Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N+]([O-])([O-])=[O:11].[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CO>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[O:11])=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(C)cc1
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CO
Product: COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
A 1.22 g quantity of p-methyl anisole and 23.0 g of ammonium cerium(IV) nitrate are placed into a reactor, and 100 ml of methanol is further placed into the reactor. The mixture is stirred at room temperature for about 30 minutes. After the completion of the reaction, the methanol is distilled off from the reaction mixture. The residue is diluted with water and then subjected to extraction with benzene three times. The extract is washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue is distilled in a vacuum, giving 1.308 g of anisaldehyde (b.p. 90°-92° C./2 mm Hg). Yield: 96.2%.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.CCN(C(C)C)C(C)C.[N:21]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[C:22]=[O:23]>C(Cl)Cl>[CH:24]1([NH:21][C:22]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCC1
Reactant: Nc1cccc2cnccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2cnccc12)NC1CCCC1
Reaction time: 24 h

Procedure:
To isoquinolin-5-amine (0.23 g, 1.595 mmol) in DCM (5 mL) was added DIEA (0.557 mL, 3.19 mmol) and isocyanatocyclopentane (0.180 mL, 1.595 mmol). After 24 h, the reaction was quenched with H2O (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (10 mL) and dried (MgSO4). An impure yellow solid was collected and was carried onto the next step. MS (ESI) m/z: 256 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([OH:24])[C:22]([Br:23])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:26])[C:22]([Br:23])=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2cccc3c(Br)c(O)cc(c23)C(=O)N1OCc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cc2c3c(cccc3c1Br)C(=O)N(OCc1ccccc1)C2=O
Yield: 92.2 %

Procedure:
2-Benzyloxy-6-bromo-5-hydroxy-benzo[de]isoquinoline-1,3-dione (2.0 g, 5.0 mmol, from Example Y), potassium carbonate (2.75 g, 20.0 mmol), and dimethyl sulfate (2.7 g, 21.0 mmol) were reacted in acetone (300 mL) following the procedure as described in Example J to give 1.9 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]#[N:13])[C:6]=2[CH:14]=1.CN(C)[C:17]1[O:18][C:19](=[O:27])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1>C(O)(=O)C>[O:18]=[C:17]1[NH:22][C:21]([C:23]([F:24])([F:25])[F:26])=[CH:20][C:19](=[O:27])[N:1]1[C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]#[N:13])[C:6]=2[CH:14]=1
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Reactant: N#CCOc1nsc2ccc(N)cc12
Solvent: CC(=O)O
Product: N#CCOc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of [(5-amino-1,2-benzisothiazol-3-yl)oxy]-acetonitrile (4.30 g, 21.0 mmol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (4.37 g, 21.0 mmol) in acetic acid is refluxed for three hours, stirred overnight at room temperature, and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and dried overnight in a vacuum oven at 55° C. to give the title product as a brown solid (2.63 g, mp 254-258° C.).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16].[CH2:19]([N:26]1[CH:30]=[C:29]([CH2:31][C@@H:32]([C:41](O)=[O:42])[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:28]([N+:44]([O-:46])=[O:45])=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:19]([N:26]1[CH:30]=[C:29]([CH2:31][C@@H:32]([C:41]([O:16][CH2:15][C:14]([F:18])([F:17])[F:13])=[O:42])[NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C:28]([N+:44]([O-:46])=[O:45])=[N:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nc1[N+](=O)[O-])C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nc1[N+](=O)[O-])C(=O)OCC(F)(F)F
Reaction time: 18 h

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (98%, 361 mg, 1.85 mmol), 4-(dimethylamino)pyridine (97%, 116 mg, 0.921 mmol) and 2,2,2-trifluoroethanol (99%, 1.36 mL, 18.5 mmol) were added to a solution of C7 (0.36 g, 0.92 mmol) in dichloromethane (30 mL), and the reaction mixture was allowed to stir for 18 hours. The reaction was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% EtOAc in heptane) afforded C8 as a solid. Yield: 223 mg, 0.472 mmol, 51%. LCMS m/z 471.1 (M−1). 1H NMR (400 MHz, CDCl3) δ 1.37 (s, 9H), 3.24 (br dd, half of ABX pattern, J=14.7, 7.9 Hz, 1H), 3.35 (dd, half of ABX system, J=15.0, 5.7 Hz, 1H), 4.42-4.52 (m, 2H), 4.59 (br ddd, J=8, 8, 6 Hz, 1H), 5.13 (br d, J=8 Hz, 1H), 5.31 (s, 2H), 7.26-7.32 (m, 3H), 7.36-7.42 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]([C:9](=[O:34])[NH:10][C:11]1([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH2:13][CH2:12]1)[CH:6]([CH3:8])[CH3:7].[CH3:36][O:37][C:38](=[O:63])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][C:53]([C:56]2[CH:61]=[CH:60][C:59](Br)=[CH:58][CH:57]=2)=[CH:54][N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[CH3:36][O:37][C:38](=[O:63])[NH:39][CH:40]([C:44]([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:52][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:22]3[CH:23]=[CH:24][C:19]([C:16]4[NH:15][C:14]([C:11]5([NH:10][C:9](=[O:34])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:35])[CH:6]([CH3:8])[CH3:7])[CH2:12][CH2:13]5)=[N:18][CH:17]=4)=[CH:20][CH:21]=3)=[CH:58][CH:57]=2)=[CH:54][N:55]=1)=[O:45])[CH:41]([CH3:43])[CH3:42]
Reactant: COC(=O)NC(C(=O)NC1(c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)CC1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)NC1(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)CC1)C(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 1.5 %

Procedure:
[2-Methyl-1-(1-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl]-cyclopropylcarbamoyl)-propyl}-carbamic acid methyl ester (85 mg, 0.21 mmol) and (1-(2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester (97 mg, 0.21 mmol) in 3:1 DME/H2O (2.5 mL) were treated with Pd(PPh3)4 (10 mg, 0.0084 mmol) and K2CO3 (2 M solution, 0.42 mL, 0.84 mmol). The mixture was stirred in a sealed tube at 80° C. for 3 hours. The mixture was filtered through a fritted glass funnel and concentrated. The mixture was subjected to a reverse phase HPLC column (5-95% MeCN—H2O; 0.1% TFA modifier) to afford (1-{2-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyrylamino)-cyclopropyl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2.3 mg, 2%) as a white solid (TFA salt): 1H NMR (CD3OD, 300 MHz) 7.93 (s, 2H), 7.84 (m, 4H), 5.20 (m, 1H), 4.23 (d, J=7.2 Hz, 2H), 4.01 (m, 2H), 3.83 (m, 4H), 3.70 (s, 3H), 3.66 (s, 3H), 3.38 (m, 2H), 2.57 (m, 2H), 2.18 (m, 4H), 2.04 (m, 4H), 1.75 (m, 4H), 1.58 (m, 4H), 0.95 (m, 12H); MS (ESI) m/z 725 [M+H]+.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH:5]([C:7]1[CH2:8][N:9]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1)[NH2:6]>O1CCCC1>[CH3:1][NH:2][C:3](=[O:4])[NH:6][NH:5][C:7]1[CH2:8][N:9]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1
Reactant: CN=C=O
Reactant: CCc1cc2c(s1)N=C(NN)CN=C2c1ccccc1Cl
Solvent: C1CCOC1
Product: CCc1cc2c(s1)N=C(NNC(=O)NC)CN=C2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.1 ml of methyl isocyanate is added to a suspension of 5 g of 2-hydrazino-5-o-chlorophenyl-7-ethyl-3H-thieno[ 2,3-e] [1,4] diazepine in 100 ml of tetrahydrofuran, and the resulting mixture is stirred at room temperature for 2 hours. Then the reaction mixture is poured into ice water, and the precipitated crystals are collected by filtration, washed with water, dried, and recrystallized from a mixture of chloroform and ligroin to give 2-(4-methylsemicarbazido)-5-o-chlorophenyl-7-ethyl-3H-thieno[ 2,3-e][1,4]diazepine, melting at 213°-215° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([N:9]2[C:13](C)=[C:12]([C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=3)[N:11]=[N:10]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:30]>ClCCl>[Cl:2][C:3]1[C:8]([N:9]2[CH:13]=[C:12]([C:15]3[CH2:16][CH2:17][N:18]([C:29]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:30])[CH2:19][CH:20]=3)[N:11]=[N:10]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(C2=CCNCC2)nnn1-c1cccnc1Cl
Reactant: COCCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)N1CC=C(c2cn(-c3cccnc3Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-3-[5-methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,3]triazol-1-yl]-pyridine hydrochloride (3.0 mg) prepared in Example 42-1 was dissolved in 1.0 ml of dichloromethane and 0.02 ml of triethylamine and 0.02 ml of 2-methoxyethyl chloroformate were added thereto followed by stirring at room temperature for 10 minutes. The solvent was evaporated in vacuo and the residue was separated and purified by a thin-layer chromatography (ethyl acetate) to give 1.36 mg of the title compound as a white solid.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][I:8].[OH:9][C:10]1[C:11](=[O:21])[C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2>C1C=CC=CC=1.[Ag]>[I:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:20][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:21])[C:10](=[O:9])[CH:19]=1
Reactant: ICCCCCCI
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ag]
Solvent: c1ccccc1
Product: O=C1C=C(OCCCCCCI)c2ccccc2C1=O
Yield: 57 %

Procedure:
A mixture of 1,6-diiodohexane (10.14 g, 30 mmol) and the silver salt of 2-hydroxy-1,4-naphthoquinone (2.81 g, 10 mmol) in benzene (60 mL) was stirred for 12 h at room temperature. The reacton mixture was filtered through Celite, concentrated in vacuo, and purified by flash chromatography (hexane/EtOAc 4:1) to give a yellow solid (2.19 g, 57%); mp 85-87° C.; 1H NMR (CDCl3) 8.12 (dd, J=6.5, 1.0 Hz, 1H), 7.86 (dd, J=6.9, 0.9 Hz, 1H), 7.70 (dt, J=7.6, 1.5 Hz, 1H), 7.58 (dt, J=7.5, 1.3 Hz, 1H), 5.95 (s, 1H), 4.15 (t, J=6.3, 2H), 3.22 (t, J=6.9 Hz, 2H), 1.80-2.05 (m, 4H), 1.45-2.10 (m, 4H).
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC)(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[SH:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=[O:30])[N:21]=2)[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(C2CCCN2C(=O)c2ccccc2)ccn1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)N1CCCC1c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 83.8 %

Procedure:
4-(1-Benzoyl-2-pyrrolidinyl)-2-pyridinecarbonitrile (0.42 g, 1.5 mmol) and methyl thiosalicylate (1.03 g, 6.1 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 14 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (4:1, v/v) were collected and concentrated to give the titled compound (0.52 g, 82%) as amorphous crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32](Cl)=O)[CH:28]=[CH:29][CH:30]=1.[O-]CC.[Na+]>C(O)C>[Cl:15][C:8]1[CH:9]=[C:10]([Cl:14])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]2=[N:1][C:32]([CH2:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=3)=[N:22][C:20](=[O:21])[C:3]2=[C:4]([C:16]([F:19])([F:18])[F:17])[NH:5]1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: NC(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(F)(F)F)c-3c(=O)n2)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 91.3 %

Procedure:
To a stirred solution of 186 mg (0.50 mmol) of 5-amino-3-trifluoromethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 555 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.26 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 23 h at reflux, and the heating mantle was then removed. The reaction was treated with 10 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:3 ether-hexanes. The off-white solid was briefly air-dried to give 230 mg (91%) of 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one. Mass spec.: 503(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:15]1([CH2:21][C:22](=[O:24])[CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:22]([CH3:23])([OH:24])[CH2:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CC(=O)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(C#Cc1ccc(Cl)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of 1-chloro-4-ethynylbenzene (3C) (1.75 mL, 12.81 mmol) in THF (40 mL) at 0° C. was added n-butyllithium (2.5 M in hexanes, 5.13 mL, 12.81 mmol) and stirred for 1 h. A solution of 1-phenylpropan-2-one (3B) (1.38 g, 10.25 mmol) in THF (5 mL) was added and the reaction mixture was warmed to room temperature overnight. The reaction mixture was quenched with saturated NH4Cl solution and extracted with diethyl ether (2×). The combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 3D as a yellow oil (2.29 g). 1H-NMR: 300 MHz, (CDCl3) δ 7.35-7.20 (m, 9H), 3.0 (AB quart, J=13.2, 9.9 Hz, 2H), 1.59 (s, 3 H).
Reaction SMILES: C(Cl)Cl.ClC(Cl)(Cl)C(=N)O[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:18][C@@H:19]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH3:24])=[O:22].FC(F)(F)S(O)(=O)=O>C1CCCCC1>[CH2:8]([O:18][C@@H:19]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCC[C@H](O)CC(=O)OC
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CCCC[C@@H](CC(=O)OC)OCc1ccccc1
Temperature: 22.5 °C
Yield: 84.5 %

Procedure:
In a 2 flask were charged 275 ml of methylene chloride, 550 ml of cyclohexane, 140 g of benzyl trichloroacetoimidate, and 75 g of methyl (S)-3-hydroxyheptanoate (compound (37), R1 =ethyl), and 6 ml of trifluoromethanesulfonic acid was added thereto over 5 minutes while maintaining at 20 to 25° C., followed by allowing the mixture to react at 35 to 40° C. for 5 hours. The by-produced salt was removed by filtration, and the filtrate was washed with a sodium hydrogencarbonate aqueous solution. The solvent was removed by distillation under reduced pressure, and the residue was distilled under reduced pressure to obtain 99.0 g (78.7%) of the titled compound (b.p.: 105-108° C./0.1 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>CN(C=O)C>[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([O:12][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH:21]=1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1OC1C=CCCC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 18.6 g of methyl 5-chlorosalicylate, 28 g of K2CO3 and 20 g of 3-bromo-cyclohexene in 200 ml of DMF is stirred at 90° C. overnight. The mixture is then poured onto water, extracted with ethylacetate., washed with water, dried over magnesium sulfate and evaporated to dryness to obtain crude product. This is purified by flash chromatography using hexane as the eluent to give pure methyl 2-(cyclohexen-3-yloxy)-5-chlorobenzoate as the first fraction which is used directly in the next step.
Reaction SMILES: I.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11](SC)=[NH:12])[CH:6]=[CH:7][C:8]=1[Cl:9].[O:15]=[C:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][C:28]([NH:30][NH2:31])=O)[CH:22]=2)[NH:17]1.O>CS(C)=O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[Cl:9])[CH2:10][C:11]1[NH:12][C:28]([CH2:27][O:26][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:15])[CH2:25][CH2:24]3)=[N:30][N:31]=1
Reactant: NNC(=O)COc1ccc2c(c1)CCC(=O)N2
Reactant: CSC(=N)Cc1ccc(Cl)c(Cl)c1
Agent: I
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCc2cc(OCc3nnc(Cc4ccc(Cl)c(Cl)c4)[nH]3)ccc2N1
Temperature: 115 °C

Procedure:
To the stirred solution of methyl 2-(3,4-dichlorophenyl)ethanimidothioate hydroiodide (0.184 g, 0.51 mmol) in dry DMSO (1 mL) were added 2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetohydrazide (0.120 g, 0.51 mmol) and TEA (0.103 g, 1.02 mmol) and heated at 115° C. in a seal tube overnight. Water was added to the reaction mixture. The solid precipate was filtered, dried and purified by preparative HPLC on a Kromasil C4 column (250×20 mm) using a gradient of ACN in 0.1% TFA (0-100%) to give 6-((5-(3,4-dichlorobenzyl)-4H-1,2,4-triazol-3-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one as an off white solid (0.070 g; 34%). 1HNMR 400 MHz, DMSO-d6: δ 2.40 (t, J=7.20 Hz, 2H), 2.82 (t, J=8.00 Hz, 2H), 4.09 (s, 2H), 5.01 (s, 2H), 6.75-6.76 (m, 2H), 6.88 (s, 1H), 7.28 (d, J=8.40 Hz, 1H), 7.59 (d, J=8.00 Hz, 2H), 9.91 (s, 1H), 13.87 (bs, 1H). LCMS: RT 1.71 min; LCMS (ES-API), m/z 403.0.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(F)cc4)cc3=O)ccc2nn1C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (500 mg), (4-fluorophenyl)methanol (494 mg) and triphenylphosphine (1.54 g) in tetrahydrofuran (40 ml) was added bis(2-methoxyethyl)azodicarboxylate (1.38 g) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (712 mg).
Reaction SMILES: Cl.[CH:2]1[C:7]([CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:5]=[C:4]([F:13])[CH:3]=1.[CH3:14]O>>[NH2:12][CH:8]([C:7]1[CH:6]=[CH:5][C:4]([F:13])=[CH:3][CH:2]=1)[C:9]([O:11][CH3:14])=[O:10]
Reactant: CO
Reactant: NC(C(=O)O)c1ccc(F)cc1
Agent: Cl
Product: COC(=O)C(N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HCl (g) was bubbled into a solution of 4-fluoro-DL-phenylglycine (810 mg, 4.79 mmol) in methanol (20 mL) for 5 min at 0° C. The reaction warmed to ambient temperature and stirred for 18 h. The mixture was concentrated to give the title compound (1 g). MS 183.9 (M+1)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=1>C(O)(=O)C>[CH3:5][O:6][C:7](=[O:19])[C:8]1[CH:9]=[C:10]([C:15]([F:18])([F:17])[F:16])[C:11]([OH:14])=[C:12]([N+:1]([O-:4])=[O:2])[CH:13]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(O)c(C(F)(F)F)c1
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
65% aq. nitric acid solution (1.76 mL, 39 mmol) and fuming nitric acid (3.25 mL, 78 mmol) were added at −10° C. to a solution of 4-hydroxy-3-trifluoromethyl-benzoic acid methyl ester (4.31 g, 19.6 mmol) in acetic acid (54 mL). The ice bath was removed and the solution was stirred at room temperature for 5 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to afford 4-hydroxy-3-nitro-5-trifluoromethyl-benzoic acid methyl ester (5.16 g, 99%). Orange solid, MS (ISP)=263.9 (M−H)−.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1.S(Cl)([Cl:21])(=O)=O>CN(C)C=O>[Cl:21][C:15]1[CH:16]=[N:17][C:7]2[O:6][CH:5]([CH2:4][CH2:3][Cl:2])[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]=2[CH:14]=1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CN1CC(CCCl)Oc2ncc(Cl)cc2C1=O
Yield: 6.4 %

Procedure:
A sample of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5-(4H)-one hydrochloride (10 g, 136 mole) was dissolved in dimethylformamide (150 ml) and heated to reflux. Sulfuryl chloride (20 g, 0.148 mole) was then added dropwise over a period of 40-50 minutes. The reaction was allowed to stir at reflux for 30 minutes following the addition of SO2Cl2. After cooling, the contents of the flask were partitioned between water (150 ml) and benzene (150 ml). The benzene layer was saved and the water layer extracted with an additional amount of benzene (2×50 ml). The benzene extracts were combined and washed with dilute aqueous potassium hydroxide (2×50 ml) followed by dilute aqueous hydrochloric acid (2×50 ml). The benzene layer was dried over sodium sulfate and concentrated by rotary evaporation (~70° C., water aspirator) yielding 2.61 g of crude material. The crude material was recrystallized from isopropyl ether giving 1.25 g (12.6%) of off-white crystals, m.p. 78°-79° C.