Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][CH:12]([F:14])[F:13])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].[Li+].[OH-].Cl.BrC[C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:28].C(N(CC)CC)C>CO>[C:18]([O:17][C:15]([N:6]1[CH2:7][CH:8]([CH2:10][O:11][CH:12]([F:14])[F:13])[CH2:9][CH:5]1[C:3]([O:2][CH2:1][C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:28])=[O:4])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1CC(COC(F)F)CN1C(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(COC(F)F)CC1C(=O)OCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
4-Difluoromethoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (398 mg, 1.29 mmol) was dissolved in MeOH (8 mL) and LiOH (1 M in H2O, 2 mL, 2 mmol) was added. After stirring at RT for 5 h, the MeOH was removed under reduced pressure. The aqueous solution was poured into a separatory funnel, diluted with 1 M HCl (2 mL, 2 mmol) and extracted with DCM (3×). The combined organics were dried over MgSO4, filtered and concentrated. The residue was dissolved in MeCN (4 mL) and treated with 2,4′-dibromoacetophenone (200 mg, 0.719 mmol), and triethylamine (0.100 mL, 0.719 mmol). After stirring for 15 h, the solvent was removed. The crude residue was purified by silica column chromatography (10% to 35% EtOAc/Hex) to afford the title compound (303 mg, 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]2[N:22]=[C:21]([NH:23][NH2:24])[NH:20][C:11]2=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH3:25][C:26](=O)[CH2:27][C:28](=O)[CH3:29].Cl>C(O)C>[CH3:25][C:26]1[CH:27]=[C:28]([CH3:29])[N:23]([C:21]2[NH:20][C:11]3=[N:12][C:13]([C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[F:1])[CH:9]=[C:10]3[N:22]=2)[N:24]=1
Reactant: CC(=O)CC(C)=O
Reactant: NNc1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)n(-c2nc3cc(-c4ccncc4F)c(-c4cccnc4)nc3[nH]2)n1
Yield: 25.9 %

Procedure:
A solution of 6-(3-fluoropyridin-4-yl)-2-hydrazino-5-pyridin-3-yl-3H-imidazo[4,5-b]pyridine (0.05 g, 0.15 mmol), pentane-2,4-dione (0.016 mL, 0.16 mmol) and hydrogen chloride aqueous solution in ethanol (1 mL) was heated in a sealed tube at 80° C. for 16 hours. The acidic pH was neutralized and then the solvent was evaporated and the crude mixture was purified by reverse phase chromatography (water/acetonitrile) to give the title compound (0.015 g, 25% of yield).
Reaction SMILES: [OH:1][C:2]([C:31]([F:34])([F:33])[F:32])([CH2:15][C:16]([CH3:30])([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2([CH3:29])OCC[O:25]2)[CH:19]=1)[CH3:17])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[CH:6]=[CH:5]1.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[C:24]([C:20]1[CH:19]=[C:18]([C:16]([CH3:30])([CH3:17])[CH2:15][C:2]([OH:1])([C:31]([F:32])([F:33])[F:34])[CH2:3][N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[CH:6]=[CH:5]2)[CH:23]=[CH:22][CH:21]=1)(=[O:25])[CH3:29]
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C2(C)OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: CC(=O)c1cccc(C(C)(C)CC(O)(Cn2ccc(=O)c3ccccc32)C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 1-{2-hydroxy-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]-2-trifluoromethylpentyl}-1H-quinolin-4-one (0.35 g, 0.75 mmol), ethanol (24 mL), water (4.8 mL), and pyridinium p-toluenesulfonic acid (95 mg, 0.37 mmol) was heated to reflux for 3 hours, cooled to room temperature, and concentrated in vacuo to remove most of the ethanol. The residue was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. Removal of the volatiles in vacuo afforded 1-[4-(3-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H-quinolin-4-one. Yield: 0.27 g (84%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cn1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cn1

Procedure:
To a mixture of methyl 5-methylpicolinate (1.25 g; 8.27 mmol) in carbon tetrachloride (45 mL) was added N-bromosuccinimide (1.78 g, 9.92 mmol) and benzoyl peroxide (0.205 g; 0.827 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 0 to 8% ethyl acetate in dichloromethane) to 0.450 g (24%) of methyl 5-(bromomethyl)picolinate as a beige solid.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[F:7][C:8]([F:20])([F:19])[C:9]1[CH:17]=[C:16]2[C:12]([C:13]([NH2:18])=[N:14][NH:15]2)=[CH:11][CH:10]=1>N1C=CC=CC=1>[F:20][C:8]([F:7])([F:19])[C:9]1[CH:17]=[C:16]2[C:12]([C:13]([NH:18][C:1](=[O:5])[CH:2]=[CH:3][CH3:4])=[N:14][NH:15]2)=[CH:11][CH:10]=1
Reactant: C/C=C/C(=O)Cl
Reactant: Nc1n[nH]c2cc(C(F)(F)F)ccc12
Solvent: c1ccncc1
Product: CC=CC(=O)Nc1n[nH]c2cc(C(F)(F)F)ccc12
Reaction time: 17 h

Procedure:
0.23 cm3 of crotonyl chloride is added to 500 mg of 6-trifluoro methyl-1H-indazole-3-amine, prepared as described in patent U.S. Pat. No. 3,133,081, in 10 cm3 of pyridine, cooled to about 10° C. The temperature is allowed to return to about 19° C. over 17 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 25 cm3 of tetrahydrofuran, 25 cm3 of ethyl acetate and 25 cm3 of distilled water. The organic phase is washed with 25 cm3 of distilled water. The combined organic phases are dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume) and collecting 30 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 30 cm3 of diisopropyl ether and then filtered off on a sinter funnel. After drying (90 Pa; 45° C.), 41 mg of N-[6-(trifluoromethyl)-1H-indazol-3-yl]-2-butenamide (E form) are obtained in the form of a white solid melting at 208° C.
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)(OC(C)(C)C)=O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2
Reactant: COc1cc2ncc(NC(=O)OC(C)(C)C)c(Cl)c2cc1OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncc(N)c(Cl)c2cc1OC
Yield: 55.2 %

Procedure:
3-BOCamino-4-chloro-6,7-dimethoxyquinoline (18 g) was dissolved in trifluoroacetic acid (200 ml) with stirring, triethylsilane (80 ml) was then added. Stirred at room temperature for 2 hours. Evaporated. The dark red oily residue was treated with ice/water and carefully basified with 880 ammonia. The resulting red gum was scratched and stirred upon which it slowly solidified. Solid was filtered off and washed with water. Dried to give 3-amino-4-chloro-6,7-dimethoxyquinoline (7 g). On standing overnight more solid came out of the filtrate this was filtered off washed with water and dried to give 3-amino-4-chloro-6,7-dimethoxyquinoline (3.5 g) (Total yield 83%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[I:16][C:17]1[CH:24]=[C:21]([CH:22]=[O:23])[C:20]([OH:25])=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:25][C:20]1[CH:19]=[CH:18][C:17]([I:16])=[CH:24][C:21]=1[CH:22]=[O:23]
Reactant: O=Cc1cc(I)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3ccc(I)cc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-iodosalicylaldehyde (496 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the mixture was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-iodobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)Cl>[Br:12][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:10][C:9]=1[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn2ccnc(Cl)c2n1
Solvent: ClCCl
Product: Cc1nc2c(Cl)nccn2c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a solution of 8-Chloro-2-methyl-imidazo[1,2-a]pyrazine (0.7 g, 4.18 mmol) in DCM (20 ml) is added N-bromosuccinimide (0.74 g, 4.18 mmol) and the reaction stirred at room temperature for 2 h. After this time the solution is washed with saturated aqueous solution of Na2CO3 (2×20 ml), dried (MgSO4), filtered and concentrated in vacuo to give 3-bromo-8-chloro-2-methyl-imidazo[1,2-a]pyrazine (0.771 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][C@@H:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][C:34]([OH:36])=[O:35].C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCCC1.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][C@@H:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][C:34]([OH:36])=[O:35])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)[C@H](N)CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H](CC(=O)O)C(C)(C)C)n3)c3cc(Cl)cnc32)cc1
Temperature: 135 °C

Procedure:
To a solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (0.100 g, 0.215 mmol: prepared in a similar manner as described below for Compound 25a in scheme 4) and (R)-3-amino-4,4-dimethylpentanoic acid, 2a, (0.031 g, 0.215 mmol) in tetrahydrofuran (1.66 mL) was added freshly ground Na2CO3 (0.068 g, 0.645 mmol) followed by acetonitrile (0.331 mL). The reaction mixture was heated to 135° C. for 30 minutes in a microwave reactor. The reaction mixture was slowly poured into 75 mL of 1N HCl. The pH of final solution was adjusted to 1. The aqueous was extracted with EtOAc (3×5 mL), washed with brine, dried over Na2SO4 and filtered to obtain a crude solid residue. The crude residue was purified via silica gel chromatography (0-10% MeOH—CH2Cl2 gradient) afforded 78 mg of the desired product 3a: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.9 minutes (M+H) 546.22.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([C:23]5[N:28]=[CH:27][C:26](B6OC(C)(C)C(C)(C)O6)=[CH:25][N:24]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.C1C[O:41]CC1>O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:18][N:19]([C:23]5[N:24]=[CH:25][C:26]([OH:41])=[CH:27][N:28]=5)[CH2:20][CH2:21][O:22]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: C1CCOC1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(B6OC(C)(C)C(C)(C)O6)cn5)CCO4)c3n2)cn1
Solvent: O
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(O)cn5)CCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
(S)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyrimidin-2-yl)morpholine 55 mg (0.11 mmol) was dissolved in THF 2 ml and H2O 2 ml, and NaBO3 16 mg (0.16 mmol) was added, followed by stirring at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:10), to give (S)-2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-ol 29 mg (two steps: 67%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([N:22]([C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([N:22]([C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)(=[NH:42])[NH2:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccccc1)c1ccc2c(C)cc(COc3ccc(C#N)cc3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(C(=O)c1ccccc1)c1ccc2c(C)cc(COc3ccc(C(=N)N)cc3)nc2c1

Procedure:
Prepared analogously to Example 1e from 2-[(4-cyanophenyl)-oxymethyl]-4-methyl-7-[N-(ethoxycarbonylmethyl)-benzoylamino]-quinoline and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[OH:14])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:21]([O:14][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=[CH:13][C:4]=1[CH2:1][CH:2]=[CH2:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: C=CCc1ccc2c(c1O)CCCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: C=CCc1ccc2c(c1OCc1ccccc1)CCCC2
Yield: 88.2 %

Procedure:
Treatment of 2-allyl-5,6,7,8-tetrahydronaphthalen-1-ol (18.48 g, 0.098 mol) with potassium carbonate (41.46 g, 0.300 mol), benzyl bromide (18.81 g, 0.110 mol), and tetrabutylammonium iodide (7.39 g, 0.020 mol) generally according to the procedure described for Intermediate 1 afforded 24.05 g (88%) of 2-allyl-5,6,7,8-tetrahydronaphthalen-1-yl benzyl ether as a pale yellow oil. Rf=0.39 (silica, ethyl acetate:hexanes 1:19); Anal. calcd. for C20H22O0.2H2O: C, 85.19; H, 8.01. Found: C, 84.95; H, 7.75.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>C1C=CC=CC=1>[C:1]1([S:7][C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[CH2:10][Cl:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(C(F)(F)F)ccc1Sc1ccccc1
Solvent: c1ccccc1
Product: FC(F)(F)c1ccc(Sc2ccccc2)c(CCl)c1

Procedure:
96 g of 2-(phenylthio)-5-trifluoromethyl-benzyl alcohol are dissolved in 450 ml of absolute benzene and heated to reflux. The solution thus obtained is treated dropwise over a period of 20 minutes with 48 ml of thionyl chloride and the mixture is subsequently stirred at reflux for 30 minutes. After cooling, the mixture is evaporated under reduced pressure. There is obtained 2-(phenylthio)-5-trifluoromethyl-benzyl chloride as a brown-yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.Cl[C:7]1[NH:8][CH2:9][CH2:10][N:11]=1.[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].[OH-].[Na+]>CO.O>[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[N:15]=[C:7]1[NH:8][CH2:9][CH2:10][NH:11]1
Reactant: ClC1=NCCN1
Reactant: Nc1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccccc1N=C1NCCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To 2-chloroimidazoline bisulfate (60.0 g, 300 mmoles) in methanol (600 ml) and water (150 ml) is added with stirring 2-chloroaniline (81.1 g, 67 ml, 636 mmoles). The heterogeneous mixture is stirred at ambient temperature overnight. After 20 hours the mixture is poured into ice water, made strongly alkaline with sodium hydroxide and extracted with dichloromethane twice. The organic extracts are washed once with water and once with saturated sodium chloride solution and then extracted with 2 N acetic acid (2×1 liter). The combined acid extracts are backwashed with dichloromethane, made strongly alkaline with sodium hydroxide, and once again extracted with dichloromethane twice. The dichloromethane extracts are combined, washed with water and then sodium chloride solution and finally dried and evaporated in vacuo. The solid residue (31 g) is dissolved in hot toluene, filtered, and diluted with hexane (total volume 3 liters). Colorless crystals separate which are filtered, washed with hexane and air-dried, to give 28.2 g of 2-(2-chlorophenylimino)imidazolidine, m.p. 133°-134° C.
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:21][NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[CH3:21][NH:22][C:23]([NH:25][C:26]1[CH:27]=[C:28]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]4[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=4)[C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:29]=[CH:30][CH:31]=1)=[O:24]
Reactant: COC(=O)c1cccc(-c2cnn3c(I)cnc3c2)c1
Reactant: CNC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)Nc1cccc(-c2cnc3cc(-c4cccc(C(=O)OC)c4)cnn23)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (2.8 mg, 0.0040 mmol) was added to a mixture of methyl 3-(3-iodoimidazo[1,2-b]pyridazin-7-yl)benzoate (0.050 g, 0.13 mmol), N-methyl-N′-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (44 mg, 0.16 mmol) and sodium carbonate (28 mg, 0.26 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) and then the reaction vessel containing the mixture was evacuated and refilled with nitrogen 3 times. The reaction was stirred at 100° C. overnight. To this mixture was added aqueous acetonitrile and then filtered, washed with aqueous AcCN, and dried to provide the product. LCMS (M+H)+: m/z=402.1
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]([F:29])([F:28])[CH2:23][C:24]([NH:26][NH2:27])=[O:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:27][NH:26][C:24](=[O:25])[CH2:23][C:22]([F:29])([F:28])[F:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC(=O)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (40 mL) were added 3,3,3-trifluoropropanehydrazide 228 (0.19 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2R,5S)-6-(benzyloxy)-7-oxo-N′-(3,3,3-trifluoropropanoyl)-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 229 (0.26 g, 72%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:12])[CH:3]=1.OS(O)(=O)=O.[CH3:18]O>>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(F)c(F)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)c(F)cc1O
Yield: 74 %

Procedure:
A mixture of 4,5-difluoro-2-hydroxybenzoic acid (20 mmol), methanol (100 ml) and concentrated H2SO4 (5 ml) was refluxed for 48 h. Then, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed with brine and a saturated NaHCO3 solution and neutralized with citric acid. The organic layer was dried over MgSO4 and concentrated in vacuo to give the product. Yield: 2.8 g (97% purity, 74% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[NH:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]3[CH2:21][CH2:20][CH2:19][C:13]=3[CH:14]=2)[N:9]=1.[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C.O>[CH3:7][C:8]1[N:17]([CH2:29][O:28][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:16](=[O:18])[C:15]2[C:10](=[CH:11][C:12]3[CH2:21][CH2:20][CH2:19][C:13]=3[CH:14]=2)[N:9]=1
Reactant: Cc1nc2cc3c(cc2c(=O)[nH]1)CCC3
Reactant: CC(C)(C)C(=O)OCCl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)CCC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (64 g) was added portionwise during 15 minutes to a stirred solution of 2-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (89 g) in DMSO (700 ml). The mixture was stirred at ambient temperature for 30 minutes. Chloromethyl pivaloate (131 g) was added dropwise during 30 minutes. The mixture was stirred at ambient temperature for 24 hours. The mixture was poured into a mixture of ammonium chloride (500 g) and a mixture (3 L) of ice and water. Ethyl acetate (2 L) was added and the mixture was filtered. The organic layer was dried (MgSO4) and evaporated. The residue was triturated under diethyl ether (500 ml). The mixture was cooled to 0° C. for 2 hours. The solid was isolated, washed with diethyl ether and dried. There was thus obtained 2-methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (72.4 g), m.p. 128° C.