cl:10]>>[Cl:10][C:9]1[N:11]=[C:12]([O:7][CH3:6])[N:14]=[C:15]([O:4][CH3:1])[N:8]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CO
Reactant: O=C([O-])O
Agent: [Na+]
Product: COc1nc(Cl)nc(OC)n1
Temperature: 10 °C
Reaction time: 3.5 h
Yield: 89.3 %

Procedure:
In a 500-ml four-necked flask equipped with a stirrer and a thermometer, 44.1 g (0.525 mol) of sodium hydrogencarbonate and 160.2 g (water content: 650 ppm, 5.0 mol) of methanol were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction was conducted at 60° C. for 3.5 hours. The weight of the reaction solution from which a salt formed had been removed was 192 g, and the water content was 49,500 ppm. After cooling, methanol was distilled off. To the residue, 200 ml of water was added, and the objective product was extracted with 250 ml of ethyl acetate. The organic layer was washed with 100 ml of water and then vacuum concentrated to obtain 39.2 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 89.2%. From the gas chromatography analysis, the purity proved to be 96.3% (% by area).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[CH3:16])=O)=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[CH3:20][NH2:21]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[CH3:16])[NH:21][CH3:20])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: Cc1ccsc1C(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CNC(Cc1ccc(Cl)cc1[N+](=O)[O-])c1sccc1C
Product: Cl
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To a cooled (-60° C.) solution of 0.06 g of 2-(4-chloro-2-nitrophenyl)-1-(3-methyl-2-thienyl)ethanone in 270 ml of toluene, 70 ml of methyl amine was added under a dry-ice-isopropanol condenser. The mixture was stirred for 0.5 hr. A solution of 4.6 ml of titanium tetrachloride in 46 ml of toluene was added dropwise. The dry-ice-isopropanol condenser was removed, a water condenser was attached, and the reaction was heated at an internal temperature of 75° C. for 2 hrs and stirred overnight at room temperature. The mixture was filtered and the filtrate was evaporated. To a solution of the residue in 250 ml of anhydrous methanol, ethereal hydrogen chloride was added dropwise until a pH of 3-5 was attained. A solution of 1.89 g of sodium cyanoborohydride in 25 ml of anhydrous methanol was added, and the mixture was stirred for 0.5 hr. An additional 1.0 g of sodium cyanoborohydride was added, and the mixture was stirred for one hr. The reaction was kept in the acidic pH range by periodic addition of ethereal hydrogen chloride. The solvent was evaporated, the residue was basified with 10% sodium hydroxide solution and extracted with ether. The combined extracts were washed with water, dried over anhydrous sodium sulfate, and concentrated. Purification was accomplished by preparative HPLC (Waters Associates Prep LC/System 500A, silica gel, 200 ml/min flow rate eluted with ethyl acetate and monitored by a Gow-Mac Model 80-800 uV detector. The appropriate fractions were collected and concentrated, and the residue was dissolved in ether and ethereal-hydrogen chloride was added to afford 5.6 g of product, mp 195°-197° C.
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:16][NH:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.[BH3-]C#N.[Na+].[OH-].[Na+].O>C(O)(C(F)(F)F)=O>[CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)c1c(n3CCC2)CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
5,6,8,9,10,11-Hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (2.84 g, 11.4 mmol) was dissolved in TFA (35 mL). The reaction was cooled to 0° C. NaCNBH3 (2.15 g, 34.27 mmol) was added in small portions over 30 min, keeping the temperature less than 5° C. The reaction was stirred at 0° C. for 2 h. Ice was added to the reaction flask, and the reaction was basified with 50% NaOH until pH=14. Water (20 mL) was added to dissolve the precipitate. The reaction was extracted with CHCl3 (3×20 mL). The combined organic layers were washed with brine, dried, and concentrated to afford the title compound (1.67 g, 68%) as a pale-brown, amorphous solid. 1H NMR (CDCl3, 300 MHz) δ6.80-7.00 (m, 2H), 6.55-6.6.70 (m, 1H), 3.20-3.40 (m, 2H), 2.95-3.20 (m, 2H), 2.75-2.95 (m, 2H), 2.50-2.75 (m, 4H), 2.00-2.20 (m, 2H), 1.85-2.00 (m, 1H), 1.70-1.85 (m, 1H) ppm.
Reaction SMILES: [C:1]([O-:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Zn+2:8].C([O-])(=O)C(C)(C)C.Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.[Mg]>>[C:1]([O-:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:24][C:23]([F:26])([F:25])[C:19]1[CH:18]=[C:17]([Zn+:8])[CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: [Zn+2]
Agent: CC(C)(C)C(=O)[O-]
Agent: [Mg]
Product: FC(F)(F)c1cccc([Zn+])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
2LiCl (2a prepared above; 2.64 g, 7.50 mmol) is placed in a 25 mL Schlenk-flask, dried for 5 min at 400° C. (heat gun) in high vacuum and then dissolved in dry THF (10.0 mL). 1-Bromo-3-(trifluoromethyl)benzene (3d; 1.13 g, 5.00 mmol) and magnesium-turnings (304 mg, 12.5 mmol) are added and the mixture was stirred for 2 h at 25° C. The solution is cannulated to a dry and argon-flushed 50 mL Schlenk-tube via syringe filter and the solvent is removed in vacuo. 3-(Trifluoromethyl)phenylzinc pivalate (1d) is obtained as a grey solid (3.72 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:37])[C:5]([C:34](O)=[O:35])=[CH:6][N:7]2[CH2:32][CH3:33].C(N(CC)CC)C.ClC(OCC(C)C)=O.CC(C[AlH]CC(C)C)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:37])[C:5]([CH2:34][OH:35])=[CH:6][N:7]2[CH2:32][CH3:33]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1cc(CO)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.1 %

Procedure:
To a suspension of 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (24 g, 41.7 mmol) in Tetrahydrofuran (THF) (450 mL) was added triethylamine (8.71 mL, 62.5 mmol), followed by careful addition of isobutyl chloroformate (7.66 mL, 58.4 mmol). The resulting mixture was stirred at r.t. for 2.5 h. Then the mixture was cooled down to −40° C. and a solution of DIBAL-H (69.5 mL, 104 mmol) in toluene (1.5 M) was added. The mixture was stirred at the same temperature for 3.5 h. After completion, the reaction was quenched with sat. NH4Cl (aq.), warmed up to r.t., diluted with sat. NH4Cl (aq.), filtered through Celite to remove gummy precipitate, and extracted with dichloromethane twice. The combined organic extracts were then saturated with brine and then dried over sodium sulfate, filtered and the resulting filtrate was concentrated in vacuo to afford 5-chloro-1-ethyl-3-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one (19 g, 30.9 mmol, 74.2% yield) as a yellow solid, which was used in the next oxidation step. LCMS: (M+H)+: 510.0.
Reaction SMILES: [CH:1]([O:8]CC)([O:5][CH2:6][CH3:7])OCC.[F:11][C:12]([F:19])([F:18])[C:13]([CH3:17])=[CH:14][CH2:15]O.[C:20](O)(=O)CC>C(OCC)C>[CH3:17][C:13]([C:12]([F:19])([F:18])[F:11])([CH:14]=[CH2:15])[CH2:20][C:1]([O:5][CH2:6][CH3:7])=[O:8]
Reactant: CCOC(OCC)OCC
Reactant: CC(=CCO)C(F)(F)F
Reactant: CCC(=O)O
Solvent: CCOCC
Product: C=CC(C)(CC(=O)OCC)C(F)(F)F
Temperature: 200 °C

Procedure:
Triethyl orthoformate (6.51 mL, 35.7 mmol) was added to an ambient temperature mixture of 4,4,4-trifluoro-3-methylbut-2-en-1-ol (ca. 500 mg, 3.57 mmol) and propionic acid (13 μL, 0.18 mmol). After heating in a sealed tube at 200° C. for 30 h, the reaction mixture was cooled, diluted with diethyl ether and washed with saturated aqueous sodium bicarbonate. The organic phase was dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-20% ethyl acetate/hexane afforded ethyl 3-methyl-3-(trifluoromethyl)pent-4-enoate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[CH:20][N:21]=4)[CH:18]=3)[OH:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.C([O-])([O-])=O.[K+].[K+].COCCOC>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.C(Cl)Cl>[N:21]1[CH:20]=[CH:19][N:17]2[CH:18]=[C:13]([CH:11]([C:8]3[N:6]4[N:7]=[C:2]([C:26]5[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[OH:12])[CH:14]=[CH:15][C:16]=12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OC(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(C(O)c4ccc5nccn5c4)n3n2)cn1
Temperature: 80 °C

Procedure:
A microwave tube was charged under argon atm. with (rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-imidazo[1,2-a]pyridin-6-yl-methanol (Stage 9.1, 89.9 mg, 0.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (62.4 mg, 0.3 mmol), Pd(PPh3)2Cl2 (6.3 mg) and 2 M K2CO3 (0.405 mL) and DME (1 mL). The mixture was heated at 80° C. for 3 h. The RM was taken up with DCM and washed with NaCl solution. After filtration of both layers, the solid part was dissolved in MeOH and evaporated to dryness. The residue was stirred in EtOAc and filtered to give the pure title compound. The organic layer of the first filtrate was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/MeOH=95:5—>80:20) to afford a second batch of the title compound (tR 2.57 min (conditions 3), MH+=346.2)