Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1F>>[CH3:9][O:10][C:11](=[O:20])[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:8]/[C:3](=[CH:4]/[CH3:5])/[C:2](/[NH2:1])=[CH:7]\[CH3:6]
Reactant: Nc1ccccc1S
Reactant: COC(=O)c1cc(F)ccc1F
Product: C/C=C(N)\C(=C/C)Sc1ccc(F)cc1C(=O)OC

Procedure:
Thus, 2-aminobenzenethiol may be reacted with 2,5-difluoro-benzoic acid methyl ester to form a 2-[(E)-2-amino-1-eth-(E)-ylidene-but-2-enylsulfanyl]-5-fluoro-benzoic acid methyl ester intermediate that can be converted by treatment with alkali to 2-[(E)-2-amino-1-eth-(E)-ylidene-but-2-enylsulfanyl]-5-fluoro-benzoic acid. The benzoic acid can be cyclized to form 2-fluoro-10H-dibenzo[b,f][1,4]thiazepin-11-one, that may be converted to 11-chloro-2-fluoro-dibenzo[b,f][1,4]thiazepine, that may be further reacted with piperazine to form the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][N:16]2[CH2:21][CH:20]=[CH:19][CH2:18][CH2:17]2)=[CH:13][CH:12]=1.[OH-].[Na+].CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1>CCOCC>[C:1]([O:10][C:11]1[CH:23]=[CH:22][C:14]([CH2:15][N:16]2[CH2:17][CH:18]=[CH:19][CH2:20][CH2:21]2)=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1ccc(CN2CC=CCC2)cc1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(Oc1ccc(CN2CC=CCC2)cc1)c1ccccc1
Reaction time: 2 h
Yield: 29 %

Procedure:
Benzoyl chloride (3.0 g.) was added to a vigorously stirred mixture of 1-(4-hydroxybenzyl)-1,2,3,6-tetrahydropyridine (4.0 g.) in N-sodium hydroxide solution (22 ml.) and ether (30 ml.). The mixture was stirred for 2 hours after the addition and then 3N-sodium hydroxide solution added to pH10. The subsequent mixture was extracted into ethyl acetate (2×30 ml.) and the combined extracts were dried (MgSO4) and evaporated. The residue was dissolved in acetone (50 ml.) and the solution was treated with concentrated hydrochloric acid to pH2. The solid which precipitated was collected by filtration and recrystallised from isopropanol to give 1-(4-benzoyloxybenzyl)-1,2,3,6-tetrahydropyridine (1.8 g.), m.p. 220°-227° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)(C)C.[C:20]([O:24][C:25](OC([O-])=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>[OH-].[Na+]>[C:20]([O:24][C:25](=[O:26])[NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)CC1
Yield: 82.8 %

Procedure:
1-Benzylpiperidin-4-ylamine (3 g, 15.8 mmol), the starting material, was dissolved in 1M aqueous sodium hydroxide solution (35.8 ml) and t-butanol (32 ml) in a 250 ml vessel, and t-butyl-dicarbonate ((t-Boc)2O; 3.79 g, 17.38 mmol) was added thereto while stirring, and the resulting mixture was reacted at room temperature for 12 hrs. After the completion of reaction, the reaction mixture was extracted with ethyl acetate twice. Then, the organic layer was washed with 0.1N hydrochloric acid solution and brine in order, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue thus obtained was purified with a silica gel column chromatography to obtain 3.80 g of the title compound as a white solid (82.8%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:10][C:11]2[C:17]([Cl:18])=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[Cl:19])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Cl:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([O:10][C:11]2[C:12]([Cl:19])=[CH:13][C:14]([NH:15][C:26]([NH:25][C:23](=[O:24])[C:22]3[C:28]([Cl:32])=[CH:29][CH:30]=[CH:31][C:21]=3[Cl:20])=[O:27])=[CH:16][C:17]=2[Cl:18])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: Cc1cc(C#N)cnc1Oc1c(Cl)cc(N)cc1Cl
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)cnc1Oc1c(Cl)cc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)cc1Cl
Yield: 71.1 %

Procedure:
To a 100 mL flask equipped with magnetic stirrer, condenser, under nitrogen atmosphere was added 4-(3-methyl-5-cyano-2-pyridinoxy)-3,5-dichloroaniline (1.7 g, 5.78 mmol) and toluene (15 mL). The resulting mixture was heated up to 90° to form a solution. A solution of 2,6-dichlorobenzoylisocyanate (2.0 g, 9.25 mmol) in 2 mL of toluene was added to the above solution. The resulting mixture was heated at 90° for 1.5 hours and then cooled. The cold reaction mixture was filtered and the solid was washed with cold toluene. The solid was vacuum dried to afford an orange solid (2.1 g, 4.11 mmol). m.p. 245°-246°
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:44])[CH2:29][C:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:32]=1)(C)(C)C>>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:44])[CH2:29][C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[N:38]=[CH:39][CH:40]=[CH:41][N:42]=4)[CH:32]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ncccn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (160 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K44) (179 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (43 mg).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:22])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[C:23]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1C(O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:22])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1

Procedure:
By the same procedure as in Example 26-D), while using (2S)-1-(tert-butoxycarbonyl)-2-(1-hydroxy-2-phenoxyethyl)pyrrolidine (1.93 g) and N-(tert-butoxycarbonyl)-L-proline (1.36 g), there was obtained 2. i0 g of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.Cl[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: ClCc1cccnc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Agent: Cl
Product: Cc1c(C)c2c(c(C)c1OCc1cccnc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 76 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 3-chloromethylpyridine hydrochloride, the title compound was obtained in the same manner as in Example 1. This was oily.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:21][N:20]=[CH:19][N:18]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]([C@H:33]([CH3:37])[C:34](O)=[O:35])[CH2:28][CH2:27][CH2:26]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]([C@H:33]([CH3:37])[C:34]([N:4]1[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]4[S:21][N:20]=[CH:19][N:18]=4)(=[O:15])=[O:14])=[CH:11][CH:12]=3)[CH2:2][CH2:3]1)=[O:35])[CH2:28][CH2:27][CH2:26]2
Reactant: C[C@H](C(=O)O)N1CCCc2cc(Cl)ccc21
Reactant: O=S(=O)(Nc1ncns1)c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C(=O)N1CCN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CC1)N1CCCc2cc(Cl)ccc21
Yield: 60.9 %

Procedure:
Synthesized according to general procedure 5, method B. The reaction was set up with 4.5 mmol 4-(piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, 4.5 mmol (R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoic acid, 5.5 mmol HATU, 5.4 mmol sodium bicarbonate and 12 mL (1:1) DMF:methylene dichloride to get (R)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a white solid (1.5 g, 61% yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=547.5; tR=3.44 min. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.58 (d, J=9.1 Hz, 2H), 7.04-6.96 (m, 4H), 6.78 (d, J=9.1 Hz, 1H), 4.88-4.84 (m, 1H), 3.73-3.69 (m, 1H), 3.58-3.53 (m, 1H), 3.43-3.37 (m, 4H), 3.26-3.18 (m, 2H), 3.11-2.95 (m, 2H), 2.73-2.64 (m, 2H), 1.84-1.73 (m, 2H), 1.84-1.08 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#N)=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C[OH:28].Cl>C1(C)C=CC=CC=1.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:28])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(O)cc2)ccc1C#N
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(-c2ccc(O)cc2)ccc1C=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
A solution of 4′-hydroxy-3-methyl[1,1′-biphenyl]-4-carbonitrile (500 mg, 2.39 mmol) in dry toluene was cooled to −78° C. and diisobutylaluminum hydride (4.0 mL of 1.5 M solution in toluene, 5.98 mmol) was added all at once. The reaction mixture was allowed to warm to room temperature over a period of 3.5 h. Methanol (1.2 mL) was added followed by water (1.2 mL) at 0° C. and the mixture was stirred at room temperature for 20 min. 1 N HCl solution was added with stirring until pH<7. The mixture was extracted with ethyl acetate (3×), washed with brine, dried over sodium sulfate, filtered, and the solvent evaporated. Purification by silica chromatography (15%-25% ethyl acetate-hexane) to yield 459 mg (91%) of the title compound as a white solid: mp 161-162° C.; 1H NMR (DMSO-d6): δ 2.67 (3H, s), 6.88 (2H, d, J=8.41 Hz), 7.59-7.65 (4H, m), 7.85 (1H,d, J=8.03 Hz), 9.78 (1H, s), 10.22 (1H, s); IR 1680 cm−1; MS (ESI) m/z 211 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1.CCN(C(C)C)C(C)C.Cl>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@H]1CNC[C@@H]1O
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2, 500 mg, 1.264 mmol, (3S,4S)-pyrrolidine-3,4-diol (157 mg, 1.517 mmol), DIPEA (442 μL, 2.53 mmol) and iPrOH (1.264 mL) were added to a MW vial, which was sealed and subjected to MW irradiation for 30 min at 140° C. The solvent was evaporated off under reduced pressure to give a residue which was treated with 0.5 M HCl (10 mL) and extracted with EtOAc. The combined extracts were washed with HCl 0.5 M and brine, diluted with MeOH (20 mL), dried over MgSO4 and the solvent was evaporated off under reduced pressure and the product was crystallized from EtOAc/MeOH afforded the title compound as a white solid. UPLC-MS (condition 1) tR=2.48 min, m/z=462.0/464.0 [M+H]+, m/z=460.0/462.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.56 (d, J=11.25 Hz, 2H) 3.94-4.06 (m, 4H) 4.79 (br. s, 2H) 7.34 (d, J=8.80 Hz, 2H) 7.88 (d, J=9.05 Hz, 2H) 8.38 (d, J=1.96 Hz, 1H) 8.71 (d, J=1.96 Hz, 1H) 10.34 (s, 1H).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[C@H:15]([NH2:35])[CH2:14][C@@H:13]1[CH3:36])(=[O:11])[CH3:10].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].BrC1C=CC=CN=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:9]([N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[C@H:15]([NH:35][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:14][C@@H:13]1[CH3:36])(=[O:11])[CH3:10]
Reactant: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](N)C[C@@H]1C
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: Brc1ccccn1
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](Nc2ccncc2)C[C@@H]1C
Temperature: 110 °C
Reaction time: 20 h
Yield: 13.88 %

Procedure:
A flask was charged with 4-bromopyridine hydrochloride (61.8 mg, 0.318 mmol), (cis)-1-acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 25) (100 mg, 0.265 mmol), racemic BINAP (8.25 mg, 0.013 mmol), sodium tert-butoxide (30.5 mg, 0.318 mmol) and tris(dibenzylideneacetone)dipalladium(0) (12.13 mg, 0.013 mmol) then filled with toluene (2.5 mL). The resulting mixture was stirred at 110° C. under nitrogen for 20 h then cooled to room temperature. An extra 1.2 equivalent of 4-bromopyridine hydrochloride (60 mg) and sodium tert-butoxide (30 mg) were added as well as racemic BINAP (0.05 equivalent, 8 mg) and the resulting mixture was stirred at 110° C. for 5 h. After the mixture was cooled to room temperature, a further 1.2 eq of bromopyridine (62 mg) was added and the reaction mixture stirred at 110° C. for 16 h then cooled to room temperature. An extra 0.05 eq of racemic BINAP (8 mg) and tris(dibenzylideneacetone)dipalladium(0) (12 mg) were added and the resulting mixture stirred at 110° C. for 5 h then cooled to room temperature and loaded onto a 5 g SCX column then eluted with MeOH (2 column volume (CV)) followed by 2M NH3 in MeOH (4 CV). The ammonia fractions were combined and concentrated in vacuo. Purification of the residue by MDAP (modifier: trifluoroacetic acid) gave cis-1-acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-N-4-pyridinyl-1,2,3,4-tetrahydro-4-quinolinamine (22 mg, 0.037 mmol, 13.88% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:26]([CH:29]([CH3:31])C)=[C:27]=[O:28]>C(N(CC)CC)C>[C:27]([N:26]1[CH2:29][CH2:31][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:2]=3[Cl:1])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:28])[CH2:8][CH2:7][CH3:16]
Reactant: CC(C)N=C=O
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccc(Cl)cc3Cl)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2,4-dichloro-benzoylamino)-naphthalene-1-sulfonyl chloride and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.87 (s, 1H), 8.70 (dd, 1H), 8.34 (dd, 1H), 8.21 (d, 1H), 8.13 (d, 1H), 8.01 (d, 1H), 7.82 (m, 2H), 7.73 (m, 1H), 7.63 (d, 1H), 4.00 (d, 1H), 3.6 (d, 1H), 3.24 (m, 1H), 2.92 (t, 1H), 2.59 (m, 1H), 2.17 (t, 2H), 1.47 (m, 2H), 1.43 (m, 2H), 1.18 (m, 2H), 0.82 (t, 3H). LC/MS m/z 548 (M−H)−, 560 (M+H)+
Reaction SMILES: C([N:8]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][OH:18])[CH:10]=[CH:9]1)C1C=CC=CC=1.[BrH:19]>O.[Pd]>[BrH:19].[OH:18][CH2:17][CH2:16][O:15][C:11]1[CH:10]=[CH:9][NH:8][CH:14]=[CH:13][CH:12]=1
Reactant: OCCOC1=CC=CN(Cc2ccccc2)C=C1
Agent: [Pd]
Agent: Br
Solvent: O
Product: OCCOC1=CC=CNC=C1

Procedure:
To a suspension of (B) (7.5 g) in water (20 ml), 1 N hydrobromic acid (30 ml) was added. The clear solution was hydrogenated over 10% palladium on carbon catalyst (4 g). After 3 hours the consumption of hydrogen ceased; the catalyst was filtered off, and the filtrate taken to dryness in vacuo. The residue was distilled twice with chloroform to give (C) as a viscous oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([OH:13])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.CCOC(C)=O>[CH3:14][O:13][C:11]1[CH:10]=[N:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=1
Reactant: Oc1cnn(Cc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of 1-benzyl-1H-pyrazol-4-ol (Intermediate 4) (3.5 g, 20.1 mmol) and Cs2CO3 (8 g, 24.6 mmol) in DMF (100 mL) was added MeI (2 mL, 32 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with EtOAc, washed with ice/brine. The aqueous was extracted with EtOAc, the combined organic solvents were removed under reduced pressure and the residue was purified by flash chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 60:40 as eluant) to give the title compound 4-(methyloxy)-1-(phenylmethyl)-1H-pyrazole (2.5 g, 13.3 mmol, 63% yield) as a yellow oil. LCMS: (M+H)+=189; Rt=0.81 min.
Reaction SMILES: C(NC1SC(S(NC2C=CC(CC([NH:24][C:25]3[C:26](=[O:45])[N:27]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[F:44])[C:28](=[O:36])[N:29]([CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:30]=3[NH2:31])=O)=CC=2)(=O)=O)=C(C)N=1)(=O)C.[Cl:46][C:47]1[N:51]([CH3:52])[N:50]=[C:49]([CH3:53])[C:48]=1[S:54]([NH:57][C:58]1[CH:59]=[CH:60][C:61]([CH2:64][C:65]([OH:67])=O)=[N:62][CH:63]=1)(=[O:56])=[O:55].NC1C(=O)N(CC2C=CC=CC=2F)C(=O)N(CCCC)C=1N>>[NH2:31][C:30]1[N:29]([CH2:32][CH2:33][CH2:34][CH3:35])[C:28](=[O:36])[N:27]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[C:26](=[O:45])[C:25]=1[NH:24][C:65](=[O:67])[CH2:64][C:61]1[CH:60]=[CH:59][C:58]([NH:57][S:54]([C:48]2[C:49]([CH3:53])=[N:50][N:51]([CH3:52])[C:47]=2[Cl:46])(=[O:55])=[O:56])=[CH:63][N:62]=1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)O)nc1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Nc2ccc(CC(=O)Nc3c(N)n(CC4CC4)c(=O)n(Cc4ccccc4F)c3=O)cc2)s1
Agent: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Product: CCCCn1c(N)c(NC(=O)Cc2ccc(NS(=O)(=O)c3c(C)nn(C)c3Cl)cn2)c(=O)n(Cc2ccccc2F)c1=O

Procedure:
Prepared as for 2-[4-(2-acetylamino-4-methyl-thiazole-5-sulfonylamino)-phenyl]-N-[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetamide (example 10, step 1) except using [5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetic acid and 5,6-diamino-1-butyl-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione. N-[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-[5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetamide was used without purification (91%); LRMS for C27H30ClFN8O5S (M+H)+ at m/z=633/635.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[N:6][CH:5]=1.[BH4-].[Na+].O>CO.O1CCCC1>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(C#N)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
6-Cyanonicotinic acid methyl ester (701 mg) was dissolved in a mixed solvent of methanol (1 ml) and tetrahydrofuran (7 ml) and sodium borohydride (197 mg) was added under ice-cooling. The mixture was directly heated to room temperature and stirred overnight. Water (20 ml) was added, and the mixture was extracted with ethyl acetate (once with 50 ml and once with 30 ml), washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified with column chromatography (Yamazen HI-FLASH™ COLUMN size 2 L, elution solvent: hexane/ethyl acetate) to give the title compound (264 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([S:23][CH3:24])=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH3:24][S:23][C:18]1[C:17]2[C:21](=[CH:22][C:14]([C:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH:12]=3)=[CH:15][CH:16]=2)[N:20]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)[N:19]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CSc1n[nH]c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc12
Product: CSc1nn(-c2ccc(C)cc2)c2cc(C3=CCNCC3)ccc12

Procedure:
The title compound was prepared as a white solid by coupling 4-(3-methylsulfanyl-1H-indazol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester and 4-methyl-phenyl boronic acid to yield an intermediate, which was de-protected to remove the N-Boc.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH2:19]([C:21]1[O:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1)[CH3:20]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:24]3[N:25]=[C:21]([CH2:19][CH3:20])[O:22][CH:23]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: CCc1nc(C(=O)O)co1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: CCc1nc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)co1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 2-ethyl-oxazole-4-carboxylic acid following procedure I yielded the title compound as a brown oil. MS (ISP): m/z=383.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[CH2:54][CH2:55][C:56]1[CH:57]=[C:58]([CH:61]=[CH:62][CH:63]=1)[C:59]#[N:60]>CCOC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:49]3[CH2:53][CH2:52][CH2:51][CH:50]3[CH2:54][CH2:55][C:56]3[CH:57]=[C:58]([CH:61]=[CH:62][CH:63]=3)[C:59]#[N:60])=[O:15])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1cccc(CCC2CCCN2)c1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(C(=O)N3CCCC3CCc3cccc(C#N)c3)cc2)cn1
Yield: 44 %

Procedure:
A flask containing 4-(6-Methoxy-pyridin-3-yl)-benzoic acid (0.114 g, 0.5 mmol) and DMF (3 mL) is stirred. To this is added Diisopropylethylamine (87 uL, 0.5 mmol) followed by TBTU (0.16 g, 0.5 mmol) and stirred 2 minutes. A solution of 3-(2-Pyrrolidin-2-(R,S)-ylethyl)-benzonitrile (0.10 g, 0.5 mmol) and DMF (1 mL) is added and the reaction stirred for 24 h. The reaction mixture is diluted with EtOAc (100 mL) and washed with saturated sodium bicarbonate (4×20 mL), brine (25 mL), dried over MgSO4 and concentrated. Purification by flash chromatography (1:1/EtOAc:Hexanes) gives the title compound as a clear oil (0.09 g, 0.22 mmol). 1H NMR (CDCl3, 300 MHz) 8.38(s, 1H), 7.81(d, 1H), 7.65-7.35(m, 8H), 6.83(d, 1H), 4.40-4.25(m, 1H), 3.97(s, 3H), 3.58-3.45(m, 2H), 2.82-2.68(m, 2H), 2.45-2.30(m, 1H), 2.25-2.10(m, 1H), 2.02-1.86(m, 1H), 1.85-1.65(m, 3H).