Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([OH:22])=O)[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH:26]1[CH2:35][CH2:34][C:33]2[N:32]=[C:31]([NH2:36])[N:30]=[CH:29][C:28]=2[CH2:27]1>>[NH2:36][C:31]1[N:30]=[CH:29][C:28]2[CH2:27][CH:26]([CH2:25][NH:24][C:20](=[O:22])[CH2:19][N:14]3[C:15]([CH3:18])=[CH:16][CH:17]=[C:12]([NH:11][S:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)(=[O:9])=[O:10])[C:13]3=[O:23])[CH2:35][CH2:34][C:33]=2[N:32]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Reactant: NCC1CCc2nc(N)ncc2C1
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NCC1CCc2nc(N)ncc2C1

Procedure:
The title compound was prepared from 2-[3-[(benzylsulfonyl)amino]-6 -methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 6-(aminomethyl)-5,6,7,8-tetrahydro-2-quinazolinamine using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a white solid compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([CH3:17])[N:11]=1.O>O1CCCC1>[Cl:9][C:10]1[N:15]=[C:14]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(F)cc2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
4-Fluorophenol (103 mg, 0.92 mmol) and potassium-tert-butylate (113 mg, 1.0 mmol) were dissolved in 7 mL of tetrahydrofurane. 2,4-dichloro-6-methylpyrimidine (150 mg, 0.92 mmol) was added and the mixture stirred at 20° C. overnight. Water was added and the mixture extracted with diethyl ether. Chromatography of the crude reaction product on silica gel using a heptane/ethyl acetate as an eluent gave the title compound (150 mg, 68%) as a slightly yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.50-7.40 (m, 2H), 7.28 (t, 1H), 7.14 (d, 2H), 6.57 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[N:1]1[C:21]([NH2:22])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1Cl
Reactant: COc1ccc(CC#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2nnn(-c3ccc(Cl)cc3Cl)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2,4-dichloro-benzene (0.400 g, 1 eq) and commercial (4-methoxy-phenyl)-acetonitrile (0.376 g, 1.2 eq) in ethanol (3 ml) kept under nitrogen, a solution of sodium methoxide (0.172 g, 1.5 eq) in ethanol (2 ml) is added drop-wise (15 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (25 ml), washed with water (2×25 ml), dried over MgSO4 and evaporated to dryness. The yellow semisolid residue (0.750 g) is purified by crystallization from a mixture of dichloromethane and hexane (1:1), to afford the title compound as white solid (0.315 g, 44% yield). M.p. 149.2-150.7° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:17])[CH3:16])[CH:5]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:30]=[CH:29]3)O1>>[C:10]([C:6]1[CH:5]=[C:4]([NH:14][C:15](=[O:17])[CH3:16])[CH:3]=[C:2]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:32]=3)[CH:27]=2)[C:7]=1[O:8][CH3:9])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC1(C)OB(c2ccc3cc(NS(C)(=O)=O)ccc3c2)OC1(C)C
Reactant: COc1c(Br)cc(NC(C)=O)cc1C(C)(C)C
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(NC(C)=O)cc1C(C)(C)C
Temperature: 90 °C

Procedure:
N-(3-bromo-5-tert-butyl-4-methoxyphenyl)acetamide (24 mg, 0.08 mmol) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-yl)methanesulfonamide (64 mg, 0.18 mmol), were reacted in the same manner as Example 43 Part C, heating in an oil bath at 90° C. for 18 hours to give crude product which was purified on an Isco 4 g silica cartridge eluting with 5% methanol/chloroform to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H), 2.02 (s, 3H), 3.06 (s, 3H), 3.16 (s, 3H), 7.34-7.76 (m, 5H), 7.84-8.00 (m, 3H), 9.91 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1.I[C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O.[Cu]I>[C:13]([C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[N:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[CH:2]1)#[N:14]
Reactant: COC(=O)c1c[nH]cn1
Reactant: N#Cc1ccccc1I
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cn(-c2ccccc2C#N)cn1
Temperature: 90 °C

Procedure:
A mixture of methyl 1H-imidazole-4-carboxylate (400 mg, 0.003 mol), 2-iodobenzonitrile (800 mg, 0.0035 mol), L-proline (0.073 g, 0.00063 mol), potassium carbonate (0.88 g, 0.0063 mol) and copper(I) iodide (0.060 g, 0.00032 mol) in DMSO (8 mL) was allowed to stir and heated at 90° C. in a sealed tube overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to afford methyl 1-(2-cyanophenyl)-1H-imidazole-4-carboxylate. LCMS: (FA) ES+ 228.1
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C@@H:17]2[NH:21][C@@H:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[C@H:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])=[C:10]([O:45][CH3:46])[CH:9]=1)(=O)=[O:3].CO>CCOC(C)=O>[CH3:1][S:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C@@H:17]2[NH:21][C@@H:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@:19]3([C:34]4[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[C@H:18]2[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=2[F:44])=[O:16])=[C:10]([O:45][CH3:46])[CH:9]=1)=[O:3]
Reactant: COc1cc(OCCS(C)(=O)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(OCCS(C)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In the preparation of chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2-methanesulfonyl-ethoxy)-2-methoxy-phenyl]-amide in Example 170, the second product chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2-methanesulfinyl-ethoxy)-2-methoxy-phenyl]-amide was obtained by chromatography (10% MeOH in EtOAc) as a yellow solid (Yield 63 mg, 36%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][C:18]=1[F:25]>>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][C:18]=1[F:25]
Reactant: Fc1cc(CBr)ccc1Br
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccc(Br)c(F)c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 4-bromo-3-fluorobenzyl bromide
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:37])([CH2:34][CH2:35][CH3:36])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:33])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=3[F:31])=[CH:20][C:19]([CH3:32])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:37])([CH2:34][CH2:35][CH3:36])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:33])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=3[F:31])=[CH:20][C:19]([CH3:32])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3cccc(F)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3cccc(F)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 35 mg (0.066 mmol) of rac-{1-[({7-[(2,3-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 118A) in 2 ml of dichloromethane was admixed with 0.079 ml (1.03 mmol) of trifluoroacetic acid. The resulting solution was stirred at room temperature overnight. The solvent was drawn off under reduced pressure and the residue was purified by preparative HPLC chromatography (Method 21), which gave 6 mg (27% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([N:29]=[C:30]=[O:31])=[O:28])=[CH:22][CH:21]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:30]([NH:29][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:31])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccncc2[N+](=O)[O-])c(F)c1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccncc2[N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
A solution of 3-fluoro-4-(3-nitropyridin-4-yloxy)benzenamine (158 mg, 0.63 mmol) in THF (3 mL) was treated with a solution of solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 1.3 mmol) and stirred at room temperature for 2 h then at 50° C. for 5 min. The mixture was concentrated and the residue treated with DMF (15 mL) and SiO2 (150 mg) and the mixture concentrated to dryness under vacuum and applied to a SiO2 column. The column was eluted with 20-60% EtOAc/hexanes to give the product, which was further purified by trituration with isopropyl ether to give a pale yellow solid (120 mg, 25%). 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.63 (s, 1H), 9.19 (s, 1H), 8.67 (d, 1H, J=5.6 Hz), 7.85 (d, 1H, J=11.7 Hz), 7.46-7.45 (m, 2H), 7.39-7.35 (m, 2H), 7.18 (dd, 2H, J=8.6, 8.6 Hz), 7.01 (d, 1H, J=6.1 Hz), 3.76 (s, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20]C)=[O:19])(=[O:13])=[O:12]>[OH-].[Na+]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([OH:20])=[O:19])(=[O:13])=[O:12]
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2ccc3ccccc3c2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(NS(=O)(=O)c2ccc3ccccc3c2)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
A solution of 10.8 g (31.7 mmol) of methyl 3-((2-naphthalenyl)sulfonyl)aminobenzoate (12) as prepared in Example 2 in 100 mL of 1N NaOH was stirred at 50° C. for 20 min. The reaction mixture was quenched with excess 2N HCl, diluted with tetrahydrofuran to dissolve the suspension. Ether was added to induce phase separation. The organic extract was dried (MgSO4) and the solvent removed in vacuo. Trituration from ether/tetrahydrofuran/hexane gave 10.0 g of the title compound: 1H-NMR (200 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.13 (t, 2H), 7.99 (d, 1H), 7.54-781 (m, 5H), and 7.77-7.43 ppm (m, 2H). Mass spectrum (MALDI-TOF) calcd. for C17H13NO4S: 328.1 (M+H) and 350.0 (M+Na). Found: 328.7 (M+H), 349.8 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([C:15]#[N:16])[C:9]2=[O:17])=[CH:4][CH:3]=1.O1CCCC1.[Br:23]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[Br:23][C:12]1[CH:11]=[C:10]([C:15]#[N:16])[C:9](=[O:17])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]=1[CH3:14]
Reactant: Cc1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(Br)cc(C#N)c(=O)n1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1 g, 4.05 mmol) in acetonitrile (10 mL)/tetrahydrofuran (5 mL) was added N-bromosuccinimide (792 mg, 4.46 mmol), and the mixture was stirred at 60° C. overnight. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with diethyl ether and collected by filtration to give the title compound (1.07 g, 86%) as a slightly yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.[Cl-].[NH4+].C([N:16](CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH2:16])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(N)=O)cc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.6 %

Procedure:
A mixture of 2-chloro-6-methylpyridine-4-carboxylic acid (9.6 g, 56 mmol), ammonium chloride (8.9 g, 170 mmol), triethylamine (23 mL, 170 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (13 g, 67 mmol), 1-hydroxybenzotriazole (9.1 g, 67 mmol) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure, aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The obtained residue was washed with diisopropyl ether to give the title compound (5.6 g, 59%) as a pale-brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]2)=[CH:6][CH:7]=1)[CH3:25]
Reactant: CCI
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(N2CC(C(=O)OC)CC2=O)cc1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
Methyl 1-(4-hydroxyphenyl)-5-oxo-3-pyrrolidinecarboxylate (3.00 g) is dissolved in dimethylformamide (30 ml) and thereto are added potassium carbonate (4.40 g) and ethyl iodide (2.56 ml). The mixture is heated with stirring at 80° C. for 22 hours. The reaction solution is concentrated under reduced pressure and the resulting residue is neutralized by adding thereto water and 1N hydrochloric acid. The precipitated crystal is collected by filtration and washed with water to give the desired product (3.07 g), m.p. 67°-69° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([F:23])[CH:22]=1)[C:7]([C:9]1[CH:18]=[C:17]([CH3:19])[C:12]2[NH:13][C:14](=[O:16])[O:15][C:11]=2[CH:10]=1)=[O:8].I[CH3:25]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:20]=[C:21]([F:23])[CH:22]=1)[C:7]([C:9]1[CH:18]=[C:17]([CH3:19])[C:12]2[N:13]([CH3:25])[C:14](=[O:16])[O:15][C:11]=2[CH:10]=1)=[O:8]
Reactant: CI
Reactant: Cc1cc(C(=O)c2cc(F)cc(F)c2)cc2oc(=O)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(F)cc(F)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.349 g (8.00 mmol) sodium hydride (55%, suspension in mineral oil) were added at RT to 2.20 g (7.61 mmol) 6-(3,5-difluoro-benzoyl)-4-methyl-3H-benzoxazol-2-one in 10 mL DMF. The reaction mixture was stirred for 30 min at RT. Then 0.634 mL (10.0 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. Then another 0.1 mL iodomethane were added and the mixture was stirred further at RT. After the addition of ice water the mixture was extracted with EtOAc. The organic phase was washed with water, dried on sodium sulphate and evaporated down i. vac. The residue was purified by flash chromatography. The fractions containing the product were combined, evaporated down and dried i. vac.
Reaction SMILES: [CH2:1]([NH:5][NH2:6])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].O>ClCCl>[C:18]1([O:17][C:15]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[NH2:6])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCNN
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCN(N)C(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
To a solution of butylhydrazine (370 mg, 4.20 mmol) and triethylamine (0.88 mL, 6.30 mmol) in dichloromethane (15 mL) at 0° C. was added phenyl chloroformate (0.53 mL, 4.20 mmol). The reaction mixture was stirred and allowed to warm up to room temperature overnight. Water (20 mL) was then added to the reaction mixture. The aqueous layer was extracted with dichloromethane (20 mL×2). The combined organic layers were dried (MgSO4). Filtration and evaporation under vacuum, followed by purification by flash column chromatography provided the title compound (250 mg, 29%). 1H NMR (400 MHz, CHCl3) δ 7.40-7.10 (m, 5H), 4.20 (t, J=7.1 Hz, 2H), 3.60 (br s, 2H), 1.71 (m, 2H), 1.41 (m, 2H), 0.98 (t, J=7.3 Hz, 3H). MH+209.
Reaction SMILES: CS([C:5]1[C:6]2[N:7]([C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH:8]=[CH:9][N:10]=1)(=O)=O.OC(C(F)(F)F)=O.[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[N:7]3[CH:8]=[CH:9][N:10]=[C:5]([NH:29][CH2:30][C:31]4[CH:32]=[C:33]([S:37]([NH2:40])(=[O:38])=[O:39])[CH:34]=[CH:35][CH:36]=4)[C:6]3=[N:13][CH:12]=2)=[CH:19][CH:18]=1
Reactant: NCc1cccc(S(N)(=O)=O)c1
Reactant: COc1ccc(-c2cnc3c(S(C)(=O)=O)nccn23)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cnc3c(NCc4cccc(S(N)(=O)=O)c4)nccn23)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
A mixture of 8-Methanesulfonyl-3-(4-methoxy-phenyl)-imidazo[1,2-a]pyrazine (0.150 g, 0.495 mmol), 3-Aminomethyl-benzenesulfonamide TFA salt (0.223 g, 0.742 mmol), DIPEA (0.260 mL, 1.50 mmol) in NMP (0.66 mL) is stirred at 100° C. for 16 hours. The reaction mixture is diluted with AcOEt, washed with water and brine, dried with MgSO4 anh., filtered and evaporated. The crude is purified by column chromatography using a gradient of (Pet.Ether 40-60/AcOEt: 1/1 to 0/1) to give 3-{[3-(4-Methoxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzenesulfonamide as a pale yellow solid (0.135 g, 67%). LC-MS m/z 410 [M+H]+.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[N:14]=[C:13]([NH:19][C:20]([NH:22][C@@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH3:24])=[O:21])[CH:12]=[C:11]4[NH:31][N:32]=[C:9]2[C:10]=34)=CC=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH3:18][C@@H:17]1[CH2:16][C:15]2[N:14]=[C:13]([NH:19][C:20]([NH:22][C@@H:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH3:24])=[O:21])[CH:12]=[C:11]3[NH:31][N:32]=[C:9]([C:10]=23)[NH:8]1
Reactant: COc1ccc(CN2c3n[nH]c4cc(NC(=O)N[C@H](C)c5ccccc5)nc(c34)CC2C)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1Cc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3[nH]nc(c23)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(3-(4-methoxybenzyl)-4-methyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-((R)-1-phenylethyl)urea (100 mg, 0.143 mmol) was taken in TFA (0.7 mL) and stirred at room temperature for 30 minutes. Triethylsilane (91 uL, 0.572 mmol) was added to the reaction mixture and stirred for 15 minutes at room temperature then heated at 80° C. for 30 minutes. The reaction mixture was concentrated, taken in DCM and washed with aqueous sodium bicarbonate, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-15% MeOH-DCM) followed by SFC separation with a Chiralpak AS-H column gave 1-((R)-4-methyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-((R)-1-phenylethyl)urea as peak 1. MS ESI calc'd. for C18H20N6O [M+H]+ 337. found 337. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.90 (s, 1H), 8.40 (br, s, 1H), 7.32 (dd, J=3.4, 7.9, 4H), 7.24-7.14 (m, 1H), 7.00 (s, 1H), 6.30 (s, 1H), 4.83 (m, 1H), 3.65 (m, 1H), 2.88-2.77 (m, 1H), 2.67-2.53 (m, 1H), 1.39 (d, J=6.9, 3H), 1.29 (d, J=6.3, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH:3]=[CH2:4].[CH:14]1([NH2:17])[CH2:16][CH2:15]1.[BH4-].[Na+]>CO>[CH2:1]([C:5]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:6]=1[CH2:7][NH:17][CH:14]1[CH2:16][CH2:15]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCc1cc(F)ccc1C=O
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCCc1cc(F)ccc1CNC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
A mixture of 2-(but-3-en-1-yl)-4-fluorobenzaldehyde (50 mg, 0.281 mmol) and cyclopropanamine (16.02 mg, 0.281 mmol) in MeOH (2 mL) was stirred at rt for 30 min. Sodium borohydride (5.31 mg, 0.140 mmol) was added and stirred at rt for 1 h. It was then quenched with NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 25% EtOAc/hexane to isolate N-(2-(but-3-en-1-yl)-4-fluorobenzyl)cyclopropanamine (20 mg, 0.091 mmol, 32.5% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.26 (dd, J=8.3, 6.1 Hz, 1H), 6.93-6.82 (m, 2H), 5.95-5.84 (m, 1H), 5.13-5.00 (m, 2H), 3.83 (s, 2H), 2.81-2.75 (m, 2H), 2.41-2.33 (m, 2H), 2.18 (tt, J=6.6, 3.5 Hz, 1H), 0.51-0.44 (m, 2H), 0.43-0.35 (m, 2H).