Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)O)=[N:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].C([O-])([O-])=O.[K+].[K+].[CH2:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.COCCOCCN(CCOCCOC)CCOCCOC>C1(C)C=CC=CC=1.O>[CH2:26]([O:33][C:2]1[C:7]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[N:6][CH:5]=[CH:4][N:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCc1ccc(C(O)c2nccnc2Cl)cc1
Reactant: OCc1ccccc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(Cc2nccnc2OCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 11 %

Procedure:
Next, to a solution of (2-chloropyrazin-3-yl)-(4-ethylphenyl)methanol (3.1 g, 0.0125 mol) in toluene (24 mL), KOH (2.8 g, 0.050 mol), K2CO3 (1.7 g, 0.0125 mol), benzyl alcohol (1.89 g, 0.0175 mol) and tris[2-(2-methoxyethoxy)ethyl]amine (0.40 g, 0.00125 mol) were added and stirred at 120° C. for 2 hours. After cooling the reaction mixture to room temperature, water was poured and the resulting mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=87:13) to give 2-benzyloxy-3-(4-ethylbenzyl)pyrazine (420 mg, 11%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.O.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[Na+]>[Cu]I.CS(C)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccccc1Br
Reactant: O=S([O-])c1ccc(Br)cc1
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccccc1S(=O)(=O)c1ccc(Br)cc1

Procedure:
Methyl 2-[(4-bromophenyl)sulfonyl]benzoate was prepared according to the method of Example 135, Step 2 using methyl 2-bromobenzoate (2.8 mL, 20 mmol) in place of (S)-1-(2-iodophenyl)ethanol and sodium 4-bromophenylsulfinate dihydrate (5.6 g, 20 mmol) in place of Intermediate 1, together with CuI (19 g, 100 mmol) and DMSO (40 mL), affording product as a white solid (3.8 g).
Reaction SMILES: [P:1]([OH:40])([OH:39])([O:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[O:8][C:7]2[CH:14]=[CH:15][C:16]([NH:18][C:19]3[C:24]([F:25])=[CH:23][N:22]=[C:21]([NH:26][C:27]4[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=4)[N:20]=3)=[N:17][C:6]1=2)=[O:2].O.O.O.O.O.O.P([O-])([O-])(OCN1C(=O)C(C)(C)OC2C=CC(NC3C(F)=CN=C(NC4C=C(OC)C(OC)=C(OC)C=4)N=3)=NC1=2)=O.[Na+].[Na+].[CH2:89]([N:91]([CH2:94][CH3:95])[CH2:92][CH3:93])[CH3:90]>C(O)(C)C.O>[F:25][C:24]1[C:19]([NH:18][C:16]2[CH:15]=[CH:14][C:7]3[O:8][C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:5]([CH2:4][O:3][P:1]([O-:39])([O-:40])=[O:2])[C:6]=3[N:17]=2)=[N:20][C:21]([NH:26][C:27]2[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=2)=[N:22][CH:23]=1.[CH2:89]([NH+:91]([CH2:94][CH3:95])[CH2:92][CH3:93])[CH3:90].[CH2:89]([NH+:91]([CH2:94][CH3:95])[CH2:92][CH3:93])[CH3:90]
Reactant: CCN(CC)CC
Reactant: COc1cc(Nc2ncc(F)c(Nc3ccc4c(n3)N(COP(=O)(O)O)C(=O)C(C)(C)O4)n2)cc(OC)c1OC
Agent: COc1cc(Nc2ncc(F)c(Nc3ccc4c(n3)N(COP(=O)([O-])[O-])C(=O)C(C)(C)O4)n2)cc(OC)c1OC
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC[NH+](CC)CC
Temperature: 20 °C

Procedure:
To [6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxo-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate; N,N-dimethylformamide solvate (Step E) (1.00 kg, 1.00 mol eq) is added a solution of triethylamine (0.34 kg, 2.20 mol eq) in isopropanol (1.32 kg) and water (3.33 kg). This is stirred at about 20° C. to give a solution which is then filtered. The resulting solution of the sub-title compound is used directly in the next step.
Reaction SMILES: CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:30]([O:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][CH2:44][C@@H:45]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:46]([OH:48])=O)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.[NH2:58][C@@H:59]([CH:63]([CH3:65])[CH3:64])[C:60]([NH2:62])=[O:61]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl.CO.CCCCCCC.CCOC(C)=O>[CH2:30]([O:37][C:38](=[O:39])[NH:40][CH2:41][CH2:42][CH2:43][CH2:44][C@@H:45]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:46](=[O:48])[NH:58][C@H:59]([C:60](=[O:61])[NH2:62])[CH:63]([CH3:65])[CH3:64])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)[C@H](N)C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.4 %

Procedure:
N-Methylmorpholine (0.87 ml, 7.9 mmol), 1-hydroxybenzotriazole (0.46 g, 3.41 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.65 g, 3.41 mmol) were added in this sequence to a solution of commercially available (R)-6-benzyloxycarbonylamino-2-tert-butoxycarbonylamino-hexanoic acid (1 g, 2.63 mmol) and commercially available (S)-2-amino-3-methylbutyramide hydrochloride (0.40 g, 2.63 mmol) in 12 ml of CH2Cl2 and 4 ml of DMF, and the mixture was stirred at RT for about 14 h. Flash chromatography (gradient heptane/AcOEt to CH2Cl2/MeOH) afforded 1 g of the product (79%).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:11]=1)[CH:2]=[CH2:3]
Reactant: CCOC(=O)CCc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(CCC(=O)OCC)cc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
Allyl bromide (2.30 g) was added to a stirred suspension of ethyl 3-(4-hydroxyphenyl)propionate (3.49 g) and anhydrous potassium carbonate (2.76 g) in butan-2-one (30 ml). The reaction mixture was heated at reflux for 18 hours. The reaction mixture was allowed to cool to ambient temperature and the mixture was filtered. The filtrate was evaporated to give an oil which was purified by column chromatography on silica gel (Merck.Art. No. 9385) using a 4:1 (v/v) mixture of n-hexane and ethyl acetate as eluent to give ethyl 3-(4-allyloxyphenyl)propionate (4.09 g) as a colourless oil; NMR (CDCl3): 1.22 (3H, t), 2.48 (2H, t), 2.88 (2H, t), 4.13 (2H, q), 4.51 (2H, m), 5.25-5.42 (2H, m), 5.95-6.15 (1H, m), 6.83 (2H, d) and 7.03 (2H, d); m/z 235 (M+H).
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=5)[C:17]4=[O:27])=[CH:12][C:11]=3[F:28])[CH2:6]2)[O:4][CH2:3][CH2:2]1.[O:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[CH2:34]OS(C)(=O)=O>>[O:4]1[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:34][C@H:30]6[CH2:31][CH2:32][CH2:33][O:29]6)[CH:22]=5)[C:17]4=[O:27])=[CH:12][C:11]=3[F:28])[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CCC3(C2)OCCO3)c(F)c1
Reactant: CS(=O)(=O)OC[C@H]1CCCO1
Product: O=c1c2ccc(OC[C@H]3CCCO3)cc2ccn1-c1ccc(N2CCC3(C2)OCCO3)c(F)c1

Procedure:
2-[4-(1,4-Dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluorophenyl]-6-hydroxy-2H-isoquinolin-1-one was reacted with (R)-methanesulfonic acid tetrahydrofuran-2-ylmethyl ester according to Method K1. In this way the product was obtained with molecular weight 466.19 (C26H27FN2O5); MS (ESI): 467 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:18]([F:29])[CH:17]=3)[O:15][C:10]=2[C:9]([F:31])=[CH:8][C:7]=1[F:32].[N-:33]=[N+:34]=[N-:35].[Na+].O>CN(C)C=O>[N:33]([CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]2[C:12](=[O:30])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:18]([F:29])[CH:17]=3)[O:15][C:10]=2[C:9]([F:31])=[CH:8][C:7]=1[F:32])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCl)c(F)cc(F)c3o2)cc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCN=[N+]=[N-])c(F)cc(F)c3o2)cc1F
Temperature: 70 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
177 mg (0.38 mmol) of the resulting 5-(3-chloropropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one was dissolved in 10 ml of dimethylformamide under argon atmosphere, 124 mg of sodium azide was added and the mixture was stirred at 70° C. for 18 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration and purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 179 mg (100%) of 5-(3-azidopropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:9]([NH:11][CH:12]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[CH2:17][CH:16]3[CH:14]([O:15]3)[CH2:13]2)=[O:10])[CH2:3][CH2:2]1.[BH4-].[Na+].CO.O>C(O)(C)(C)C.C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:35][CH2:36]2)[C:9]([NH:11][CH:12]2[CH2:13][CH:14]([OH:15])[CH2:16][CH2:17][CH:18]2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)=[O:10])[CH2:2][CH2:3]1
Reactant: COc1ccc(C2CC3OC3CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCC(O)CC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Yield: 68.2 %

Procedure:
16.5 g of (±)-3,4-bis-cyclopropylmethoxy-N-[(3RS,4RS)-4-(3,4-dimethoxyphenyl)-7-oxabicyclo[4.1.0]-hept-3-yl]benzamide (compound E1) are dissolved in 500 ml of tert-butanol, 5.0 g of sodium borohydride are added and the reaction mixture is heated to boiling. After slow addition of 70 ml of methanol, the reaction mixture is cooled and treated with 200 ml of water and 150 ml of ethyl acetate. The organic phase is dried using sodium sulfate, concentrated and the residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate in the ratio 1/2. 11.3 g of the title compound are obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:14][C@H:15]3[CH2:19][CH2:18][CH2:17][C@@H:16]3[NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]3[N:32]=[CH:31][CH:30]=[N:29]3)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=2)C[CH2:2]1.ClC1C(N[C@H]2CCC[C@@H]2NC(=O)C2C=CC=CC=2N2N=CC=N2)=NC=C(C(F)(F)F)N=1.C(B1OC(C)(C)C(C)(C)O1)=C.[H][H]>CO.[Pd]>[CH2:1]([C:4]1[C:5]([NH:14][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[NH:20][C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]2[N:29]=[CH:30][CH:31]=[N:32]2)=[N:6][CH:7]=[C:8]([C:10]([F:12])([F:11])[F:13])[N:9]=1)[CH3:2]
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1)c1ccccc1-n1nccn1
Reactant: [H][H]
Agent: [Pd]
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Cl)c1ccccc1-n1nccn1
Solvent: CO
Product: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 109) from N-[(1S,2S)-2-{[3-chloro-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 29; 170 mg, 0.38 mmol) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS number 75927-49-0; 174 mg, 1.13 mmol) except this was then dissolved in methanol (1.4 ml) and to this was then added palladium on carbon (10% wt, 50% wet) (15 mg, 0.014 mmol) and the resulting mixture was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][C:26]=3[CH3:28])[N:21]([CH3:29])[CH:20]=2)[C:10]1=[O:30])[CH2:6][O:7][CH3:8].Cl>O1CCOCC1.O>[CH3:29][N:21]1[C:22]2[C:27](=[C:26]([CH3:28])[CH:25]=[CH:24][CH:23]=2)[C:19]([CH2:18][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:9]([CH:5]([CH2:6][O:7][CH3:8])[CH2:4][C:3]([OH:31])=[O:2])[C:10]2=[O:30])=[CH:20]1
Reactant: COCC(CC(=O)OC)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COCC(CC(=O)O)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Reaction time: 2 h
Yield: 12.8 %

Procedure:
To a solution of 3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-butyric acid methyl ester (200 mg, 0.48 mmol) in 1,4-dioxane (2.0 mL) is added LiOH monohydrate (25 mg, 0.59 mmol) in water (2.0 mL) at room temperature. The solution is stirred at the same temperature for 2 hours. Then 1.0 mL of 1.0 M HCl solution is added along with 10 mL of water. Then the mixture is extracted with EtOAc (3×25 mL) and the organic layers are combined, dried and concentrated to give 190 mg (97%) of crude product. 30 mg of this crude is purified by preparative TLC to give 25 mg of 3-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-4-methoxy-butyric acid. LCMS (ESMS): m/z 408.25 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH2:26]([S:30](Cl)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]>>[CH2:26]([S:30]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CCCCS(=O)(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 10.4 μL (0.11 mmol) 1-butanesulfonyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][C:4]2[S:14][CH:15]=[CH:16][C:3]1=2.[H-].[Na+].[CH3:19]I>C1COCC1>[CH3:19][O:1][C@@H:2]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][C:4]2[S:14][CH:15]=[CH:16][C:3]1=2
Reactant: CI
Reactant: CCOC(=O)N1CCc2sccc2[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCc2sccc2[C@H](OC)C1
Reaction time: 0.25 h

Procedure:
3.39 g (14.0 mmol) ethyl (S)-4-hydroxy-4,5,7,8-tetrahydro-thieno[2,3-d]azepine-6-carboxylate in 40 ml THF are mixed batchwise with 0.86 g of 60% NaH mineral oil dispersion while cooling with an ice bath, the mixture is stirred for 15 min and then 1.07 ml methyl iodide are slowly added dropwise. The mixture is stirred for 1 h, poured onto ice water and extracted 3× with ethyl acetate. The combined organic phases are dried with NaSO4 and concentrated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([C:20]2[N:21]=[CH:22][N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=2)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:10]=1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([C:20]2[N:21]=[CH:22][NH:23][CH:24]=2)([OH:19])[CH:16]([CH3:18])[CH3:17])[CH:10]=1
Reactant: CC(C)C(O)(c1cccc(-c2ccc(F)cc2F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(O)(c1cccc(-c2ccc(F)cc2F)c1)c1c[nH]cn1
Yield: 80.7 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 1-(2′,4′-difluoro[1,1′-biphenyl]-3-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (6.31 g) and pyridine hydrochloride (2.17 g), the title compound (2.93 g) was obtained as colorless needle crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[O:18]1[CH2:17][CH:16]1[CH2:14][O:12][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: ClCC1CO1
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCC1CO1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 21.1 %

Procedure:
Quinoline-6-carboxylic acid (1 g; 5.78 mmol) is dissolved in DMF (10 mL) at ambient temperature. Epichlorohydrin (0.4517 mL; 5.59 mmol) is added followed by mortar ground potassium carbonate (0.80 g; 5.79 mmol). The mixture is stirred at ambient temperature for 48 hours. Potassium iodide (96 mg; 0.58 mmol) is added and stirring is continued at ambient temperature for 24 hours. The mixture is heated to 60° C. and maintained for 72 hours. After cooling, the mixture is poured onto water (700 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts are washed successively with water (100 mL), and brine (50 mL), then dried over MgSO4, filtered, and concentrated in vacuo at 30C. The residue is purified via silica gel chromatography with gradient elution (20%→67% ethyl acetate in hexanes) affording the desired product (270 mg) as a white solid. ESMS: MH+ 230.0 (base).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[C:13]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH2:20][CH2:19]3)=[O:17])=[C:12]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:33][CH:32]=3)[N:11]2[CH3:41])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+].[ClH:44]>C(O)C>[ClH:44].[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13]([C:16]([N:18]3[CH2:19][CH2:20][CH:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:22][CH2:23]3)=[O:17])=[C:12]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:33][CH:32]=3)[N:11]2[CH3:41])=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)COC1CCN(C(=O)c2c(-c3ccc(C(C)(C)C)cc3)n(C)n(-c3ccc(C(=N)N)cc3)c2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(-c2ccc(C(C)(C)C)cc2)c(C(=O)N2CCC(OCC(=O)O)CC2)c(=O)n1-c1ccc(C(=N)N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 100 mg of 1-(4-amidinophenyl)-3-(4-t-butylphenyl)-4-{[4-(ethoxycarbonylmethyloxy)-1-piperidinyl]carbonyl}-2-methyl-2H-pyrazol-5-one, 0.36 ml of 1N aqueous sodium hydroxide and 0.72 ml of ethanol was stirred at room temperature for 1 hour, and the reaction solution was adjusted to pH 3 with dilute hydrochloric acid. The solvent was removed by evaporation under reduced pressure. The resulting residue was recrystallized in water to give 70.7 mg of the title compound as colorless crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=O.[CH3:25][NH2:26]>>[CH3:25][NH:26][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CN
Reactant: COC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Product: CNC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Yield: 50 %

Procedure:
In a similar fashion using route 53 general procedure 122, 8-benzenesulfonylamino-quinoline-4-carboxylic acid methyl ester 225 (50 mg, 0.15 mmol) and methyl amine (33% in EtOH, 3 ml) gave the title compound (23 mg, 50%) after purification by column chromatography with DCM/MeOH (95:5) as the eluent.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14]>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:18][CH2:17][CH2:16][N:15]([CH2:19][CH3:20])[CH2:13][CH3:14])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:18][CH2:17][CH2:16][N:15]([CH2:19][CH3:20])[CH2:13][CH3:14])[CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNc1cc(Cl)cc(NCCN(CC)CC)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
0.2 mole (45.3 g) of 2,4,6-trichloronitrobenzene is added in small portions to 180 ml of N,N-diethylethylenediamine heated to 60° C., with stirring. Heating is continued for 30 minutes after the addition is complete. The reaction medium is diluted with 180 ml of ice-cold water. The product expected precipitates. It is drained, washed with water and then dried under vacuum at 60° C. in the presence of phosphorous pentoxide. After recrystallizing from 96° ethanol, it melts at 90° C.
Reaction SMILES: [C:1]1([C:7]2[C:12]3[CH:13]=[CH:14][O:15][C:11]=3[C:10](O)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.O.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:10]1[C:11]2[O:15][CH:14]=[CH:13][C:12]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][N:9]=1
Reactant: Oc1nnc(-c2ccccc2)c2ccoc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: Clc1nnc(-c2ccccc2)c2ccoc12

Procedure:
A slurry of 4-phenylfuro[3,2-d]pyridazin-7-ol (0.327 g, 1.5 mmol) and pyridine (0.38 ml, 4.6 mmol) in 5 mL POCl3 was heated with a water-cooled reflux condenser with drying tube to 130° C. for 3 h. The brown solution was cooled and the reaction judged complete by LCMS. The reaction was poured onto ice with stirring. The solution was neutralized with 6 N NaOH and ice to control temperature. The resulting mixture was extracted into DCM (3×). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The solid was adsorbed onto 2 g silica gel from DCM/MeOH and dried. The material was purified by silica gel chromatography, eluting with 0-20% EtOAc/DCM to give 7-chloro-4-phenylfuro[3,2-d]pyridazine as an off-white solid. MS m/z=231 [M+H]+. Calc'd for C12H7ClN2O: 230.7.
Reaction SMILES: C[Si](Cl)(C)C.[CH3:6][C:7]1[N:8]=[C:9]([NH:22]C(=O)C)[S:10][C:11]=1[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>C(O)C>[CH3:6][C:7]1[N:8]=[C:9]([NH2:22])[S:10][C:11]=1[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cncc(C(F)(F)F)c2)s1
Agent: C[Si](C)(C)Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1cncc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Trimethylsilyl chloride (0.3 ml) is added to N-[4-methyl-5-(5-trifluoromethyl-pyridin-3-yl)-thiazol-2-yl]-acetamide (44 mg) in ethanol (2 ml) at room temperature and the mixture is stirred at room temperature for 4.5 hours. The reaction is then heated at 50° C. for 18 hours, cooled, evaporated and the title compound is obtained by filtration after trituration with diethyl ether.