Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl.[OH:11][C@H:12]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@:18]3([OH:35])[CH2:19][CH2:20][C@@H:21]2/[CH:22]=[CH:23]/[CH:24]=O)[CH2:13]1>O.O1CCOCC1>[NH:6](/[N:5]=[CH:24]/[CH:23]=[CH:22]/[C@H:21]1[CH2:20][CH2:19][C@:18]2([OH:35])[C@H:17]3[C@H:29]([CH2:28][CH2:27][C@:26]12[CH3:34])[C@:30]1([CH3:33])[C@@H:14]([CH2:13][C@@H:12]([OH:11])[CH2:32][CH2:31]1)[CH2:15][CH2:16]3)[C:7]([NH2:9])=[NH:8]
Reactant: N=C(N)NN
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=O)CC[C@]12O
Agent: Cl
Agent: O=C(O)O
Solvent: O
Solvent: C1COCCO1
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=N/NC(=N)N)CC[C@]12O
Yield: 65.4 %

Procedure:
A mixture of 1.05 g of aminoguanidine hydrogencarbonate in 23 ml of water and 70 ml of dioxane was made acid to pH 3 with 3N HCl. A solution of 2.08 g of (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxaldehyde (Fullerton D. S. et al., J. Med. Chem., 1976, 19, 1330) in 20 ml of dioxane was added at room temperature. After 3 days the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 80/20/3 as the eluant; the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with diethyl ether and ethanol to give 1.58 g of the title compound (I-aa) as a white solid.
Reaction SMILES: [Li]CCCC.CCCCCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[C@@H:30]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[C:32](=[O:38])[CH2:31]1)[C:25]#[N:26]>C1COCC1>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C@:32]1([OH:38])[C:33]2[N:34]([CH:35]=[N:36][CH:37]=2)[C@@H:30]([C:29]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=2[F:21])[CH2:31]1
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2C[C@](O)(c3nc4ccccc4s3)c3cncn32)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a 1.6 M solution of n-BuLi in hexane (0.29 mL, 0.46 mmol) cooled to −78° C. was added a solution of benzo[d]thiazole (56 mg, 0.42 mmol) in THF (1 mL). The crude was stirred at −78° C. for 1 hr. This solution was then cannulated to a solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (50 mg, 0.21 mmol) in THF (1 mL) cooled at −78° C. After stirring at −78° C. for 2 hrs, the crude was warmed to room temperature. The crude was stirred at room temperature for 1 hr. The crude was quenched with sat. NH4Cl. The crude was diluted in EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude was purified via preparation plate using 7% (2M NH3 in MeOH)/CH2Cl2 to give 18 mg of the entitled product as the major diastereomer. MS 377.0 (M+H); LCMS condition A, retention time 1.23 min. 1H NMR (400 MHz, CDCl3) δ ppm 3.09 (dd, 1H), 3.84 (dd, 1H), 5.96 (d, 1H), 7.02 (s, 1H), 7.24-7.53 (m, 6H), 7.85 (d, 1H), 7.93 (d, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[CH:53]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[CH:53]=2)[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)c1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)c2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 66A (0.023 g, 0.076 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol) and the mixture was stirred at 25° C. for 2 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.013 g, 42% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.89 (m, 9 H), 1.47 (m, 2 H), 2.28 (s, 3 H), 2.39 (m, 1 H), 2.78 (m, 6 H), 3.22 (m, 1 H), 3.54 (m, 4 H), 3.84 (d, J=9.93 Hz, 1 H), 3.93 (m, 1 H), 4.04 (s, 1 H), 4.25 (m, 3 H), 4.45 (d, J=6.99 Hz, 1 H), 6.88 (d, J=9.93 Hz, 1 H), 7.05 (m, 7 H), 7.24 (m, 4 H), 7.32 (m, 1 H), 7.54 (d, J=9.56 Hz, 1 H), 7.89 (m, 5 H), 8.65 (d, J=4.41 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:31][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: NC1CCCCCC1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NC3CCCCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 71 at rt but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq.) and cycloheptylamine (1.0 mL) as a white powder (8 mg, 13%). HPLC, Rt: 3.85 min. (purity 95.9%). LC/MS, M+(ESI): 419.3, M−(ESI): 417.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH2:23]C(O)=O)[C:13]2=[O:27])=[O:10])[CH:7]=1.O=C1N(C2[CH:48]=[CH:47][C:46]([CH2:49][C:50](=[O:60])[NH:51][CH2:52][CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:45][CH:44]=2)C(=O)C2C(=CC=CC=2)N1CC(O)=O.C1(N)CCCC1.ClC1C(OC)=CC(OC)=C(N)C=1>>[Cl:1][C:2]1[C:3]([O:30][CH3:31])=[CH:4][C:5]([O:28][CH3:29])=[C:6]([NH:8][C:9](=[O:10])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([C:23]3[CH:48]=[CH:47][C:46]([CH2:49][C:50](=[O:60])[NH:51][CH2:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[CH:45][CH:44]=3)[C:13]2=[O:27])[CH:7]=1
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CC(=O)O)c(=O)c3ccccc32)cc1Cl
Reactant: O=C(O)Cn1c(=O)n(-c2ccc(CC(=O)NCCc3ccccc3)cc2)c(=O)c2ccccc21
Agent: COc1cc(OC)c(Cl)cc1N
Agent: NC1CCCC1
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(-c3ccc(CC(=O)NCCc4ccccc4)cc3)c(=O)c3ccccc32)cc1Cl

Procedure:
This compound is made analogously to Example 1-2 by replacing {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid (Intermediate A) with ({2,4-dioxo-3-[4-(phenethylcarbamoyl-methyl)-phenyl]-3,4-dihydro-2H-quinazolin-1-yl}-acetic acid) (Intermediate D) and by replacing cyclopentylamine with 5-chloro-2,4-dimethoxy-phenylamine to afford the title compound. The reaction is carried out using DMF as the solvent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[N+:16](/[CH:19]=[CH:12]/[C:11]1[CH:14]=[CH:15][C:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][CH:10]=1)([O-:18])=[O:17]
Reactant: O=Cc1ccc(Oc2ccccn2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc(Oc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A mixture of 4-(pyridin-2-yloxy)-benzaldehyde (9.3 g, 47 mmol) described in Manufacturing Example 209-1-1, nitromethane (14 g, 230 mmol), ammonium acetate (11 g, 140 mmol), and acetic acid (50 mL) was stirred for 1 hour and 30 minutes at 100° C. This mixture was cooled to room temperature, and water was added to precipitate a solid. The solid was filtered to obtain the title compound (9.9 g, 87%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([F:17])[C:10]=2[F:16])[CH2:31]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: NC1CCN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reaction time: 8 h
Yield: 82 %

Procedure:
To 2.0 g (6.64 mmol) of the 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 1.5 g (8.3 mmol) of 3-t-butoxycarbonylaminopyrrolidine and 1.01 g (6.64 mmol) of 1,8-diazabicyclo[5.4.0]undec-7ene. The mixture was stirred overnight and refluxed for two hours. The solids were filtered and washed with ether. They were treated with 5 ml of trifluoroacetic acid and stirred at 25° C. for 1.5 hours. The trifluoroacetic acid was removed and the mixture taken up in water. The pH was adjusted to 7.0 and the solids were filtered and dried to give 2.0 g of the title compound, mp 290°-292° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][CH:19]([NH2:21])[CH3:20].CCO>C(CC(C)(C)C)(C)C>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:21][CH:19]([CH3:20])[CH3:18])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CC(C)N
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Solvent: CC(C)CC(C)(C)C
Product: CC(C)NCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), propan-2-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 303 (M+, 0.3), 95 (10), 86 (14), 75 (8), 72 (bp), 58 (9).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N([O-])=[O:19].[Na+].O>Cl.CO>[OH:19][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(N)cc(N(C)S(C)(=O)=O)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(O)cc(N(C)S(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a mixture of methyl 3-amino-5-[methyl(methylsulfonyl)amino]benzoate 1.29 g (5.0 mmol) in 2N hydrochloric acid (10 mL) and methanol (15 mL) was added sodium nitrite 0.759 g (11 mmol) under ice-cooling. Thereto was further added water (20 mL) and the mixture was stirred at 70° C. for 2 hours. The mixture was extracted twice with ethyl acetate (30 mL) and dried on magnesium sulfate and the solvent was evaporated to give 1.33 g (5.0 mmol) of the title compound (yield: 100%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1(=[N:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.[C:14](Cl)(=[N:21][OH:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C(Cl)Cl>[C:15]1([C:14]2[N:12]([NH2:13])[C:7]3([CH2:11][CH2:10][CH2:9][CH2:8]3)[O:22][N:21]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NN=C1CCCC1
Reactant: ON=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: NN1C(c2ccccc2)=NOC12CCCC2
Temperature: 25 °C
Yield: 50341.3 %

Procedure:
A round bottom flask was charged with a solution of 20 g of K2CO3 in 50 mL of water and cooled in an ice bath. Cyclopentylidene-hydrazine (7.9 g, 80 mmol) in 25 mL of CH2Cl2 was added, followed by a drop-wise addition of benzohydroximoyl chloride (5 g, 0.032 mmol) in 25 mL of CH2Cl2 over a period of 15 minutes. The mixture was stirred for several days, and allowed to warm to room temperature. Water (50 mL) and CH2Cl2 (50 mL) were added and the phases were separated. The organic layer was washed twice with 50 mL of water, dried over MgSO4, and filtered. The solvent was removed in vacuo, leaving 9 g of a waxy solid. Crystallization from ethyl acetate/hexane provided 3.5 g (50%) of 3-phenyl-1-oxa-2,4-diaza-spiro[4.4]non-2-en4-ylamine after drying. 1H-NMR (300 MHz, CDCl3)δ(ppm): 7.72 ((m, 2H), 7.46 (m, 3H), 3.54 (s, 2H), 2.1 (m, 2H), 1.85 (m, 2H), 1.8 (m., 2H).
Reaction SMILES: [CH:1]1[C:6]([C:7]#[N:8])=[CH:5][N:4]=[C:3](Cl)[CH:2]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12]>>[NH2:12][CH2:11][CH2:10][NH:13][C:3]1[N:4]=[CH:5][C:6]([C:7]#[N:8])=[CH:1][CH:2]=1
Reactant: NCCN
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(NCCN)nc1
Temperature: 50 °C

Procedure:
6-Chloronicotinitrile (2.0 g) was treated with ethylenediamine (5 ml). The mixture was then heated at 50° C. for 22 hours. Excess ethylenediamine was removed by rotary evaporation. The residue was partitioned between 2.5 M aqueous sodium hydroxide and dichloromethane. The aqueous layer was extracted 4× more with dichloromethane. The combined organic layers were washed with a saturated sodium chloride solution, dried and then concentrated in vacuo to give 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile as an amber liquid which solidified upon standing. The amine (0.97 g, 6 mmol) was shaken overnight with benzotriazole carboxamidinium 4-methylbenzenesulfonate (2.0 g, 6 mmol) and DIEA (1.05 ml, 6 mmol) in acetonitrile (10 ml). Addition of ether gave amino{2-[(5-cyano(2-pyridyl)amino]ethyl}carboxamidinium 4-methylbenzenesulfonate as a white solid.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH2:5][S:4][CH2:3]1.[NH:14]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:22][O:21][C:19]([C:17]1[N:16]([CH:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=3)[CH2:5][S:4][CH2:3]2)[CH:15]=[N:14][CH:18]=1)=[O:20]
Reactant: COC(=O)c1c[nH]cn1
Reactant: N#Cc1ccc2c(c1)CSCC2O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1CSCc2cc(C#N)ccc21
Temperature: 0 °C

Procedure:
To a solution of 4-hydroxy-isothiochroman-7-carbonitrile (630 mg, 3.3 mmol) in THF (20 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 460 mg, 3.6 mmol), and triphenylphosphine (909 mg, 3.4 mmol). The reaction is cooled to 0° C. and diisopropyl azodicarboxylate (0.66 mL, 3.4 mmol) is added. The reaction is permitted to warm to room temperature and stirred until LC-MS analysis indicates complete consumption of 4-hydroxy-isothiochroman-7-carbonitrile. The reaction mixture is diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:1) to provide 3-(7-cyano-isothiochroman-4-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 300.1 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 3.08-3.23 (m, 1 H), 3.32 (dd, J=14.4, 4.0 Hz, 1 H), 3.73-4.07 (m, 2 H), 3.91 (s, 3 H), 6.46-6.61 (m, 1 H), 7.15 (d, J=8.1 Hz, 1 H), 7.46 (s, 1 H), 7.49-7.54 (m, 1 H), 7.56 (s, 1 H), 7.84 (s, 1 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(7-cyano-isothiochroman-4-yl)-3H-imidazole-4-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)[C:15]([C:32](=[O:34])N)=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=[O:36]>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:32]([OH:34])=[O:36])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCN(C(=O)OC(C)(C)C)C3)n2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Nc2ncc(C(=O)O)c(NCC3CCNC3)n2)c1

Procedure:
A solution of tert-butyl 3-((2-(3-acetamidophenylamino)-5-carbamoylpyrimidin-4-ylamino)methyl)pyrrolidine-1-carboxylate (65 mg, 0.138 mmol) in TFA (1 mL) and CH2Cl2 mL) was stirred at room temperature for 2 h. TFA and CH2Cl2 were removed in vacuo. The residue was purified by HPLC to give the titled compound (25 mg). MS 370.3 (M+H); UV 206.4, 244.2 nm.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[F:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[C:21](Cl)=[O:22].C(N(CC)CC)C>O1CCCC1>[F:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[C:21]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][CH:2]([CH3:12])[CH3:1])=[O:22]
Reactant: CC(C)CCc1ccccc1N
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1CCC(C)C
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
326.5 mg (2.0 mmol) of [2-(3-methylbutyl)phenyl]amine (III-1) are added to a solution comprising 388.5 mg (2.2 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride and 0.45 ml (3.2 mmol) of triethylamine in 20 ml of tetrahydrofuran. The reaction solution is stirred at 60° C. for 90 min, filtered through silica gel and concentrated. Column chromatography (cyclohexane/ethyl acetate gradient) gives 592 mg (98% of theory) of 5-fluoro-1,3-dimethyl-N-[2-(3-methylbutyl)phenyl]-1H-pyrazole-4-carboxamide of logP (pH 2.3)=3.12.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[O:18][C:12]2[NH:13][CH:14]=[CH:15][C:16](=O)[C:11]=2[CH:10]=1)=[O:8]>CN(C)C=O>[CH3:5][O:6][C:7]([C:9]1[O:18][C:12]2=[N:13][CH:14]=[CH:15][C:16]([Cl:3])=[C:11]2[CH:10]=1)=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc2c(=O)cc[nH]c2o1
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)ccnc2o1

Procedure:
After adding thionyl chloride (8.0 ml) and dimethylformamide (0.08 ml) to 4-oxo-4,7-dihydro-furo[2,3-b]pyridine-2-carboxylic acid methyl ester (2.0 g), the mixture was heated to reflux for 1 hour. After cooling, the mixture was concentrated under reduced pressure and the precipitated crystals were filtered out and washed with tetrahydrofuran and ethyl acetate to obtain the title compound (2.1 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-])=O.[Cl-].[NH4+]>CC(C)=O.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1/C=C/c1ccc(O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: Nc1cc(O)ccc1/C=C/c1ccc(O)cc1
Yield: 81.2 %

Procedure:
To a solution of the product of 3-nitro-4-[(E)-2-(4-hydroxyphenyl)-vinyl]phenol (216 mg, 0.84 mmol) in acetone (6 mL) was added a solution of ammonium chloride (89.9 mg, 1.68 mmol) in 2 mL of water. The mixture was heated to reflux, and the oil bath was removed. Zinc dust (164.8 mg, 2.5 mmol) was added in small portions to the reaction mixture to maintain a moderate reaction. After the reaction subsided an additional portion of zinc (82.4 mg, 1.25 mmol) was added. The reaction mixture was then heated to reflux for an additional 2 h. The precipitate was removed by filtration, washed with acetone (2×20 mL) and with ethyl acetate (2×30 mL). The combined washings were concentrated in vacuo and the crude product was purified by column chromatography using 5% methanol in dichloromethane to afford 3-Amino-4-[(E)-2-(4-hydroxy-phenyl)vinyl]phenol (155 mg, 72%). MS (ES) m/z: 228.11 (M+11), 134.06; 13C-NMR (DMSO-d6): δ 158.3, 156.9, 147.9, 130.4, 130.2, 127.9, 126.9, 124.5, 122.0, 115.9, 115.5, 114.2, 105.4, 102.2. Mp. 229-232° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=O)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)[CH3:2].[CH:14]1[C:19]([NH:20][NH2:21])=[CH:18][CH:17]=[C:16]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:15]=1.Cl>>[CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[N:21][NH:20][C:19]3[CH:18]=[CH:17][C:16]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CCc1ccc2c(c1)NC(=O)C2=O
Agent: Cl
Product: CCc1ccc2c(c1)NC(=O)C2=NNc1ccc(S(N)(=O)=O)cc1
Yield: 79 %

Procedure:
The title compound was prepared from 6-ethyl-1H-indole-2,3-dione (Krantz and Young, 1989, U.S. Pat. No. 4,873,232) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 79% yield: 1H NMR (DMSO-d6): δ 1.16 (t, J=7.5 Hz, 3H), 2.60 (q, J=7.5 Hz, 2H), 6.74 (s, 1H), 6.89 (d, J=7.5 Hz, 1H), 7.22 (s, 2H), 7.46 (d, J=7.5 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 11.02 (s, 1H), 12.70 (s, 1H); APCI-MS m/z 343 (M−H)−. Anal. Calcd for C16H16N4O3S.0.32H2O: C, 54.88, H, 4.79; N, 16.00; S, 9.16. Found C, 54.81, H, 4.59; N, 16.06; S, 9.04.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](B(O)O)[N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[CH2:21]([O:28]N1C=CC=C(Br)C1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.CN(C=O)C>[CH2:21]([O:28][C:2]1[CH:3]=[C:4]([C:7]2[NH:8][C:9]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH:5]=[CH:9][CH:10]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: BrC1=CC=CN(OCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2cc(-c3cccc(OCc4ccccc4)c3)[nH]c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A flask is charged with 6-chloro-1-Boc-indole-2-boronic acid (0.839 g, 2.83 mmol), 1-benzyloxy-3-bromo-pyridine (0.500 g, 1.89 mmol), potassium phosphate (1.2 g, 5.67 mmol) and DMF (5 mL). The flask is evacuated and filled with nitrogen thrice and Pd(PPh3)4 (0.164 g, 0.141 mmol) is added. The flask is evacuated and filled with nitrogen thrice again, and heated to 80° C. for 3.5 h. The mixture is then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is redissolved in DCM (1 mL) and trifluoroacetic acid (2 mL) is added. After 1 h, 4M aqueous NaOH is added and following extraction with DCM, the organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to afford 2-(3-benzyloxy-phenyl)-6-chloro-1H-indole as a yellow solid. MS (ESI) m/z 335.07 (M+H)+.