Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+].Br[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].O>CO>[C:20]([O:19][C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(CCCNC(=O)OC(C)(C)C)C(=O)OC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To dimethyl malonate (102 mL), a solution of sodium methoxide in methanol (28%, 90.4 mL) was added at room temperature, and the mixture was stirred at 60° C. for 30 minutes. The white suspension was cooled to room temperature. Then, tert-butyl (3-bromopropyl)carbamate (106 g) was added thereto at once, and the mixture was stirred at room temperature for 12 hours. To the reaction solution, water was added, and organic matter was extracted with diethyl ether. The organic layer was washed with a 1 N aqueous sodium hydroxide and saturated sodium chloride solution in this order, then dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product of dimethyl {3-[(tert-butoxycarbonyl)amino]propyl}malonate. The obtained ester (94 g) was dissolved in methanol (100 mL). To the solution, a solution of lithium hydroxide monohydrate (13.6 g) in water (300 mL) and methanol (300 mL) was added at 0° C., and the mixture was stirred at room temperature for 15 hours. Methanol was distilled off under reduced pressure, and organic matter was extracted with ethyl acetate. 2 N hydrochloric acid (160 mL) was added to the aqueous layer, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (eluting solvent: methylene chloride-methylene chloride/methanol=10/1) to obtain the title compound (69.1 g).
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12](CC2C=CC=CC=2)[CH2:13][CH:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][C:5]=1[OH:31])(=[O:3])[NH2:2]>C(O)(C)C>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([OH:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:6][C:5]=1[OH:31])(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccc(OCCCN(Cc2ccccc2)CC(O)c2ccccc2)cc1O
Solvent: CC(C)O
Product: NC(=O)c1ccc(OCCCNCC(O)c2ccccc2)cc1O

Procedure:
16.6 g of crude N-[3-(4-carbamoyl-3-hydroxyphenoxy)propyl]-N-(2-hydroxy-2-phenyl-ethyl)-benzylamine are hydrogenated analogously to Example 4 and the reaction mixture is worked up. α-[N-[3-(4-Carbamoyl-3-hydroxy-phenoxy)-propyl]-aminomethyl]-benzyl alcohol with a melting point of 208°-210° is obtained by recrystallisation from isopropanol.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=O)[CH2:11][CH2:10]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:18][O:19][NH2:20]>N1C=CC=CC=1>[CH3:18][O:19][N:20]=[C:12]1[C:13]2[C:9](=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: CON
Reactant: O=C1CCc2cc(N3CCCCC3)ccc21
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCc2cc(N3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 40 h

Procedure:
5-Piperidin-1-ylindan-1-one (4.31 g, 20 mmol) in pyridine (20 ml) was treated with methoxyamine hydrochloride (1.84 g, 22 mmol). After stirring at ambient temperature for 40 hours, the solvent was removed under vacuum and the residue taken in water and extracted with diethyl ether. The combined organic layers were washed with water, dried with magnesium sulfate, filtered, and the filtrate was removed under vacuum to provide the title compound which was used without further purification. 1H NMR (CDCl3) δ 1.56-1.73 (m, 6H), 2.78-2.89 (m, 1H), 2.91-3.02 (m, 1H), 3.20-3.30 (m, 2H), 3.95 (s, 3H), 6.78 (m, 1H), 6.84 (m, 1H), 7.54 (d, 1H); MS (DCI): 245 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([Cl:13])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCC(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(F)(F)F
Yield: 57 %

Procedure:
Method 5 General Experimental: 4,4,4-Trifluorobutyric acid (70.0 mmol, 10.0 g) in CH2Cl2 (190 ml) was treated with oxalyl chloride (140 mmol, 12.3 ml) and DMF (1 drop), then heated to reflux for 1 h. Solvent and excess oxalyl chloride were removed from the volatile product by simple distillation of the reaction mixture at atmospheric pressure to provide crude 4,4,4-trifluorobutyric acid chloride (6.4 g). 1H NMR (CDCl3) δ 3.20 (2H, t, J=7.2), 2.65-2.45 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:19]([O-:21])=[O:20])=[CH:4][C:3]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1.[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[C:19]([OH:21])=[O:20])=[CH:4][C:3]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1
Reactant: O=C([O-])C(CC1CC1)c1cc(OCC2CC2)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(CC1CC1)c1cc(OCC2CC2)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.1 %

Procedure:
2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (80 mg) was dissolved in 10 mL of MeOH/THF/H2O (10 mL/10 mL/5 mL) and 57 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and then concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave compound 2-(6-chloro-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid (45 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.71 (d, 2H), 7.54 (d, 2H), 6.95 (d, 1H), 6.87 (s, 1H), 3.97 (d, 2H), 3.64 (t, 1H), 2.55 (m, 2H), 1.96 (m, 1H), 1.08 (m, 1H), 0.84 (m, 1H), 0.44 (m, 4H), 0.16 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C([Li])CCC.B(F)(F)F.[CH2:16]([CH:18]1[O:20][CH2:19]1)[Cl:17]>C1COCC1>[Cl:17][CH2:16][CH:18]([OH:20])[CH2:19][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C1CCCN1
Reactant: ClCC1CO1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCCN1CC(O)CCl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 16.4 %

Procedure:
2-Pyrrolidinone (4.47 g, 52.5 mmol) was mixed with THF (25 mL) and cooled to −78° C. Butyllithium (1.6 M in hexanes) (32.8 mL, 52.5 mmol) was added slowly then and the mixture was agitated for 10 minutes. Boron trifluoride ethereate (6.59 mL, 52.5 mmol) was added dropwise, followed by dropwise addition of epichlorohydrin (4.11 mL, 52.5 mmol). The resulting mixture was allowed to warm up overnight, then cooled and quenched with saturated sodium bicarbonate solution, and extracted 3 times with ethyl acetate. The extracts were washed with brine, dried and evaporated to give ˜4 g of crude oil. The crude oil was purified by chromatography on silica gel, eluting with 1-2% methanol/dichloromethane, to provide the title compound (1.53 g, 16.4% yield) as clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:22]#[N:23])([CH3:21])[CH2:9]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:9])[CH2:21][NH:23][CH2:22]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C#N)c2ccc(Br)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(c2ccc(Br)cc2)CNC1
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a stirred solution of toluene-4-sulfonic acid 2-(4-bromo-phenyl)-2-cyano-2-methyl-ethyl ester (10 g, 25.38 mmol) in dry tetrahydrofuran (100 mL) was added 1M lithium aluminum hydride (25.3 mL diluted with 25.3 mL of dry tetrahydrofuran) via syringe pump at −10° C. for 1 h and stirring was continued for 30 min at 10° C. The reaction mixture was quenched with water (1 mL), diluted with tetrahydrofuran (3 mL) followed by a 15% aqueous sodium hydroxide solution (1 mL) and water (3 mL), and filtered through a Celite® pad. The filtrate was concentrated in vacuo. Flash chromatography (8% methanol/methylene chloride) afforded 3-(4-bromo-phenyl)-3-methyl-azetidine as an off-white solid (4.0 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (s, 3H) 2.42-2.57 (m, 1H) 3.40 (d, J=7.34 Hz, 2H) 3.72 (d, J=7.34 Hz, 2H) 7.15 (d, J=8.80 Hz, 2H) 7.39-7.61 (m, 2H). LC-MS calcd. for C10H12BrN [M+] 226, obsd. 226.0/228.2.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].C[O-].[Na+].[CH3:12][C:13]([CH3:32])([CH3:31])[CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]([F:30])([CH3:29])[C:25](OC)=[O:26])=[CH:20][C:18]=2[N:19]=1.[Cl-].[NH4+]>O1CCCC1.O>[Cl:8][C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][C:25](=[O:26])[C:24]([C:21]1[CH:22]=[CH:23][C:17]2[O:16][C:15]([CH2:14][C:13]([CH3:31])([CH3:12])[CH3:32])=[N:19][C:18]=2[CH:20]=1)([F:30])[CH3:29]
Reactant: Cc1nsc(N)c1Cl
Reactant: COC(=O)C(C)(F)c1ccc2oc(CC(C)(C)C)nc2c1
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nsc(NC(=O)C(C)(F)c2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
5-Amino-4-chloro-3-methylisothiazole (0.28 g, 0.00188 mol) was added to a suspension of sodium methoxide (0.24 g, 0.004 mol) in tetrahydrofuran (6 ml) and the mixture was stirred at room temperature for 20 minutes. A solution of methyl 2-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]-2-fluoropropionate (0.50 g, 0.00171 mol) in tetrahydrofuran (2 ml) was added, dropwise, and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water, acidified with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:hexane 12:88, to give the desired product (0.575 g) as a pale yellow gum.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH:4]=[CH2:5].Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([C:26]#[N:27])[N:9]=1>C1COCC1>[CH2:3]([O:6][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([C:26]#[N:27])[N:9]=1)[CH:4]=[CH2:5]
Reactant: COc1ccc2c(Cl)nc(C#N)c(-c3ccccc3)c2c1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (60% in mineral oil, 14 mg) in 2 mL TEF was added 23 uL of allyl alcohol. The mixture was stirred for 15 min at room temp, then 100 mg of 1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile in 1.5 ml THF was added via cannula. The reaction was heated to 66 C for 16 h, then cooled to room temp, quenched with saturated aqueous NH4Cl, and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic solution was washed once with brine, then dried (Na2SO4) and concentrated. Flash chromatography (35 g silica, 3-25% EA/hex) gave a white solid.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].C(=O)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CS(C)=O.O.CC(O)=O.N1CCCCC1>[C:11]1([CH2:10]/[CH:9]=[CH:1]/[CH2:2][C:3]([OH:5])=[O:4])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=CCCc1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=C(O)C/C=C/Cc1ccccc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A solution of malonic acid (17.06 g, 163.96 mmol) in DMSO (65 mL) was treated with a solution of AcOH (0.1 mL, 1.49 mmol) and piperidine (0.15 mL, 1.49 mmol) in DMSO (4 mL). The reaction solution was warmed to 65° C. and hydrocinnamaldehyde (10 g, 74.53 mmol) was added dropwise within 1.5 hr. After the addition ended, the reaction mixture was stirred for further 2 h at 65° C. The solution was cooled to room temperature, taken up in H2O and extracted with Et2O. The combined organic extracts were washed with 5% aqueous KHSO4 and brine, dried over MgSO4, and evaporated to dryness. The crude compound was purified by a silica gel column to produce the title compound (10.4 g, 75˜90%)
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[S:7][C:8]([CH3:11])=[CH:9][N:10]=1)=[O:4].ClC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:35][C:36]1[CH:41]=[C:40](I)[CH:39]=[C:38]([Cl:43])[CH:37]=1.[OH-].[NH4+].O>CN1CCCC1=O>[Cl:35][C:36]1[CH:41]=[C:40]([N:10]2[CH:9]=[C:8]([CH3:11])[S:7]/[C:6]/2=[N:5]\[C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])[CH:39]=[C:38]([Cl:43])[CH:37]=1
Reactant: Cc1cnc(NC(=O)C(C)(C)C)s1
Reactant: Clc1cc(Cl)cc(I)c1
Agent: Clc1cc2cccnc2c2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cn(-c2cc(Cl)cc(Cl)c2)/c(=N/C(=O)C(C)(C)C)s1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
In a 4 mL vial charged with a stir bar, 2,2-dimethyl-N-(5-methyl-1,3-thiazol-2-yl)propanamide (71 mg, 0.35 mmol) was added, followed by copper(I) trifluoromethanesulfonate benzene complex (35 mg, 0.07 mmol), 5-chloro-1,10-phenanthroline (30 mg, 0.14 mmol) and cesium carbonate (126 mg, 0.39 mmol). A loose cap with septum was placed on the vial and the vial was placed under vacuum in a vacuum oven for 30 minutes. The solid mixture was purged with nitrogen gas a couple of times. Then 1,3-dichloro-5-iodobenzene (115 mg, 0.42 mmol) dissolved in 1-methyl-2-pyrrolidinone (1.0 mL) was added to the solid mixture. The vial was capped and placed on a heater/stirrer and heated to 120° C. overnight. Then a 1 mL solution of concentrated ammonium hydroxide/water (1:2) was added. The reaction was filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (C8, gradient 10-100% acetonitrile/water/0.1% trifluoroacetic acid).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.CO>[CH2:16]([O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cccc(OCc3ccccc3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cccc(OCc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 7-benzyloxyindole-2-carboxylic acid ethyl ester in 600 ml of tetrahydrofuran and 200 ml of methanol is combined with 500 ml of 2N sodium hydroxide solution and stirred for 3 hours at room temperature. The reaction mixture is then acidified under ice cooling with 10% hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are dried, treated with active carbon, and concentrated. The residue is recrystallized from toluene, thus producing 35 g of 7-benzyloxyindole-2-carboxylic acid, mp 166°-168° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:31])=[CH:5][C:6]([F:30])=[C:7]([C@:9]23[CH2:18][O:17][C@@H:16]([CH2:19][F:20])[CH2:15][C@H:14]2[CH2:13][S:12][C:11]([NH:21]C(=O)C2C=CC=CC=2)=[N:10]3)[CH:8]=1)#[N:2].NC1SC[C@@H]2C[C@H](COCC3C=CC=CC=3)OC[C@]2(C2C(F)=CC(F)=C(C=2)C#N)N=1>>[NH2:21][C:11]1[S:12][CH2:13][C@@H:14]2[CH2:15][C@H:16]([CH2:19][F:20])[O:17][CH2:18][C@:9]2([C:7]2[C:6]([F:30])=[CH:5][C:4]([F:31])=[C:3]([CH:8]=2)[C:1]#[N:2])[N:10]=1
Reactant: N#Cc1cc([C@]23CO[C@@H](CF)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c(F)cc1F
Agent: N#Cc1cc([C@]23CO[C@@H](COCc4ccccc4)C[C@H]2CSC(N)=N3)c(F)cc1F
Product: N#Cc1cc([C@]23CO[C@@H](CF)C[C@H]2CSC(N)=N3)c(F)cc1F

Procedure:
N-[(4aR,6R,8aS)-8a-(5-Cyano-2,4-difluorophenyl)-6-(fluoromethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C14) was converted to the product using the method described for the synthesis of 5-[(4aR,6R,8aS)-2-amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile (2) in Example 2. Yield: 67.0 mg, 0.197 mmol, 88%. LCMS m/z 342.2 [M+H+]. 1H NMR (400 MHz, CD3OD), δ 7.64 (t, J=7.9 Hz, 1H), 7.31 (dd, J=12.1, 9.2 Hz, 1H), 4.41-4.48 (m, 1H), 4.29-4.36 (m, 1H), 4.04 (dd, J=11, 2.4 Hz, 1H), 3.83-3.93 (m, 1H), 3.69 (d, J=11.1 Hz, 1H), 2.86-2.97 (m, 2H), 2.69-2.73 (m, 1H), 1.82 (qd, J=12.4, 2.7 Hz, 1H), 1.52 (ddd, J=13.2, 4.2, 2.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:49]([O:51][C:52](=[O:56])[CH2:53][NH:54][CH3:55])[CH3:50]>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:49]([O:51][C:52](=[O:56])[CH2:53][N:54]([C:10](=[O:11])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:16])=[O:17])[CH3:55])[CH3:50]
Reactant: CCOC(=O)CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C)C(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a solution of compound A (10.0 g, 25.7 mmol) in DMF (100 mL) was added HOBt (5.2 g, 38.5 mmol) and the reaction mixture was cooled to −10° C. To this reaction mixture, EDC-HCl (5.4 g, 28.2 mmol) was added in portions over 10 min and stirred at −10° C. for 20 min. To the reaction mixture, Sarcosine ethyl ester (256.8 mmol) in CHCl3 (300 mL) was added drop wise over 30 min. The reaction mixture was stirred at this temperature for 30 min followed by stirring at ambient temperature overnight. Solvents were then removed in vacuo, and the residue was dissolved in EtOAc (500 mL), washed with water (3×300 mL), saturated aqueous NaHCO3 (2×300 mL) and brine (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford compound B (11.5 g, 91%) as a cream solid. LC-MS [M+H] 489.5 (C19H28N4O9S+H, calc: 489.3). Purity >95% (UV/254 nm). Compound B was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH3:11][C:12](OC(C)=O)=O>CC(O)=O>[CH3:11][C:12]1[NH:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=1
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 150 °C

Procedure:
To a solution of 3,4-diaminobenzonitrile (500 mg) in AcOH (10 ml) was added Ac2O (372 μl) at room temperature. The reaction mixture was refluxed for 15 hours (oil bath at 150° C.). It was cooled to room temperature, and concentrated until the amount of AcOH was reduced to a half. It was neutralized with an aqueous Na2CO3 solution, and extracted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution and saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 2-methyl-1H-benzimidazole-5-carbonitrile (390 mg) as a pale red one.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:19]([O:26][C:27](=[O:30])[CH2:28][NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O:31]=[C:32]1[C:41](=[O:42])[NH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([S:43](Cl)(=[O:45])=[O:44])[CH:38]=2)[NH:33]1>>[CH2:19]([O:26][C:27]([CH2:28][NH:29][S:43]([C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:31])[C:41](=[O:42])[NH:40]2)(=[O:44])=[O:45])=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(CNS(=O)(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1)OCc1ccccc1
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of 4.14 g (0.03 mole) of potassium carbonate in 25 ml of water 10.12 g (0.03 mole) of aminoacetic acid benzyl ester tosylate are added in small portions, under stirring. Then 5.21 g (0.02 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added to the mixture, it is stirred at room temperature for 6 hours and allowed to stand for 16 hours. The separated crystals are filtered off, washed with water and acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated with water. Thus 3.50 g (45%) of N-(benzyl-oxycarbonylmethyl)-1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxaline sulfonamide are obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS([O:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47]C[CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:45][CH2:44][N:43]4[CH2:42][CH2:41][O:40][CH2:47][CH2:48]4)=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(O)cc3)nn3ccnc23)n1
Reactant: CS(=O)(=O)OCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(OCCN4CCOCC4)cc3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 80.1 %

Procedure:
To a mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc) to give N-(6-(2-Methylpyrrolidin-1-yl)pyridin-2-yl)-6-(4-(2-morpholinoethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (40 mg, 80%). 1H NMR (300 MHz, CDCl3): δ 8.63 (s, 1H), 8.05-7.90 (m, 4 h), 7.57 (s, 1H), 7.42 (t, 1H, J=8.0 Hz), 7.04-7.01 (m, 2H), 6.22 (d, 1H, J=7.5 Hz), 6.04 (d, 1H, J=8.4 Hz), 4.30-4.19 (m, 3H), 3.80-3.77 (m, 4 h), 3.70-3.64 (m, 1H), 3.51-3.48 (m, 1H), 2.87 (t, 2H, J=5.7 Hz), 2.65-2.62 (m, 4 h), 2.17-2.05 (m, 3H), 1.78 (brs, 1H), 1.26 (d, 3H, J=6.3 Hz). LC/MS: 500 [M+H]+, tR=1.11 min. HPLC: 99.73% at 214 nm, 99.60% at 254 nm, tR=99.73% min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[C:6]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[N:5]=[C:4]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: FC(F)(F)Oc1ccc(Nc2nc(Cl)cc(Cl)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cc(-c3ccc(F)cc3)nc(Nc3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
(4,6-Dichloro-pyrimidin-2-yl)-(4-trifluoromethoxy-phenyl)-amine (0.3 g, 0.92 mmol) was reacted with 4-fluoro-phenyl boronic acid (0.25 g, 1.8 mmol) in presence of a catalyst Pd(OAc)2 (7 mg, 0.02 mmol) and sodium carbonate (0.78 g, 7.4 mmol) in a solvent DMF (10 mL) at 80° C. for 12 hours. Followed by work up and column purification to yield [4,6-bis-(4-fluoro-phenyl)-pyrimidin-2-yl]-(4-trifluoromethoxy-phenyl)-amine.