Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1.O>CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:14])[C:4]([C:1](=[O:3])[CH3:2])=[CH:5]2)=[CH:24][CH:23]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(=O)c1c[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cn(Cc2ccc(F)cc2)c2ccccc2c1=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 22.4 %

Procedure:
A solution of 3-acetyl-4(1H)-quinolinone (1a) (0.8 g, 45 mmol) in dry DMF (40 mL) was treated with anhydrous K2CO3 (0.86 g, 62 mmol) and 4-fluorophenylmethylbromide (2.46 g, 13 mmol) and the resulting suspension was stirred for 1.5 hours at 100° C. After cooling, water was added (100 mL) and the precipitate that formed was filtered, washed with water, light petroleum ether in turn and then dried under IR lamp to provided compound 2a (0.86 g, 65%); mp 213-214° C. (toluene). Analogs 2b (R1═C1, R2═H) and 2c (R1═H, R2═Cl) were similarly prepared by this method. Compound 2b: 92% yield; mp 214-216° C. (toluene/cyclohexane); compound 2c: 73% yield; mp 185-187° C. (toluene/cyclohexane).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][C:18]([CH:22]=[O:23])=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].N1C=CN=C1>ClCCl.ClCCCl>[Si:24]([O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][C:18]([CH:22]=[O:23])=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc2c(c1)c1ccccc1n2CCCCCCO
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCCn1c2ccccc2c2cc(C=O)ccc21

Procedure:
In Reaction 1, a reactant reacts with 1,2-dichloroethane at 0° C. to thus prepare a precursor 2, which is then further reacted in the presence of 10% HCl, affording a precursor 3. The reaction is progressed through reflux. Then, 9-(6-hydroxyhexyl)-9H-carbazole-3-carbaldehyde, dichloromethane, tert-butyldimethylsilyl chloride, and imidazole are reacted together, thus producing 4 (9-(6-(tert-butyldimethylsilyloxy)hexyl)-9H-carbazole-3-carbaldehyde) as a precursor. Then, the precursor 4 is dissolved in sodium borohydride and methanol to thus allow the obtained solution to react, yielding 5 ((9-(6-(tert-butyldimethylsilyloxy)hexyl)-9H-carbazol-3-yl)methanol as a precursor.
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=CC=1)(O)=O.[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH2:11]([N:12]([CH2:27][C:28]1[CH:29]=[CH:30][C:21]([CH2:14][CH2:13][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:22][CH:23]=1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[C@@H:21]1[CH2:22][CH2:23][C:28]2[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:29]=2[CH2:30]1)[CH3:10]
Reactant: C1CCNCC1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: CCN(Cc1ccc(CCN2CCCCC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 21.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and piperidine (20 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (1.9 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[C:18](=[O:19])[CH:17]=[CH:16][N:15]([C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:10]=[N:9]1.[CH3:30]I.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[C:18](=[O:19])[CH:17]=[CH:16][N:15]([C:20]3[CH:21]=[C:22]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:10]=[N:9]1
Reactant: CC(=O)Nc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from N-(3-{3-[2-(2-Fluoro-phenyl)-2H-pyrazol-3-yl]-4-oxo-4H-pyridazin-1-yl}-phenyl)-acetamide (example 292) and methyl iodide in presence of sodium hydride in DMF at room temperature over night. MS: M=404.4 (M+H)+
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[C:12]([F:13])=[C:11]([F:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].C(OCC)(=O)C.O1CCCC1>C(O)C.O>[F:14][C:11]1[C:12]([F:13])=[C:5]2[C:6]([C:7]([NH2:8])=[N:2][NH:3]2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: N#Cc1ccc(F)c(F)c1F
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1n[nH]c2c(F)c(F)ccc12
Temperature: 75 °C

Procedure:
0.32 cm3 of hydrazine monohydrate is added to 0.46 cm3 of 2,3,4-trifluorobenzonitrile in 10 cm3 of absolute ethanol. The medium is heated at about 75° C. for 17 hours and then 10 cm3 of ethyl acetate, 5 cm3 of tetrahydrofuran and 5 cm3 of distilled water are added. The organic phase is separated out after settling of the phases has taken place, and is washed again with 10 cm3 of distilled water and then with 10 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 1.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 by volume). The fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40° C.); after drying (90 Pa; 40° C.), 100 mg of 6,7-difluoro-1H-indazole-3-amine are obtained in the form of a white solid melting at 183° C.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.C(O)C#C.C1C2C(=CC=CC=2)C=CC=1O>>[CH3:18][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccccc1
Agent: C#CCO
Agent: Oc1ccc2ccccc2c1
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1

Procedure:
4-methyl-4'methoxybenzophenone was prepared from anisole and p-toluoyl chloride using the procedure described in Comparative Example 2. The resulting ketone was converted to the propargyl alcohol and then reacted with 2-naphthol as in Comparative Example 2 to produce 2.1 grams of light yellow crystals having a melting range of 146-147° C. NMR analysis confirmed the product to be 3(4-methylphenyl)-3-(4-methoxyphenyl)-3H-naphtho[2,1-b]pyran.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([Cl:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[OH:23].[O:24]=[C:25]1[CH2:30][S:29][C:28]2[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[N:34][C:27]=2[NH:26]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][C:35]([C:33]5[CH:32]=[CH:31][C:28]6[S:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=6[N:34]=5)=[O:36])[C@H:3]([OH:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)C[C@H]1O
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CSc2ccc(C(=O)N[C@H]3CCN(CC4Cn5c(=O)ccc6ncc(Cl)c4c65)C[C@H]3O)nc2N1
Yield: 59 %

Procedure:
The free base of the title compound was synthesised from racemic 4-{[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (79 mg), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (for a synthesis see WO2003087098, Example 301(b)) (50 mg), triethylamine (0.066 ml) and HATU (95 mg) in DMF (2 ml) according to the general method of Example 9 in 59% yield.
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[CH:22]1([NH:28][C:29](=[O:32])[NH:30][NH2:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)C.C([O-])(=O)C.[Na+]>O>[CH:22]1([NH:28][C:29](=[O:32])[NH:30]/[N:31]=[C:10]2/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:18]([CH3:20])[CH3:19])[CH:1]([CH3:3])[CH3:2])[C:17]3[C:12]/2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Reactant: NNC(=O)NC1CCCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)N(CCN1C(=O)/C(=N/NC(=O)NC2CCCCC2)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.2 %

Procedure:
To a suspension of 0.91 g of 1-(2-diisopropylaminoethyl)isatin and 1.00 g of 4-cyclohexylsemicarbazide hydrochloride in 17 ml of a mixture of ethanol and water (2:1) was added 0.42 g of sodium acetate, and the mixture was stirred for 17 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and an aqueous sodium bicarbonate solution was added to the residue. The precipitates were collected by filtration, washed with water, and recrystallized from aqueous ethanol to obtain 0.99 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-(4-cyclohexylsemicarbazone) having a melting point of 164°-166° C.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:21])([F:20])[CH:15]([OH:19])[CH2:16][CH:17]=[CH2:18].[H-].[Na+].Cl>O1CCOCC1>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:19][CH:15]([CH2:16][CH:17]=[CH2:18])[C:14]([F:21])([F:20])[F:13])[CH:11]=1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: C=CCC(O)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCC(Oc1cc(F)ccc1C(=O)OC)C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Methyl 2,4-difluorobenzoate (1.72 g, 9.99 mmol) was dissolved in dioxane. To this was added 1,1,1-trifluoropent-4-en-2-ol (1.40 g, 9.99 mmol) followed by 60% (mineral oil) NaH (0.40 g, 9.99 mmol). The resulting mixture was heated to 90° C. and stirred overnight. After cooling to RT, 1N HCl was added and the mixture transferred to separatory funnel. The mixture was extracted with ethyl acetate after which the organic solution was washed with 1N NaOH (2 times) and sat'd NaCl. The solution was dried over Na2SO4, filtered and the solvent removed to yield the title compound as an oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH2:34][CH3:35])[C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:36])[CH:21]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4].[BH4-].[Na+].C(Cl)Cl.CCOC(C)=O.C(Cl)Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH2:16][CH3:17])([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH2:34][CH3:35])[CH:28]([OH:33])[C:29]([CH3:30])([CH3:31])[CH3:32])=[C:22]([CH3:36])[CH:21]=3)[CH2:18][CH3:19])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)OC)ccc3c2)cc1C)C(=O)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)OC)ccc3c2)cc1C)C(O)C(C)(C)C
Yield: 8 %

Procedure:
Following the procedure described in Example 2; treat 6-{1-[4-(3,3-dimethyl-1-ethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carboxylic acid methyl ester with NaBH4 in THF at 0 C. Chromatograph the residue (CH2Cl2 to 2% EtOAc/CH2Cl2) to give diastereomeric isomer pair 1 of the title compound as a glassy foam (1.004 g, 77%) and diastereomeric isomer pair 2 of the title compound as a glassy foam (102 mg, 8%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:15](=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:21]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>>[CH:21]([N:24]1[CH2:29][CH2:28][CH:27]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][CH2:13][N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:15](=[O:16])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:26][CH2:25]1)([CH3:23])[CH3:22]
Reactant: CC(C)N1CCC(O)CC1
Reactant: COCCN1CCCn2c(cc3cc(O)ccc32)C1=O
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCCN1CCCn2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 2 %

Procedure:
The title compound was synthesized in analogy to example 1, from 9-hydroxy-2-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butylazodicarboxylate, to give the desired product as a light yellow oil (2%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]2[CH2:10][CH2:11][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH3:14])[O:13][C:8]=2[C:7]=1[CH2:23][CH2:24][CH3:25].[CH3:26][CH2:27][CH2:28][C:29]1[C:34]([OH:35])=[C:33]([C:36]([CH3:38])=[O:37])[CH:32]=[CH:31][C:30]=1[OH:39]>>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([O:39][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:22]=[CH:21][C:9]3[CH2:10][CH2:11][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH3:14])[O:13][C:8]=3[C:7]=2[CH2:23][CH2:24][CH3:25])=[C:29]([CH2:28][CH2:27][CH3:26])[C:34]=1[OH:35])(=[O:37])[CH3:38]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCBr)ccc2c1OC(C)(CCC(=O)OC)CC2
Product: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C)(CCC(=O)OC)CC3)ccc(C(C)=O)c1O

Procedure:
The title compound mp. 53°-55°, was prepared by the method of Example 6 using the product of Example 11 and 2,4-dihydroxy-3-propylacetophenone as starting materials. Structure assignment was confirmed by nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[NH:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[N:45]=[C:44]1[CH2:52][N:53]([CH:58]1[C:67]2[N:66]=[CH:65][CH:64]=[CH:63][C:62]=2[CH2:61][CH2:60][CH2:59]1)[CH2:54][CH2:55][CH2:56][NH2:57]>CN(C=O)C.C(OCC)(=O)C.O>[NH:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[N:45]=[C:44]1[CH2:52][N:53]([CH:58]1[C:67]2[N:66]=[CH:65][CH:64]=[CH:63][C:62]=2[CH2:61][CH2:60][CH2:59]1)[CH2:54][CH2:55][CH2:56][NH:57][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=1
Reactant: NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reactant: O=C(O)c1cncc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of 5-bromonicotinic acid (120 mg, 0.60 mmol) in DMF (3 mL) was added 1-hydroxybenzotriazole hydrate (96 mg, 0.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (137 mg, 0.72 mmol), N,N-diisopropylethylamine (0.21 mL, 1.19 mmol), and N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (200 mg, 0.60 mmol). The reaction mixture was stirred at room temperature overnight. Then it was diluted with ethyl acetate (40 mL) and water (25 mL). The aqueous layer was concentrated and dried in vacuo to afford a brown oil. Purification by radial chromatography (1 mm plate, using NH4OH/CH3OH/CH2Cl2; 1:1:100→1:4:100) afforded the product as pale yellow foam (220 mg, 71%). 1H NMR (CDCl3) δ 1.59-1.85 (m, 4H), 1.99-2.03 (m, 1H), 2.16-2.20 (m, 1H), 2.58-2.62 (m, 1H), 2.73-2.85 (m, 3H), 3.27-3.34 (m, 1H), 3.50-3.54 (m, 1H), 3.95 (d, 2H, J=2.4 Hz), 4.03-4.08 (m, 1H), 7.09-7.16 (m, 3H), 7.31 (br s, 1H), 7.42 (d, 1H, J=7.5 Hz), 7.58 (br s, 1H), 7.91 (t, 1H, J=5.7 Hz), 8.07 (t, 1H, J=2.1 Hz), 8.40 (d, 1H, J=3.6 Hz), 8.64 (d, 1H, J=2.4 Hz), 8.74 (d, 1H, J=1.8 Hz).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[NH:27][NH2:28].CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1>>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[N:20][C:21]([NH:28][NH:27][C:26]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2ccc(Cl)nn2)c(OCC(O)CNC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)NN
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Product: COc1ccc(-c2ccc(NNC(=O)OC(C)(C)C)nn2)c(OCC(O)CNC(C)(C)C)c1

Procedure:
i. A mixture of 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-6-chloro-pyridazine, t-butyl carbazate and 1,8-bis-(dimethylamino)naphthalene was heated for 2 hours to give 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-6-(2-t-butyloxycarbonylhydrazino)pyridazine.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:17]=[C:16]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11].O>C1COCC1>[F:7][C:8]1[CH:17]=[C:16]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[CH:15]=[CH:14][C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1ccc(-n2cccn2)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-n2cccn2)cc1F
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of lithium aluminium hydride (0.16 g) in THF (5.50 mL) was added a solution of methyl 2-fluoro-4-(1H-pyrazol-1-yl)benzoate (0.89 g) in THF (5.50 mL) under ice-cooling, and the mixture was stirred for 1 hr. To the reaction solution was added water, the insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.71 g) as a crude product.
Reaction SMILES: [F:1][C:2]1[C:3]([C:27]([OH:29])=O)=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)[N:7]([CH3:25])[C:6]=2[CH:26]=1.[CH2:30]([O:32][CH2:33][CH2:34][NH2:35])[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([O:32][CH2:33][CH2:34][NH:35][C:27]([C:3]1[C:2]([F:1])=[CH:26][C:6]2[N:7]([CH3:25])[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:22])([F:24])[F:23])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[N:9][C:5]=2[CH:4]=1)=[O:29])[CH3:31]
Reactant: CCOCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)c(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1F
Yield: 59.4 %

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (52 mg) was prepared by following General Procedure F starting from 6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 2-ethoxyethylamine (17 mg), HBTU (80 mg), and DIEA (46 uL). LC/MS: m/z 498.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.35 (bs, 1H), 8.14 (d, 1H), 7.92 (s, 1H), 7.89 (d, 1H), 7.73 (d, 1H), 7.50 (d, 1H), 7.37 (s, 1H), 3.60 (bs, 3H), 3.56-3.41 (m, 6H), 1.14 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:4]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:3]=1.[O:35]=[C:36]([CH3:40])[C:37](Cl)=[O:38]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([S:17]([N:20]3[CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH2:25]3)(=[O:19])=[O:18])=[CH:15][CH:16]=2)=[C:4]([N:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:37](=[O:38])[C:36](=[O:35])[CH3:40])[CH:3]=1
Reactant: O=C(CCc1ccc(S(=O)(=O)N2CCC(O)CC2)cc1)c1ccc(Cl)cc1Nc1ccccc1
Reactant: CC(=O)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=O)N(c1ccccc1)c1cc(Cl)ccc1C(=O)CCc1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 1-(4-chloro-2-phenylamino-phenyl)-3-[4-(4-hydroxypiperidine-1-sulfonyl)-phenyl]propan-1-one (0.200 g) in toluene (20 mL) was added 2-oxopropanoyl chloride (0.427 g). The reaction mixture was heated at 120° C. for 3 h, then stirred at RT overnight to produce N-(5-chloro-2-{3-[4-(4-hydroxypiperidine-1-sulfonyl)-phenyl]-propionyl}-phenyl)-2-oxo-N-phenyl-propionamide, which was used without further purification.
Reaction SMILES: [C:1]([NH:4][CH:5]([PH:17]([OH:19])=[O:18])[CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2].[H-].[Na+].[CH2:22](I)[CH:23]([CH3:25])[CH3:24].C(O)(=O)C>CS(C)=O>[C:1]([NH:4][CH:5]([PH:17]([OH:19])=[O:18])[C:6]([CH2:22][CH:23]([CH3:25])[CH3:24])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(C)CI
Reactant: CCOC(=O)C(C(=O)OCC)C(NC(C)=O)[PH](=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCOC(=O)C(CC(C)C)(C(=O)OCC)C(NC(C)=O)[PH](=O)O
Temperature: 10 °C
Yield: 44 %

Procedure:
12.0 g of diethyl 2-[(acetamido)(hydroxyphosphinyl)methyl]malonate were dissolved in 100 ml of dry dimethyl sulphoxide and the solution was cooled to 10° C. while stirring under a nitrogen atmosphere. 3.2 g of 60% sodium hydride in mineral oil were added, the mixture was stirred at room temperature for 2 hours and then 8 g of isobutyl iodide were added. The mixture was stirred at room temperature in the dark for 20 hours and 20 ml of glacial acetic acid were added. The volatiles were removed by evaporation in a high vacuum and the resulting semi-solid residue was dissolved in 100 ml of water containing 15 ml of 50% hypophosphorous acid. The solution was extracted eight times with ethyl acetate and the combined extracts were dried over sodium sulfate and evaporated. The residue was dissolved in dichloromethane and the solution was washed in sequence with water and saturated sodium chloride solution. The dichloromethane solution was dried over sodium sulfate and evaporated, and the residue was crystallized from diethyl ether/n-hexane to give 6.28 g of diethyl 2-[(acetamido)-(hydroxyphosphinyl)methyl]-2-isobutylmalonate in the form of a white solid; MS: 352 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[N:29][CH:30]=2)[CH:7]=[C:8]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH:9]=1.Cl>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[N:29][CH:30]=2)[CH:7]=[C:8]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH:9]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)cc(CNc3ccc(-c4ccc(F)cc4)cc3)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)cc(CNc3ccc(-c4ccc(F)cc4)cc3)c2)cn1
Temperature: 40 °C

Procedure:
A 1M aqueous solution of NaOH (0.47 mL, 0.47 mmol) was added to a THF solution (5 mL) of ethyl 3-(5-(3-chloro-5-(((4′-fluoro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (100 mg, 0.19 mmol) and the resulting mixture was heated to 40° C. After 4 h the resulting mixture was acidified with 1 M HCl and the aqueous phase was extracted with EtOAc. The combined organics were washed with water, dried (Na2SO4), and concentrated to yield the title compound.