Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[CH3:35][NH2:36]>CN(C)C=O.O1CCCC1>[CH3:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[O:24][CH:25]=[C:26]([C:28]([NH:36][CH3:35])=[O:29])[N:27]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: CN
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)co2)c(=O)[nH]c1=S
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1coc(Cn2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=S)[nH]c2=O)n1

Procedure:
N,N'-Carbonyldiimidazole (0.073 g) and the product of example 37(0.2 g) in N,N-dimethylformamide (3 ml) was stirred at room temperature. After 0.5 h Methylamine (0.6 ml of a 2M solution in tetrahydrofuran) was added. After a further 0.5 h the solution was partitioned between water and ethyl acetate. The organic solution was washed with water and brine, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 20% ethyl acetate in iso-hexane. Yield 0. lg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Cl)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:5])[CH3:2].CC(C)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:26]=[N+:27]=[N-:28])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(N=[N+]=[N-])nc1-c1ccc(C(F)(F)F)cc1
Yield: 99.3 %

Procedure:
To a stirred solution of 2.41 g (7.18 mmole) of 2-chloro-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester, 2.4 mL of acetone and 2.4 mL of water was added 2.34 g (35.63 mmole) of sodium azide. The reaction mixture was heated at 70 degrees for 16 hours and then partitioned between 200 mL of ethyl acetate and 75 mL of water. The aqueous layer was extracted twice with 55 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2.44 g of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a dark amber oil.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[NH:10][C:11]([NH:13]C(=O)C1C=CC=CC=1)=[O:12])#[N:2].[OH-].[Na+]>CCO>[NH2:2][C:1]1[C:3]2[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=2[NH:10][C:11](=[O:12])[N:13]=1
Reactant: Cc1sc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc2[nH]c(=O)nc(N)c2c1C
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamoyl)benzamide (example 4a) (44.35 g, 148.1 mmol) and NaOH (2 N, 204 mL) in EtOH (400 mL) was stirred at 100° C. under nitrogen for four hours. The clear reaction solution was filtered and the filtrate was cooling to room temperature, and then was carefully neutralized with 10% AcOH (˜120 mL) with vigorous stirring at 0° C. After stirring overnight from 0° C. to room temperature, the resultant precipitate was collected by filtration, washed with warm water (60-70° C., 150 mL×4) and 20% EtOH in water (200 mL×2), and then dried at 50° C. under vacuum overnight to give the final product 4-amino-5,6-dimethylthieno[2,3-d]pyrimidin-2(1H)-one (27.7 g, 96%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (brs, 1H), 2.24 (s, 3H), 2.19 (s, 3H). MS 196 (MH+).
Reaction SMILES: [O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH:34]=[O:35])[N:31]=[C:30]2[N+:36]([O-:38])=[O:37])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].CC(C)=O>C(O)C>[O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH2:34][OH:35])[N:31]=[C:30]2[N+:36]([O-:38])=[O:37])[CH2:25][O:24][C:23]([CH3:26])([CH3:27])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:17])([CH3:16])[CH3:18])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2cc(C=O)nc2[N+](=O)[O-])CO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2cc(CO)nc2[N+](=O)[O-])CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
107 mg (0.20 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-formyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane was dissolved in 3.0 mL of ethanol, 10 mg (0.24 mmol equivalents) of sodium borohydride was added thereto, and the mixture was stirred at room temperature (25° C.) for 10 minutes. After completion of the reaction, acetone was added dropwise, and the mixture was concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=1/1) to give 101 mg (0.19 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-{(4-hydroxymethyl-2-nitro-1H-imidazol-1-yl)methyl}-1,3-dioxane.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[S:11].[Cl:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:12][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[S:11]
Reactant: CC1C(=S)Nc2ccccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(Cl)C(=S)Nc2ccccc21

Procedure:
A solution of 3-methylthiooxindole (1.70 g, 0.0095 mol) and N-chlorosuccinimide (1.34 g, 0.01 mol) in 100 ml of carbon tetrachloride was stirred at room temperature for 1 hour, the precipitate of succinimide was removed by filtration, and the filtrate was evaporated, yielding crude 3-chloro-3-methylthiooxindole. The residue, which was thus obtained, was dissolved in a minimum of tetrahydrofuran and added to a vigorously stirred slurry of red mercuric oxide powder (2.17 g, 0.01 mol) and boron trifluoride etherate (1.43 g, 0.01 mol) in 20 percent aqueous tetrahydrofuran (70 ml). After stirring at room temperature for 1 hour, 200 ml of ether was added, the reaction mixture was filtered through a pad of Celite and the organic phase of the filtrate was separated, dried over anhydrous magnesium sulfate, filtered, and this filtrate was evaporated to give isatin (1.07 g, 78%), mp 200°-202° after recrystallization from benzene.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@@:16]2([CH3:17])[N:12]([C:13](=[O:29])[N:14]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[C:20]=3[CH3:28])[C:15]2=[O:18])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C1COCC1>[Cl:27][C:21]1[C:20]([CH3:28])=[C:19]([N:14]2[C:15](=[O:18])[C@@:16]3([CH3:17])[C@H:9]([OH:8])[CH2:10][CH2:11][N:12]3[C:13]2=[O:29])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: Cc1c(N2C(=O)N3CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@]3(C)C2=O)ccc(C#N)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)N3CC[C@@H](O)[C@]3(C)C2=O)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A solution of (7R,7aR)-4-[7-(tert-Butyldimethylsilanyloxy)-7a-methyl-1,3-dioxotetrahydropyrrolo[1,2-c]imidazol-2-yl]-2-chloro-3-methylbenzonitrile (60B) (32 mg, 0.07 mmol) in THF (2 mL) in a plastic vial was cooled to 0° C. HF/pyridine complex (0.12 mL) was added and the reaction was stirred at 0° C. for 1 h and at rt overnight. Saturated aqueous NaHCO3 and CH2Cl2 were added. The layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified via chromatography (silica gel) eluting with 75% EtOAc in hexane to provide the title compound (16 mg). LC/MS m/z 320 [M+H]+.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([N:20]([C@H:22]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH3:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2N=CC=CC=2N=N1.[CH3:47][NH:48][CH2:49][CH2:50][C:51]1[CH:60]=[CH:59][CH:58]=[CH:57][C:52]=1[O:53][CH2:54][CH2:55][OH:56].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[N:20]([C@@H:22]([C:23](=[O:25])[N:48]([CH2:49][CH2:50][C:51]1[CH:60]=[CH:59][CH:58]=[CH:57][C:52]=1[O:53][CH2:54][CH2:55][OH:56])[CH3:47])[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[CH3:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CNCCc1ccccc1OCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.2 %

Procedure:
At 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (558 mg, 2.91 mmol) was given to a solution of (2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)propionic acid (959 g, 2.91 mmol) and 1-Hydroxy-7-azabenzotriazole (396 mg, 2.91 mmol) in N,N-dimethylformamide (5 ml) and dichloromethane (5 ml). The solution was stirred for 20 min at 0° C. A solution of 2-(2-(2-(Methylamino)ethyl)phenoxy)ethanol (608 mg, 2.91 mmol) in dichloromethane (5 ml) and ethyldiisopropylamine (0.50 ml, 2.91 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (150 ml) and washed with a 10% aqueous sodium hydrogen sulfate solution (70 ml). The aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate soltuion (150 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (110 g), using ethyl acetate/heptane (1:1) as eluent, to give 1.02 g of N-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:15]=3[N:14]=[C:13]2[C:24](=[O:35])NC2CCN(C(C)C)CC2)=[O:10])=[N:6][CH:7]=1.NCC[OH:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:15]=3[N:14]=[C:13]2[C:24]([OH:39])=[O:35])=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)N1CCC(NC(=O)c2nc3cc(C(=O)O)ccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Reactant: NCCO
Product: O=C(Cn1c(C(=O)O)nc2cc(C(=O)O)ccc21)Nc1ccc(Cl)cn1

Procedure:
5-[(2-hydroxy-ethyl)-amide]2-[(1-isopropyl-piperidin-4-yl)-amide]1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2,5-dicarboxylic acid 5-[(2-hydroxy-ethyl)-amide]2-[(1-isopropyl-piperidin-4-yl)-amide] was prepared by a procedure according to example 22 starting from 50 mg (0.10 mmol) 1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid and 6.8 mg (0.11 mmol) 2-amino-ethanol. The title compound was obtained as its formiate in form of a white amorphous solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[O:10][C:9](=[O:18])[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:26]([O:28][CH2:29][CH3:30])=[CH2:27])CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:17][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([C:26]([O:28][CH2:29][CH3:30])=[CH2:27])=[CH:8][C:9](=[O:18])[O:10]2)=[CH:15][CH:14]=1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2ccc(Br)cc2o1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(=O)oc2cc(Br)ccc12
Temperature: 80 °C

Procedure:
To a solution of 7-bromo-2-oxo-2H-chromen-4-yl trifluoromethanesulfonate (prepared as described in U.S. Pat. No. 5,552,437) (5 g, 13.4 mmol) and tributyl(1-ethoxyvinyl)tin (4.75 mL, 14.1 mmol) in 1,4-dioxane (50 mL), lithium chloride (1.7 g, 40.2 mmol) was added. The reaction flask was then purged twice with nitrogen and tetrakis(triphenylphosphine) palladium(0) (774 mg, 0.7 mmol) was added. The reaction was then heated 4 hours at 80° C. After cooling, the reaction mixture was concentrated under reduced pressure and the crude residue obtained was diluted with ethyl acetate, washed with a saturated ammonium chloride aq. solution, water and brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (hexanes/CH2Cl2/acetone, 25:75:0 to 0:95:5) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.83 (d, 1H), 7.60 (s, 1H), 7.52 (d, 1H), 6.46 (s, 1H), 4.67 (s, 2H), 4.05 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]45[CH2:25][CH2:24][C:21]([CH2:26][C:27]([O:29]C)=[O:28])([CH2:22][CH2:23]4)[CH2:20][CH2:19]5)=[CH:14][CH:13]=3)[C:8]([CH3:32])([CH3:31])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO.C1COCC1>[NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]45[CH2:23][CH2:22][C:21]([CH2:26][C:27]([OH:29])=[O:28])([CH2:20][CH2:19]4)[CH2:24][CH2:25]5)=[CH:16][CH:17]=3)[C:8]([CH3:32])([CH3:31])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)CC12CCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Oc2ncnc(N)c2N=C1c1ccc(C23CCC(CC(=O)O)(CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl {4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]bicyclo[2.2.2]oct-1-yl}acetate (122 mg, 0.28 mmol) in MeOH (10 mL) and THF (5 mL) was added 2M NaOH (0.7 mL). The reaction mixture was stirred at ambient temperature overnight then further 2M NaOH (0.7 mL) was added and the reaction mixture heated to 50° C. for 5 hrs. The mixture was allowed to cool, the solvent was removed under reduced pressure and the residue was acidified to pH 2 with 2M HCl and the suspension filtered and dried. The product was purified on a basic reverse phase preparative HPLC system loading in NMP (˜2 mL), water (˜2 mL) and 1-2 drops of 0.88 ammonia, and eluting with 13-40% water (+1% NH3)-MeCN, to provide the title compound as a solid, 40 mg (0.0952 mmol, 34%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[CH:8][N:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:20][CH:21]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)CN1C(=O)CCc2cnccc21
Product: O=C(CN1C(=O)CCc2cnccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetic acid (40 mg, 0.195 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (24 mg, 0.0979 mmol) according to protocol A. Retention time (min)=8.108, method [6], MS(ESI) 433.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.61-8.48 (m, 3H), 7.51 (d, J=6.8 Hz, 1H), 7.16 (s, 1H), 5.08 (s, 2H) 3.29-3.25 (m, 2H), 2.98-2.93 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: Fc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
Ferric chloride (0.5 g) was added to a mixture of 4-bromo-3-fluoro-benzenesulfonyl chloride (2.5 g) and fluorobenzene (3 ml) and then stirred at reflux for 18 hours. The flask was cooled to room temperature and the residue was partitioned between aqueous NaHCO3 and DCM, The DCM layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was recrystallised from ethanol to give buff coloured crystals.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][N:5]=[C:4]([CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[N:3]=1.[CH3:18][N:19]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:38].[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:10]1([CH2:9][O:8][C:7]2[C:2]([C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:38])[N:19]([CH3:18])[CH:28]=3)=[N:3][C:4]([CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:5][CH:6]=2)[CH2:12][CH2:11]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CS(=O)(=O)Cc1ncc(OCC2CC2)c(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2nc(CS(C)(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O
Temperature: 70 °C
Yield: 42.9 %

Procedure:
The title compound of step 2 (100 mg, 0.36 mmol), the title compound of Example 89, step 1 (124 mg, 0.43 mmol), Pd(dppf)Cl2 (27 mg, 0.03 mmol) and K3PO4 (154 mg, 0.72 mmol) in dioxane (5 mL) and water (5 drops) were N2 purged and heated to 70° C. for 18 h. After concentration under vacuum, the residue was purified using silica gel chromatography followed by prep-HPLC to give the title compound (61.7 mg, 42.7%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, J=7.2 Hz, 1H), 7.69-7.65 (m, 3H), 7.53 (t, J=7.2 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 3.76 (d, J=6.8 Hz, 2H), 3.58 (s, 3H), 3.26 (s, 3H), 0.94-0.88 (m, 1H), 0.35-0.31 (m, 2H), 0.10-0.08 (m, 2H). LCMS: 400.1 (M+1)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][NH2:18])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[CH:6]=2.C(O)(=O)C.[S:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:30]([CH2:29][CH:26]3[CH2:27][CH2:28][S:23][CH2:24][CH2:25]3)=[N:18][N:17]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[CH:6]=2
Reactant: COC(=O)c1cc2nc(Cl)c(NN)nc2cc1C
Reactant: O=CCC1CCSCC1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc2nc(Cl)c3nnc(CC4CCSCC4)n3c2cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a mixed liquid of 1.40 g of methyl 3-chloro-2-hydrazino-7-methylquinoxaline-6-carboxylate and 28.0 mL of acetic acid was added 820 mg of tetrahydro-2H-thiopyran-4-ylacetaldehyde, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and to the residue was added 28.0 mL of N,N-dimethylformamide, followed by replacement with argon. Then, a mixed liquid of 706 mg of copper(II) chloride and 28.0 mL of N,N-dimethylformamide was added thereto, followed by stirring at 50° C. for 20 minutes and at 100° C. for 1 hour. To the reaction liquid were added water and chloroform, followed by extraction with chloroform, the organic layer was washed with 1 M hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine and, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 600 mg of methyl 4-chloro-8-methyl-1-(tetrahydro-2H-thiopyran-4-ylmethyl)[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate as a brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:10]([CH3:24])[CH2:9]1)=O)(C)(C)C.Cl>O>[C:18]1([CH2:17][CH2:16][CH2:15][N:11]2[C@H:10]([CH3:24])[CH2:9][NH:8][CH2:13][C@@H:12]2[CH3:14])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCCc1ccccc1
Agent: Cl
Solvent: O
Product: C[C@@H]1CNC[C@H](C)N1CCCc1ccccc1
Reaction time: 1 h

Procedure:
To 11.76 g (35.4 mmol.) of cis-1-tert-butoxycarbonyl-3,5-dimethyl-4-(3-phenylpropan-1-yl)piperazine was added, at room temperature, 10 ml (120 mmol.) of 12N hydrochloric acid. The mixture was stirred for one hour. To the reaction system was added water. Impurities were removed by extraction with ethyl acetate. The solution was made alkaline by the addition of an aqueous solution of sodium hydroxide, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, which was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give the object compound as a yellow oily product. This compound was used for the subsequent reaction without purification. The yield was 5.51 g (67%)
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:29]=[CH:28][N:14]3[C:15](=[O:27])[C:16]([CH:25]=O)=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[S:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36]>N1CCCCC1.C(O)(=O)C.C1C=CC=CC=1>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:29]=[CH:28][N:14]3[C:15](=[O:27])[C:16]([CH:25]=[C:34]4[S:30][C:31](=[O:36])[NH:32][C:33]4=[O:35])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)n1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(C)c1csc(CCc2ccn3c(=O)c(C=C4SC(=O)NC4=O)c(N4CCOCC4)nc3c2)n1
Yield: 76.1 %

Procedure:
8-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]-pyrimidine-3-carbaldehyde (18 mg) and 2,4-thiazolidinedione (53 mg) were added with benzene (10 ml), piperidine (one drop) and acetic acid (two drops) and refluxed by heating for 3 hours in a vessel provided with a Dean-Stark trap. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (17 mg) as yellow powder.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: c1c[nH]nn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (289 mg; 60% suspension in paraffin oil) in THF (10 ml) was treated under an argon atmosphere at RT dropwise with a solution of 1,2,3-triazole (500 mg) in THF (10 ml). The mixture was stirred at RT for 1 hour and was then treated at 0° C. dropwise with (2-(chloromethoxy)ethyl)trimethylsilane (1.21 g). Stirring was continued for 2 h. The reaction was quenched with water (10 ml), the layers were separated and the aqueous layer once extracted with AcOEt (15 ml). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo to give the title compound as a crude product that was used without further purification. Colorless liquid (1.5 g). MS (m/e): 198.204 (M-H+).