Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([CH:20]=O)[N:17]=[N:16]1.[CH3:22][N:23](CC#C)[CH:24]1[C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCCl>[CH3:22][N:23]([CH2:20][C:18]1[N:17]=[N:16][N:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH:19]=1)[CH:24]1[C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26][CH2:25]1
Reactant: C#CCN(C)C1CCCc2cccnc21
Reactant: O=Cc1cn(CCCN2C(=O)c3ccccc3C2=O)nn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(Cc1cn(CCCN2C(=O)c3ccccc3C2=O)nn1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of 1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1H-1,2,3-triazole-4-carbaldehyde, 22, (0.24 g, 0.84 mmol), N-methyl-N-(prop-2-ynyl)-5,6,7,8-tetrahydroquinolin-8-amine, 5, (0.17 g, 1.01 mmol), sodium triacetoxyborohydride (0.27 g, 1.26 mmol) and a catalytic amount of acetic acid (2 drops) in 1,2-dichloroethane (10 mL) was warmed to 65° C. and stirred at this temperature for 24 h. The reaction mixture was cooled to room temperature. A saturated aqueous solution of sodium bicarbonate was added. The product was extracted with dichloromethane. The combined organic layers were dried over potassium carbonate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-5% methanol/CH2Cl2) to afford 0.19 g (80% yield) of the desired product, AH: 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=4.4 Hz, 1H), 7.79-7.76 (m, 2H), 7.71 (s, 1H), 7.68-7.65 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.00 (dd, J=4.8, 8.0 Hz, 1H), 4.32 (dt, J=3.2, 7.2 Hz, 2H), 3.91 (dd, J=6.0, 9.2 Hz, 1H), 3.77-3.66 (m, 4H), 2.82-2.70 (m, 1H), 2.70-2.60 (m, 1H), 2.29 (s, 3H), 2.29-2.23 (m, 2H), 2.12-2.02 (m, 1H), 2.02-1.92 (m, 1H), 1.92-1.80 (m, 1H), 1.70-1.56 (m, 1H); ESI+ MS: m/z (rel intensity) 431.2 (100, [M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[NH2:11][C:12]([NH2:14])=[NH:13].[ClH:15]>>[NH:1]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[C:12]([NH2:13])=[NH:11].[ClH:15].[NH:13]([C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[C:12]([NH2:14])=[NH:11]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: N=C(N)N
Agent: Cl
Product: N=C(N)Nc1cccc(C(=O)O)c1

Procedure:
3-guanidinobenzoic acid was prepared from 3-aminobenzoic acid by the method of Miller, et al., cited in Example 1C. The guanidine was treated with ethereal hydrogen chloride to give 3-guanidino-benzoic acid hydrochloride.
Reaction SMILES: [N:1]1([C:9]([C@@H:11]([C@H:21]([CH2:34][OH:35])[O:22][CH2:23][P:24]([O:30][CH:31]([CH3:33])[CH3:32])([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[O:12]C(=O)C2C=CC=CC=2)=[O:10])[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].N>CO>[N:1]1([C:9]([C@@H:11]([C@H:21]([CH2:34][OH:35])[O:22][CH2:23][P:24]([O:30][CH:31]([CH3:33])[CH3:32])([O:26][CH:27]([CH3:28])[CH3:29])=[O:25])[OH:12])=[O:10])[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: CC(C)OP(=O)(CO[C@@H](CO)[C@@H](OC(=O)c1ccccc1)C(=O)n1ccc(=O)[nH]c1=O)OC(C)C
Agent: N
Solvent: CO
Product: CC(C)OP(=O)(CO[C@@H](CO)[C@@H](O)C(=O)n1ccc(=O)[nH]c1=O)OC(C)C
Yield: 95 %

Procedure:
A solution of 13 (2.03 g, 4.0 mmol) in MeOH saturated with ammonia (300 mL) was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=20:1) to give compound 17 (1.52 g, 3.8 mmol) as a white powder in 96% yield which was characterized as follows:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](B(O)O)[C:24]([O:30][CH3:31])=[CH:23][C:22]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:25]3[C:24]([O:30][CH3:31])=[CH:23][C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=4)=[C:21]([Cl:20])[CH:26]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2cc(SCc3ccccc3)ccc12
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(SCc3ccccc3)ccc12

Procedure:
A microwave vial was charged with 7-(benzylthio)-4-chloroquinazoline (0.372 g, 1.298 mmol), (2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)boronic acid (0.364 g, 1.298 mmol), tetrakis(triphenylphosphine)palladium(0) (0.150 g, 0.130 mmol), and potassium carbonate (0.897 g, 6.49 mmol). Dioxane (3.24 ml) and Water (1.081 ml) were added; the vial was flushed with argon and sealed, and microwaved at 90° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-75% EtOAc:Heptane) to afford 7-(benzylthio)-4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinazoline as a yellow solid. (ESI) 487.1 (M+H)+.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][N:10]=1)([O-:8])=[O:7]>CC(O)(C)C.CCOC(C)=O>[C:17]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([N+:6]([O-:8])=[O:7])=[N:10]1)([CH3:12])([CH3:9])[CH3:16]
Reactant: O=[N+]([O-])c1n[nH]c2ccccc12
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)n1nc([N+](=O)[O-])c2ccccc21
Temperature: 25 °C
Yield: 147.7 %

Procedure:
Cone. H2SO4 (2 mL) was added to a suspension of 3-nitro-1 H-indazole (3.4 g, 21 mmol) in 2-methyl-propan-2-ol (30 mL) and the resulting mixture was heated to 180° C. in a steel bomb. The reaction mixture was cooled to RT and diluted with EtOAc. The organic phase was washed with brine, dried (MgSO4) and concentrated to give 1-tert-butyl-3-nitro-1 H-indazole (3.4 g, 76%). 1H NMR (400 MHz, DMSO-d6): δ 8.18-8.15 (m, 2 H), 7.59-7.49 (m, 2 H), 1.76 (s, 9 H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone and 2-fluoro-5-trifluoromethylpyridine. ESI-MS (m/z): 471 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[Br:11][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
17.3 g 2-Chloro-4-methyl-benzonitrile were dissolved in 50 ml tetrachloromethane and heated to reflux. A mixture of 24.3 g N-bromosuccinimide and 7.48 g 2,2′-azobis(2-methylpropionitrile) were added in five portions over a period of one hour. The reaction mixture was heated under reflux for additional three hours. The cooled reaction mixture was then filtered through a celite pad. The filtrate was washed with 100 ml saturated NaHCO3 solution, dried over MgSO4 and the solvent was removed in vacuo. The resulting residue was dissolved in 200 ml tetrahydrofuran and cooled in an ice bath to 0° C. 88.0 ml diethyl phosphite were added, followed by the addition of 117.0 ml N,N-diisopropylethylamine. The cooling bath was removed and the reaction mixture stirred at room temperature for four hours. The reaction mixture was poured in 400 ml 50% NaHCO3 solution and extracted with 400 ml diethylether. The organic layer was separated and washed with 200 ml 50% NaHCO3 solution and 200 ml water and then dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified on silica gel with the eluent n-heptane:ethyl acetate=19:1 to obtain 13.0 g 4-Bromomethyl-2-chloro-benzonitrile as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24](Cl)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][N:37]=[CH:38]2)=[CH:33][CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:30][C:31]4[CH:40]=[C:39]5[C:34]([CH:35]=[CH:36][N:37]=[CH:38]5)=[CH:33][CH:32]=4)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3Cl)ccc2C(C)(C)C1
Reactant: Nc1ccc2ccncc2c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3Nc3ccc4ccncc4c3)ccc2C(C)(C)C1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
To a mixture of 7-[(2-chloro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (20.8 g, 50 mmol, 1.0 eq.), 7-aminoisoquinoline (7.2 g, 50 mmol, 1.0 eq.), Pd2(dba)3 (915 mg, 1 mmol, 0.02 eq), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (CAS#213697-53-1, Strem Chemicals cat no. 15-1145; 785 mg, 2 mmol, 0.04 eq) under N2 in a 250 mL pressure reaction vessel was added 1.0 M LiNTMS2 THF solution (120 mL, 120 mmol, 2.4 eq.). The reaction vessel was sealed with a Teflon screwcap and the mixture was stirred at 70° C. for 17 h. The mixture was then cooled to RT. 100 mL of water was added to the mixture and the mixture was extracted with 500 mL of EtOAc. The organic layer was washed with sat. NH4Cl solution, 1M NaHPO4 solution (4×200 mL) then dried over MgSO4. After filtration and concentration, the crude was purified through a silica gel column chromatography, eluting with CH2Cl2/EtOAc. The desired title compound was obtained as a yellow solid. MS (ES+): 524 (M+H)+. Calc'd for C31H33N5O3—523.26
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[C@@H:27]([CH2:38][O:39]C(=O)C)[O:26][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:16])[NH2:15])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[C:12]([C:14](=[O:16])[NH2:15])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)[C@@H:6]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:5]1[OH:4]
Reactant: CCc1ccc(Cc2ccc(C(N)=O)cc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(Cc2ccc(C(N)=O)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of 5-carbamoyl-2-(4-ethylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.13 g) in methanol (3 mL) was added sodium methoxide (28% methanol solution; 0.043 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on (benzenesulfonylpropyl) silica gel (eluent: methanol). To the obtained compound was added diethyl ether, and the resulting precipitates were collected by filtration and dried under reduced pressure to give 5-carbamoyl-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside (0.079 g).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([NH:16][N:17]([CH3:19])[CH3:18])=[O:15])[S:13][C:6]=12.[NH4+].[Cl-].O>CCO.[Fe]>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]([NH:16][N:17]([CH3:19])[CH3:18])=[O:15])[S:13][C:6]=23)=[C:2]([F:1])[CH:23]=1
Reactant: CN(C)NC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN(C)NC(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reaction time: 0.67 h
Yield: 85.4 %

Procedure:
To a mixture of 7-(2-fluoro-4-nitrophenoxy)-N′,N′-dimethylthieno[3,2-b]pyridine-2-carbohydrazide 238 (772 mg, 2.05 mmol) and NH4Cl (93 mg, 1.74 mmol) in EtOH (20.5 mL)/water (10.3 mL) at 100° C., Fe (973 mg, 17.73 mmol) was added in one portion and the mixture was heated to reflux with vigorous stirring 40 min. The mixture was filtered through Celite®, the Celite® washed with EtOH and the combined organic solutions concentrated under reduced pressure. The residue was purified by flash chromatography (MeOH/DCM 1:9) giving 239 (605 mg, 1.75 mmol, 85%). MS (m/z): (M+1) 347.0 (100%).
Reaction SMILES: [Cl-].[CH:2]1([NH:5][C:6](=[O:39])[C@@H:7]([OH:38])[C@@H:8]([NH:12][C:13]([C@@H:15]2[CH2:19][C@@H:18]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=4)[N:24]=[C:23]([N:33]4[CH:37]=[CH:36][CH:35]=[N:34]4)[CH:22]=3)[CH2:17][NH2+:16]2)=[O:14])[CH2:9][CH2:10][CH3:11])[CH2:4][CH2:3]1.[C:40]([NH:44][C:45](=[O:55])[NH:46][C@H:47]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:48](O)=[O:49])([CH3:43])([CH3:42])[CH3:41].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CS(C)=O.O>[C:40]([NH:44][C:45](=[O:55])[NH:46][C@@H:47]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:48]([N:16]1[CH2:17][C@H:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[N:24]=[C:23]([N:33]3[CH:37]=[CH:36][CH:35]=[N:34]3)[CH:22]=2)[CH2:19][C@H:15]1[C:13]([NH:12][C@@H:8]([CH2:9][CH2:10][CH3:11])[C@H:7]([OH:38])[C:6]([NH:5][CH:2]1[CH2:4][CH2:3]1)=[O:39])=[O:14])=[O:49])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)NC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)C[NH2+]1)[C@H](O)C(=O)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-n3cccn3)nc3cc(OC)ccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)[C@H](O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of (2S,4R)-2-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-ylcarbamoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidinium chloride (6.3 g, 11.2 mmol) in dimethylsulfoxide (20 mL) was added (R)-2-(3-tert-butylureido)-3,3-dimethylbutanoic acid (2.33 g, 10.2 mmol), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 4.74 g, 12.1 mmol) followed by diisopropylethylamine (4.95 g, 38.4 mmol), and the reaction mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. Completion of the reaction was monitored by TLC analysis. The reaction mixture was diluted with water and the resulting solid was filtered and dried under reduced pressure to yield 6.3 g (71.6%) of (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxamide (HPLC purity: 99.2% by area; HPLC retention time: 15.06 minutes).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[C:20]([O:22]C)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][C@H:9]1[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylcarboxylate (5.31 g, 16.5 mmol) in THF (132 ml) was added 0.25N NaOH (132 ml, 33.0 mmol). The reaction mixture was stirred overnight at room temperature. The residue obtained by concentrating the reaction mixture under reduced pressure was acidified with 1N HCl, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The crude crystals thus obtained were recrystallized from hexane-chloroform, whereby the title compound (2.96 g, 58%) was obtained as a white crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:26])[N:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH2:17][CH2:16]2)[CH3:14])[CH:6]=1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12](=[O:26])[N:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH2:17][CH2:16]3)[CH3:14])[CH:6]=2)=[C:2]([F:1])[CH:30]=1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 98 %

Procedure:
After adding 20% palladium hydroxide-carbon (18.3 mg) to a solution of 3-[6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (240 mg) in tetrahydrofuran (10 ml), the mixture was stirred for 15.5 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered and washed with methanol. The filtrate was then concentrated to provide the title compound (220 mg, 98.0%) as a yellow amorphous substance.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[F:14].S(Cl)([Cl:17])=O>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:17])=[O:10])=[CH:7][C:6]=1[F:14]
Reactant: O=C(O)c1ccc(OCCBr)c(F)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OCCBr)c(F)c1
Yield: 93 %

Procedure:
4-(2-Bromoethoxy)-3-fluorobenzoic acid (1.08 g, 4.1 mmol) and thionyl chloride (10 mL) were refluxed for 7 h. The excess thionyl chloride was removed by repeated evaporation with dry toluene in vacuo, giving 1.07 g (93%) the subtitle compound as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=8.8 Hz, 1H), 7.86 (d, J=11.2 Hz, 1H), 7.04 (dd, J=8.4 Hz, 8.4 Hz, 1H), 4.46 (t, J=6.4 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H).
Reaction SMILES: C(OC([NH:8][C:9]([NH:24]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[ClH:32].[CH3:23][C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:24])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccnc1-c1cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cccnc1-c1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-methylpyridin-2-yl)phenyl)guanidine (213 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 8 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-methylpyridin-2-yl)phenylguanidine dihydrochloride (119 mg).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13](OCC)=O)=[O:9])=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:4][NH:3]1.O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.ON1C2C=CC=CC=2N=N1.[O:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:63]=CC(CN)=[CH:58][CH:57]=2)[CH2:52][CH2:51]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[N:53]1([C:56]2[CH:63]=[CH:13][C:12]([CH2:11][NH:10][C:8]([C:7]3[C:2](=[O:1])[NH:3][N:4]=[C:5]([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[CH:6]=3)=[O:9])=[CH:58][CH:57]=2)[CH2:54][CH2:55][O:50][CH2:51][CH2:52]1
Reactant: CCOC(=O)CCNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: NCc1ccc(N2CCOCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(N2CCOCC2)cc1)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 13 for the preparation of ethyl 3-[(3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carbonyl)amino]propionate, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 30 cm3 of N,N-dimethylformamide, 0.233 g of 1-hydroxybenzotriazole, 0.265 g of 4-morpholinobenzylamine, 0.31 cm3 of N,N-diisopropylethylamine and 0.65 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, and after purification by chromatography on silica gel (particle size 40-63 μm, under an argon pressure of 150 kPa), eluting with dichloromethane, 0.13 g of N-(4-morpholin-4-ylbenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a yellow solid melting at 252° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:6]([CH3:30])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][S:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[C:9]=1[CH3:10].ClC1C=CC=C(C(OO)=[O:40])C=1>ClCCl>[CH3:1][O:2][C:3](=[O:31])[CH2:4][C:5]1[C:6]([CH3:30])=[N:7][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][S:19]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=3)=[O:40])=[CH:16][CH:17]=2)[C:9]=1[CH3:10]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(CSc3ccc(C(F)(F)F)cc3)cc2)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)Cc1c(C)nn(Cc2ccc(CS(=O)c3ccc(C(F)(F)F)cc3)cc2)c1C
Reaction time: 1 h

Procedure:
{3,5-Dimethyl-1-[4-(4-trifluoromethyl-phenylsulfanylmethyl)-benzyl]-1H-pyrazol-4-yl}-acetic acid methyl ester (intermediate 16.1.3, 170 mg, 0.38 mmol) was dissolved in 3 ml dichloromethane and 3-chloroperbenzoic acid (79 mg, 0.45 mmol) was added at 5° C. After 1 h at that temperature, the mixture was diluted with dichloromethane and washed with aqueous NaHCO3 solution. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure.