Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])=[C:17]([O:27][CH3:28])[CH:16]=2)[C:11](=[O:29])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:26])([CH3:24])[CH3:25])=[C:17]([O:27][CH3:28])[CH:16]=2)[C:11](=[O:29])[CH:10]=1
Reactant: COc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1OCC(C)(C)O
Agent: [Pd]
Solvent: CO
Product: COc1cc(-n2ccc(O)cc2=O)ccc1OCC(C)(C)O
Reaction time: 4 h
Yield: 98 %

Procedure:
A mixture of 4-(benzyloxy)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one Part B (287 mg, 0.73 mmol) and 10% Pd/C (7.72 mg, 0.073 mmol) in MeOH (15 mL) was hydrogenated at 50 PSI of H2 for 4 hours. Pd/C was filtered off and the filtrate was concentrated giving 4-hydroxy-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one 7C (228 mg, 98% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.C([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[C:29](Cl)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:21]1=[O:37])(=O)C>ClCCl>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7]/[C:29](=[C:22]2\[C:21](=[O:37])[NH:20][C:28]3[C:23]\2=[CH:24][CH:25]=[CH:26][CH:27]=3)/[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.18 g (1.5 mmol) of 4-methoxyaniline and 0.2 g (0.28 mmol) of triethylamine are dissolved in 5 ml of dichloromethane and at 5° C. combined with a solution of 0.45 g (1.5 mmol) of 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone in 10 ml of dichloromethane and then stirred for 3 hours at ambient temperature. After removal of the solvent in vacuo the residue is taken up in ethyl acetate/water. The organic phase is washed with water, dried and the solvent is eliminated in vacuo. Then the mixture is dissolved in 15 ml of methanol, combined with 3 ml of 1N sodium hydroxide solution, stirred for 3 hours at ambient temperature and diluted with water and ethyl acetate. The organic phase is dried and concentrated by evaporation. The residue is heated in ethyl acetate, cooled, then suction filtered and dried.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1.[H-].C([Al+]C(C)C)(C)C.[Cl-].[NH4+].Cl>ClCCl.CCCCCC.O>[F:13][C:12]([F:14])([F:15])[C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CCc1cccc(C(F)(F)F)c1
Agent: CC(C)[Al+]C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: O=CCCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 101.5 %

Procedure:
2.40 g of 3-(3-trifluoromethylphenyl)-propionic acid methyl ester synthesized in Step 1 was dissolved in 20 ml of dry dichloromethane. 13 ml of diisopropyl aluminum hydride solution (0.91 M) in hexane was dropped over 5 minutes at −78° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 40 minutes. 50 ml of a saturated ammonium chloride aqueous solution was dropped, and then the mixture was stirred and the temperature was raised to room temperature. 20 ml of water and 5 ml of concentrated hydrochloric acid were added, and the resultant was separated into an aqueous layer and an organic layer. The aqueous layer was extracted with dichloromethane, and the extract was combined with the separated organic layer, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to afford 2.12 g of the captioned compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:5]=[C:4]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[N:5]=[C:4]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1N1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1N1CCCCC1
Yield: 32.2 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-2,6-di(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.042 g; 0.112 mmol), sodium hydroxide 10N (0.150 mL; 1.50 mmol) in methanol (2 mL) at 60° C. for 18 h. Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane, followed by a purification by preparative HPLC (HPLC method 2) furnished 0.013 g (31%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:15][OH:16]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH:15]=[O:16]
Reactant: CN(C)CCCc1c(CO)[nH]c2ccccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CN(C)CCCc1c(C=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Manganese dioxide (10 equiv.) was added to a solution of [3-(3-dimethylaminopropyl)-1H-indol-2-yl]methanol (2.2 g) in DCM. The mixture was stirred at room temperature for 18 hr. Insoluble materials were removed by filtration and the filtrate was concentrated. The residue was column chromatographed to give 3-(3-dimethylaminopropyl)-1H-indole-2-carbaldehyde as a cream-colored solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:5]1[N:6]([CH3:28])[C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[C:16]([CH3:25])=[C:17]3[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=[C:10]([OH:26])[CH:9]=2.C([O-])([O-])=O.[K+].[K+].BrC[CH2:43][CH2:44][OH:45]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:34])[CH:4]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:5]1[N:6]([CH3:28])[C:7](=[O:27])[C:8]2[C:13]([C:14]=1[C:15]1[C:16]([CH3:25])=[C:17]3[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=[C:10]([O:26][CH2:43][CH2:44][OH:45])[CH:9]=2
Reactant: OCCCBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccc(O)cc2c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2ccc(OCCO)cc2c(=O)n1C
Yield: 34.6 %

Procedure:
To a solution of tert-Butoxy-[7-hydroxy-2-methyl-4-(5-methyl-chroman-6-yl)-1-oxo-1,2-dihydro-isoquinolin-3-yl]-acetic acid methyl ester (50 mg, 0.17 mmol) in DMF (1 ml) was added K2CO3 (44.5 mg, 0.322 mmol) and 3-bromopropan-1-ol (40.3 mg, 0.322 mmol) at RT. The resultant mixture was stirred at 70° C. for 3 hr. The reaction mixture was diluted with water and extracted with EA (10 mL*3), dried over sodium sulfate and concentrated to dryness. The mixture was purified by Pre-TLC to afford the title product (30 mg, 55%). LCMS (10-80 AB—2MIN.M): Rt=1.223, purity=93.7%, M+1=510.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=3)=[N:9][C:7]=2[N:8]=1.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]2[N:38]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[NH:36][N:35]=2)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O.CN(C=O)C>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:19]3[CH:26]=[CH:25][C:22]([CH2:23][N:28]4[CH2:33][CH2:32][CH:31]([C:34]5[NH:38][C:37]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=6)=[N:36][N:35]=5)[CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[N:9][C:7]=2[N:8]=1
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Reactant: CSc1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CSc1ncc2cc(-c3ccccc3)c(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)nc2n1
Reaction time: 3 h

Procedure:
A mixture of 4-[2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]benzaldehyde (1-4) (0.200 g, 0.56 mmol), 2-(3-piperidin-4-yl-1H-1,2,4-triazol-5-yl)pyridine HCl salt (A [see synthesis below]; 0.193 g, 0.727 mmol), and TEA (0.074 g, 0.727 mmol) were stirred in 5% AcOH in DMF for 0.5 hr. Sodium triacetoxyborohydride (0.178 g, 0.0.839 mmol) was then added and the reaction was stirred for 3 hr. The reaction was quenched with 3N NaOH and extracted 3×w/CH2Cl2. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by silicon gel chromatography (6% MeOH in CH2Cl2) to give the titled compound. 1H-NMR (500 MHz, d6 DMSO) δ 9.50 (s, 1H), 8.64-8.72 (m, 2H), 8.58 (s, 1H), 7.88-8.07 (m, 3H), 7.28-7.56 (m, 9H), 3.52 (s, 2H), 2.84 (m, 2H), 2.66 (s, 3H), 2.11 (m, 3H), 1.96 (m, 2H), 1.78 (m, 2H). LRMS m/z (M+H) calcd: 571.7, found: 571.2.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH2:27][CH2:28][CH2:29]Cl)(=[O:26])=[O:25])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:29][CH2:28][CH2:27][S:24]4(=[O:26])=[O:25])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCC1CN(c2ccc(NS(=O)(=O)CCCCl)cc2)C(=O)O1)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCC1CN(c2ccc(N3CCCS3(=O)=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 100 °C

Procedure:
A mixture of 13.5 mg (0.027 mmol) of 5-chloro-N-{[3-(4-{[(3-chloropropyl)sulphonyl]amino}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophene-carboxamide (from Example 159) and 7.6 mg (0.055 mmol) of potassium carbonate in 0.2 ml of DMF is heated at 100° C. for 2 h. After cooling, the mixture is diluted with dichloromethane and washed with water. The organic phase is dried and concentrated. The residue is purified by preparative thin-layer chromatography (silica gel, dichloromethane/methanol, 95:5). Yield: 1.8 mg (14.4% of theory),
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
(+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (150 mg, 0.38 mmol, prepared in example 17) was treated with 4-cyanophenyl boronic acid (56 mg, 0.38 mmol), palladium tetrakis triphenylphosphine (22 mg, 0.02 mmol) and cesium carbonate (150 mg, 0.46) under nitrogen in 10 mL of degassed dioxane. The reaction was heated to 85° C. and stirred overnight. The reaction was concentrated in vacuo and purified by radial chromatography eluting with 30:70 ethyl acetate:hexanes to give 12 mg (9%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[C:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:26]=1.C(N(CC)CC)C>CS(C)=O.O>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[CH:18]=[C:19]2[CH2:20][CH2:21][N:22]([C:32]([NH:31][C:27]3[N:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[O:33])[CH2:23][CH2:24]2)=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: CC(C)Oc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.1 %

Procedure:
To a solution of 5-isopropoxy-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.18 g, 0.55 mmol) in DMSO (3 mL) was added phenyl pyridazin-3-ylcarbamate (0.118 g, 0.55 mmol) followed by triethylamine (0.235 mL, 1.692 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% acetone, 70% hexane) to give the title compound (0.13 g, 52.6%). 1H NMR (500 MHz, CDCl3): δ 8.80 (s, 1H), 8.30 (s, 1H), 7.86 (d, J=3 Hz, 1H), 7.40 (m, 1H), 7.31 (t, J=8 Hz, 1H), 7.28 (m, 1H), 6.93 (m, 3H), 6.86 (d, J=8.5 Hz, 1H), 6.40 (s, 1H), 4.45 (q, J=6 Hz, 1H), 3.67 (m, 2H), 3.57 (m, 2H), 2.6 (m, 2H), 2.46 (m, 2H), 1.33 (d, J=6 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 157.33, 156.57, 155.18, 150.69, 138.70, 137.37, 135.54, 129.41, 128.33, 128.03, 125.0, 124.58, 120.63, 118.43, 112.45, 71.65, 45.64, 44.62, 35.75, 29.13, 21.96; m/z (446.2, M+ H+); HPLC: 98.5%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH2:15])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[Cl:16])=[O:4].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[Cl:16])=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1cc2c(cc1Cl)[C@@H](N)CCS2
Product: COC(=O)c1cc2c(cc1Cl)[C@@H](NC(=O)OCc1ccccc1)CCS2

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 4 using (S)-4-amino-6-chlorothiochromane-7-carboxylic acid methyl ester (450 mg) and benzyloxycarbonyl chloride (0.31 ml), the objective (S)-4-(benzyloxycarbonylamino)-6-chlorothiochromane-7-carboxylic acid methyl ester (478 mg) was obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:22](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][N:22]=[CH:9]2
Reactant: Cc1cc(Br)ccc1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Brc1ccc2[nH]ncc2c1
Temperature: 68 °C
Reaction time: 0.83 h
Yield: 94 %

Procedure:
A flask containing 4-bromo-2-methylaniline (95.0 g) in chloroform (0.70 L) was treated with acetic anhydride (0.109 L) at <40° C. The solution was stirred for 50 minutes and potassium acetate (14.6 g) and isoamyl nitrite (0.147 L) was charged. The solution was refluxed at 68° C. for 20 h. The temperature was cooled to 25° C. and the volatiles distilled at 30 mmHg vacuum (T=30-40° C.). Once most of the solvents had distilled, a total of 225 mL of water was charged in portions and the azeotrope of water and the various volatiles distilled. The product mass was transferred back into the reaction vessel using water (50 mL) and concentrated hydrochloric acid (400 mL) charged. The mixture was heated to 50-55° C. and another 100 mL acid charged in portions over 2 h. The solution was cooled to 20° C. and 50% sodium hydroxide (520 g) was charged at <37° C. to bring the pH to 11. Water (100 mL) and ethyl acetate (350 mL) was added and the mixture filtered through a Celite pad. The layers were separated and the aqueous phase further extracted with ethyl acetate (2×200 mL). The combined organic layers were mixed with brine (240 mL), filtered through a Celite pad and separated. The organic solution was dried over magnesium sulfate (3 g) and filtered through a silica gel pad (45 g) with ethyl acetate. The eluant was concentrated by rotary evaporation, adding a total of 0.45 L of heptane during the distillation and continueing until only dry solids remain. The solids were slurried with heptane (0.1 L), filtered and dried under vacuum at 45° C. to produce 91.9 g of 5-bromoindazole (94% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([Cl:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)ccn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1cc(Br)ccn1)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 61.6 %

Procedure:
1.0 g (5.8 mmol) of 4-bromo-2-methylpyridine and 2.14 g (11.6 mmol) of ethyl 4-chlorobenzoate are placed under a stream of argon in a round-bottomed flask and dissolved in 10 ml of anhydrous tetrahydrofuran. The solution is cooled to 0° C. and 12 ml of a lithium hexamethyldisilazane (LiHMDS) solution (1M in tetrahydrofuran) are added. After addition, the mixture is heated at 45° C. for 3 h and cooled to ambient temperature, and then water is added. The tetrahydrofuran is subsequently evaporated under reduced pressure and the aqueous phase is extracted three times with ether. The organic phase is separated, dried and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel, elution being carried out with a mixture of dichloromethane and heptane. 1.11 g (62%) of compound are obtained.
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[CH:6][N:5]=[N:4][C:3]=1[OH:9].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[C:7]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:6][N:5]=[N:4][C:3]=2[OH:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: Oc1nncc(Cl)c1Cl
Product: Oc1nncc(N2CCCCC2)c1N1CCCCC1
Yield: 75 %

Procedure:
4,5-Dichloro-3-hydroxypyridazine (25.0 g; 0.151 mol) was dissolved in piperidine (120 mol), under reflux condition for 24 hours. After cooling, the deposited crystal was filtered, to give 4,5-dipiperidino-3-hydroxypyridazine in white crystal (30.3 g as a yield of 75%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O>C(OCC)(=O)C.C(O)(=O)C.ClCCl.[Pd]>[N:16]1([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)cc(N2CCOCC2)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(-c2ccccc2)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pd/C (53.9 mg, 0.051 mmol) was added to a solution of 4-(5-nitrobiphenyl-3-yl)morpholine (144 mg, 0.506 mmol) in ethyl acetate (5 mL) and acetic acid (0.5 mL). The reaction mixture was stirred under H2 atmosphere (1 atm) for 2 hours at room temperature. The reaction mixture was diluted with dichloromethane and filtered through CELITE and washed with ethyl acetate. The resultant solution was concentrated in vacuo to provide 5-(morpholin-4-yl)biphenyl-3-amine as a grey solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=5.7 Hz, 2H), 7.36 (dd, J=32.4, 26.2 Hz, 3H), 6.58 (s, 1H), 6.49 (s, 1H), 6.27 (s, 1H), 5.13 (s, 2H), 3.89 (s, 4H), 3.21 (s, 4H).
Reaction SMILES: [C:1](O)(C(F)(F)F)=[O:2].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][NH:24][S:23](=[O:27])(=[O:26])[NH:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:28][C:29]([C:31]2[N:32](COCC[Si](C)(C)C)[CH:33]=[C:34]([C:36]#[N:37])[N:35]=2)=[O:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1>C(Cl)Cl.CCO>[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][NH:24][S:23](=[O:26])(=[O:27])[NH:22][CH2:21]3)[C:17]([CH2:1][OH:2])=[CH:16][C:15]=2[NH:28][C:29]([C:31]2[NH:32][CH:33]=[C:34]([C:36]#[N:37])[N:35]=2)=[O:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2cc(CO)c(C3CNS(=O)(=O)NC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
TFA (0.3 mL) was added to a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenyl]-amide (as prepared in Example 5, step (d), 21 mg, 0.030 mmol) in DCM (1 mL) and EtOH (30 μL). The resulting mixture was stirred at RT for 2 h and concentrated in vacuo. The residue obtained was purified on silica (20-50% EtOAc-hexane) to obtain the title compound (8.0 mg, 46%): 1H-NMR (CD3OD; 400 MHz): δ 8.10 (s, 1H), 8.05 (s, 1H), 7.11 (s, 1H), 5.78 (br s, 1H), 4.7 (ABq, 1H, J=16 Hz), 4.48 (ABq, 1H, J=16 Hz), 4.3 (m, 1H), 3.87 (m, 1H), 3.52 (m, 1H), 3.6 (m, 1H), 3.18 (m, 1H), 2.62 (br s, 1H), 2.22-2.34 (m, 4H), 1.72-1.90 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H24N6O4S, 439.1 (M−H2O+H). found 439.2.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.NN.O>C(O)CO>[CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c2ccccc2sc2ccccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: c1ccc2c(c1)Cc1ccccc1S2
Temperature: 140 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
Thioxanthone (0.21 g) was dissolved in ethylene glycol (1.5 ml). Potassium hydroxide (0.19 g) and hydrazine monohydrate (0.15 ml) were added to the solution. The mixture was heated at 140° C. with stirring for 2 hr and then at 200° C. for 4 hr. The temperature of the reaction solution was returned to room temperature. Water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4. The solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform) to give thioxanthene (0.12 g).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:10]=1[CH2:11][N:12]1[CH2:18][CH:17]([NH:19]C(=O)OC(C)(C)C)[C:16](=[O:27])[N:15]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:14][CH2:13]1>ClCCl>[NH2:19][CH:17]1[CH2:18][N:12]([CH2:11][C:10]2[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:9]=2[F:8])[CH2:13][CH2:14][N:15]([CH2:28][C:29]([F:31])([F:32])[F:30])[C:16]1=[O:27]
Reactant: CC(C)(C)OC(=O)NC1CN(Cc2cccc(F)c2F)CCN(CC(F)(F)F)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CN(Cc2cccc(F)c2F)CCN(CC(F)(F)F)C1=O
Reaction time: 1 h
Yield: 94 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl 1-(2,3-difluorobenzyl)-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-diazepan-6-ylcarbamate (62 mg, 0.142 mmol) in dichloromethane (5 mL). After 1 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (45 mg). MS 338 (M+1).