Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O-:3])[CH3:2].Cl.Cl.[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1.C(Cl)(=O)C>>[C:1]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=[O:3])[CH3:2]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CC[O-]
Agent: Cl
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 78.3 %

Procedure:
Beginning with 2.00 gm (5.74 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole dihydrochloride ethanolate and 1.13 gm (25.8 mMol) acetyl chloride, 1.22 gm (78.3%) of the title compound were recovered as a white powder.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:27])[CH2:9][CH2:10][C@@H:11]2/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH2:25][OH:26])[CH2:3]1>C(Cl)(Cl)Cl.C(O)(C)C.O=[Mn]=O>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:27])[CH2:9][CH2:10][C@@H:11]2/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[CH:25]=[O:26])[CH2:3]1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=C/CO)CC[C@]12O
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=C/C=O)CC[C@]12O
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 4.90 g of (E,E)-5-(3β,14β-dihydroxy-5β-androstane-17β-yl)-2,4-pentadien-1-ol in 160 ml of chloroform and 40 ml of iso-propanol, 10.40 g of MnO2 were added at room temperature. The mixture was stirred overnight and then filtered through Celite. The organic solution was evaporated to dryness to give 4.80 g of the title compound (II-a) as an off-white solid.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[O:19][C:18]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][CH:16]=2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+]>CO.O>[CH2:20]([C:18]1[O:19][C:15]([CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[CH:16][N:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(c1ccccc1)N1CCC(c2cnc(Cc3ccccc3)o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1ccc(Cc2ncc(C3CCNCC3)o2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To 40 mg of 1-benzoyl-4-(2-benzyl-oxazol-5-yl)piperidine (step F) in 4.5 mL MeOH and 0.5 ml H2O was added 260 mg of potassium hydroxide. The reaction was stirred at 80° C. overnight, 20 ml of H2O was added and the mixture was extracted with 3×20 mL EtOAc. The combined organic layer was dried over MgSO4. The solvent was evaporated under reduced pressure to give 22 mg of the title compound. ESI-MS 242.9 (M+H); HPLC A: 2.29 min.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[C:4]([C:6]1[C:11]([O:12][CH2:13][C:14]2C=CC=[CH:16][C:15]=2F)=[C:10]([O:21][CH3:22])[C:9]([O:23][CH3:24])=[CH:8][C:7]=1[CH3:25])=[O:5].C(OC1C(C(=O)C2C(C)=CC=CC=2C)=C(C)C=C(OC)C=1OC)C1C=CC=CC=1.BrC1C=CC(OC)=C(C=1C)C(C1C(OC)=C(OC)C(OC)=CC=1C)=O>>[CH2:13]([O:12][C:11]1[C:6]([C:4](=[O:5])[C:3]2[C:2]([Cl:1])=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:30])=[C:7]([CH3:25])[CH:8]=[C:9]([O:23][CH3:24])[C:10]=1[O:21][CH3:22])[CH2:14][CH2:15][CH3:16]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(OCc2ccccc2F)c1OC
Agent: COc1cc(C)c(C(=O)c2c(C)cccc2C)c(OCc2ccccc2)c1OC
Agent: COc1cc(C)c(C(=O)c2c(OC)ccc(Br)c2C)c(OC)c1OC
Product: CCCCOc1c(OC)c(OC)cc(C)c1C(=O)c1c(Cl)cccc1Cl

Procedure:
2,6-dichloro-4′,5′-dimethoxy-6′-(2′fluorobenzyloxy)-2′-methylbenzophenone (coded BB-2); 6′-benzyloxy-4′,5′-dimethoxy-2,6-dimethyl-2′-methylbenzophenone (coded BB-3); and 5-bromo-2′,6-dimethyl-2,4′,5′,6′-tetramethoxybenzophenone (coded BB-4), most preferred BB-4.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl>O1CCCC1>[CH2:10]([C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7]([OH:9])=[O:8])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CCCCCCCCCCCCCCCBr
Reactant: Cc1cccc(C(=O)O)c1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCc1cccc(C(=O)O)c1
Reaction time: 1 h

Procedure:
Meta-toluic acid (4.0 g) was dissolved in tetrahydrofuran (98 mL). Thereto, 2M lithium diisopropylamide (59 mL) was added at room temperature, followed by stirring for 1 hour. Thereto, 1-bromo pentadecane (9.4 mL) was added, followed by stirring at room temperature for 21 hours. The reaction solution was poured to 1N hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (3.7 g) having the following physical property values.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:9]=1.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:32][CH2:33][C:34]([NH:7][C:8]1[CH:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=2)[N:9]=1)=[O:35]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cc3c(Cl)cccc3Cl)n2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)cc(NC(=O)CCl)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
Pyridine (1 ml) was added to a mixture of 4-[[4-amino-6-[(2,6-dichlorophenyl)-methyl]-2-pyrimidinyl]amino]benzonitrile (0.00135 mol) in CH2Cl2 (19 ml). A solution of chloroethanoyl chloride (0.001375 mol) in CH2Cl2 (0.5 ml) was added dropwise on an ice bath. The mixture was stirred at room temperature for 2 hours. More chloroethanoyl chloride (0.00625 mol) in CH2Cl2 (0.5 ml) was added. The mixture stood in the refrigerator overnight. The solvent was evaporated. The residue was treated with a saturated Na2CO3 solution and the mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and concentrated. The residue was purified by flash column chromatography over silica gel (eluent: CH2Cl2CH3OH/NH4OH 99/110.1). The desired fractions were collected and the solvent was evaporated, yielding 0.22 g (36.5%) of 2-chloro-N-[6-[(2,6-dichloro-phenyl)methyl]-2-[(4-cyano-phenyl)amino]-4-pyrimidinyl]acetamide (interm. 13).
Reaction SMILES: [N+]([C:4]1C=CC=CC=1O)([O-])=O.[Br:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[Br:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[O:21][CH3:4]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=[N+]([O-])c1cccc(O)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
The nitrophenol starting material B2 (3.1 g; 14.2 mmol) was dissolved in DMF (20 mL) and to the solution was added ground cesium carbonate (5.58 g; 17.1 mmol) followed by MeI (2.6 mL; 42.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated, the residue taken up in ether (1×200 mL), washed with water (1×200 mL), brine (4×100 mL), dried (MgSO4), filtered and evaporated to afford the crude 2-bromo-3-nitroanisole B3 (94%; 3.1 g) as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>CO.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Solvent: CCOCC
Solvent: CO
Product: COC(=O)Cc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Step H (1): To a solution of 2-(5-bromo-1H-indol-3-yl)acetic acid (1.0 g 3.94 mmol) in MeOH (5 mL) and Et2O (15 mL) was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, 10 mL). The reaction was stirred at rt for 2 h. The solvents were removed and the residue was purified by flash chromatography to yield 900 mg of methyl 2-(5-bromo-1H-indol-3-yl)acetate (yield 85%). 1H NMR (500 MHz, CDCl3) δ ppm 3.71 (s, 3 H) 3.72 (s, 2 H) 7.16 (d, J=2.14 Hz, 1 H) 7.21 (d, J=8.55 Hz, 1 H) 7.27 (dd, J=8.55, 1.83 Hz, 1 H) 7.72 (d, J=1.53 Hz, 1 H) 8.12 (s, 1 H)
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[O:4][N:3]=1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C=O)C>[Cl:26][CH2:25][CH2:24][CH2:23][N:11]1[C:10]2[CH:9]=[N:8][C:7]([C:5]3[O:4][N:3]=[C:2]([CH3:1])[N:6]=3)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: Cc1noc(-c2cc3c(cn2)[nH]c2ccccc23)n1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2cc3c4ccccc4n(CCCCl)c3cn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of 3-(3-methyl-1,2,4-oxadiazol-5-yl)-β-carboline (2.00 g, 0.008 mol) in anhydrous DMF (50 mL) was added 50% sodium hydride in mineral oil (0.42 g, 0.01 mol). The mixture was stirred for 1 h at room temperature, and then carefully added to a solution of 1-bromo-3-chloropropane (1.39 g, 0.0088 mol) in anhydrous DMF (150 mL). The resulting mixture was stirred at ambient temperature over night. The reaction mixture was concentrated in vacuo, and the crude product was purified on a silica gel column (Eluent: CH2Cl2 /methanol (9:1)) to give the title compound 2.11 g (81%). M.p. 180°-185° C.
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]2[CH2:12][O:11]2)=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5].[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(O)C>[C:4]([C:3]1[C:2]([F:1])=[C:9]([CH:10]([OH:11])[CH2:12][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@H:23]2[CH2:27][OH:28])[CH:8]=[CH:7][C:6]=1[F:13])#[N:5]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: N#Cc1c(F)ccc(C2CO2)c1F
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2F)[C@H](CO)C1
Temperature: 150 °C

Procedure:
2,6-Difluoro-3-(oxiran-2-yl)benzonitrile (1.50 g, 8.28 mmol) and (S)-4-N—BOC-2-hydroxymethylpiperazine (2.40 g, 11.1 mmol) were suspended in ethanol (15 mL) then heated in a microwave apparatus for 30 min at 150° C. The reaction mixture was cooled and evaporated dryness. The residue was purified by chromatography through a 120 g Redi-sep column eluting with 5% MeOH/95% EtOAc to yield the title compound LC-MS: M+1=398.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1.CN1C(C(C2C=CC=CN=2)O)=CN=C1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1cccnc1)c1cccc(F)c1
Agent: Cn1cncc1C(O)c1ccccn1
Product: O=C(c1cccnc1)c1cccc(F)c1

Procedure:
The title compound was prepared analogously to the method in Intermediate 25: step b using (3-fluorophenyl)(pyridin-3-yl)methanol (Intermediate 32: step a) in place of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:26])[C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.7 %

Procedure:
To a solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-[4-(trifluoromethyl)phenyl]propanoic acid XXI (1 g, 3 mmol) in dry THF (10 mL) was added sodium hydride (60% suspension in mineral oil) (0.72 g, 18 mmol; 6 eq. of pure NaH) in portions. Methyl iodide (1.12 mL, 18 mmol) was then added and the mixture was stirring at r.t. for 3 days. The mixture was then treated with water before removing the THF under reduced pressure. The aqueous phase was acidified and extracted 2× EtOAc. The combined EtOAc was washed with sodium thiosulfate, dried and evaporated under reduced pressure. The residue was crystallized to produce (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[4-(trifluoromethyl)phenyl]-propanoic acid XXII (0.73 g, 2 mmol, 70% yield).
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(OCC)(=O)C>C(Cl)Cl>[C:1]([NH:4][NH:5][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(=O)NN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NNC(C)=O
Yield: 47.3 %

Procedure:
To a solution of acetohydrazide (36.0 g, 486 mmol) in CH2Cl2 (250 mL) stirring at 0° C. under N2, was added triethylamine (250 mL, 1.46 mol) followed by ethyl chlorooxoacetate (65.0 mL, 584 mmol) over 1 h. The reaction mixture was stirred at rt for 8 h at which time ethyl acetate was added and the salts were removed by filtration. The filtrate was concentrated in vacuo and the residue purified by column chromatography using a gradient of 5-15% EtOAc/hexane to afford the product as an off-white solid (40.0 g, 47%). 1H NMR (300 MHz, CDCl3): δ 9.85 (1H, bs), 9.29 (1H, bs), 4.35 (2H, q, J=7 Hz), 2.10 (3H, s), 1.36 (3H, t, J=7 Hz). MS (M+H): 175.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[CH3:23][NH:24][CH3:25]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][C:13]([N:24]([CH3:25])[CH3:23])=[O:15])[C:6]3[CH2:18][CH2:19][N:20]([CH3:22])[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: CNC
Reactant: CCOC(=O)CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCC(=O)N(C)C)C1
Temperature: 120 °C

Procedure:
A mixture of ethyl 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)propanoate (CD17) (100 mg) and dimethylamine (1 ml) was heated at 120° C. for 15 h to obtain 3-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-N,N-dimethylpropanamide (CD52) after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient. The free base was converted into its HCl salt by treatment of ethanol-HCl.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35](Cl)=[O:36]>C1COCC1>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:35]([C:25]3[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:27][O:28][C:24]=3[CH3:23])=[O:36])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:20])[CH3:21]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 489.3 (M+H)+.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]([O:10][CH:11]([CH2:15][CH2:16][CH2:17][Cl:18])[C:12](O)=[O:13])(=[O:9])[CH3:8]>>[C:7]([O:10][CH:11]([CH2:15][CH2:16][CH2:17][Cl:18])[C:12]([Cl:4])=[O:13])(=[O:9])[CH3:8]
Reactant: CC(=O)OC(CCCCl)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: CC(=O)OC(CCCCl)C(=O)Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
Oxalyl chloride (114 g, 0.90 mol) was added to 2-acetoxy-5-chloropentanoic acid g, 0.37 mol). The mixture was stirred at room temperature for 15 h. The volatiles were evaporated and the oily residue was distilled in vacuo to give 75 g (96%) of product. B.p. 93-95° C. (2 mm Hg).
Reaction SMILES: [OH:1]O.[OH:3][CH:4]([CH2:14][Cl:15])[CH2:5][S:6][C:7]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[Na+].[Cl-]>O.CO>[OH:3][CH:4]([CH2:14][Cl:15])[CH2:5][S:6]([C:7]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:1]
Reactant: OO
Reactant: OC(CCl)CSc1ncc(Cl)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(CC(O)CCl)c1ncc(Cl)cn1
Yield: 59 %

Procedure:
A solution of 35% H2O2 (1.7 mmol) and SeO2 (1.7 mmol) in water (2.5 ml) was added to a solution of 2-(2-hydroxy-3-chloropropyl)thio-5-chloropyrimidine (1.7 mmol) in methanol (10 ml). The mixture was stirred at room temperature for 18 h before saturated NaCl aq. (40 ml) was added and the mixture extracted with chloroform (3×20 ml). The dried (MgSO4) chloroform solution was evaporated and the residue crystallized from ethyl acetate; yield 59%; m.p. 170° C. 1H NMR (DMSO-d6): δ3.0-4.4 (6H, m), 9.10 (H-4, H-6). IR (KBr): 3400 (OH), 1060-1070 cm-1 (SO).
Reaction SMILES: [NH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[NH2:2].[CH3:13][O:14][C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:13][O:14][C:15]([NH:2][NH:1][C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:16]
Reactant: NNc1n[nH]c2cc(Cl)ccc12
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)NNc1n[nH]c2cc(Cl)ccc12
Yield: 73 %

Procedure:
Analogously to Example 1, 0.04 mol of 3-hydrazino-6-chloro-indazole and 0.044 mol of chlorocarbonic acid methyl ester in 25 ml of pyridine at 0° - 5° C, followed by 2 hours at room temperature, give 3-methoxycarbonylhydrazino-6-chloroindazole (melting point 223°- 224° C after recrystallisation from methanol: yield, 73% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH:22]=[O:23])[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:22]([OH:23])[CH2:21][CH:18]2[CH2:19][CH2:20][CH:15]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: CCCCCC1CCC(CC=O)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCC1CCC(CC(O)C#Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
4-Fluorophenylacetylene (1.3 g) was dissolved in THF (20 ml), followed by dropwise adding a n-butyllithium-hexane solution (1.61M, 0.62 ml) while stirring the above solution under ice-cooling, stirring the reaction solution under ice-cooling for 30 minutes, dropwise adding a solution of 2-(4-pentylcyclohexyl)acetaldehyde (1.5 g) in THF (10 ml), raising the temperature of the reaction solution up to room temperature after completion of the dropwise addition, stirring the mixture for 5 hours, adding dilute hydrochloric acid (5 ml) to the resulting raw solution, extracting with ethyl acetate (50 ml), washing the organic layer with water, drying over anhydrous MgSO4, concentrating under reduced pressure to obtain a brown oil, and recrystallizing this oil from a mixed solution of ethyl acetate-heptane, to obtain 1-(4-fluorophenyl)-4-(4-pentylcyclohexyl)-1-butyn-3-ol (white crystal) (2.3 g) .
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH3:24].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:23]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:3]=[C:4]3[C:12](=[O:13])[C:11]4[CH:14]=[C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=4[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=2)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]
Reactant: CC(C)N1CCNCC1
Reactant: CS(=O)(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)N1CCN(c2cnc3ccc4ccc(NS(C)(=O)=O)cc4c(=O)c3c2)CC1
Temperature: 105 °C
Reaction time: 12 h

Procedure:
N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide (0.050 g, 0.15 mmol), isopropylpiperazine (0.038 g, 0.30 mmol), Pd2(dba)3 (1.5 mg, 0.0015 mmol), BINAP (3.0 mg, 0.0045 mmol), and sodium tert-butoxide (0.043 g, 0.45 mmol) were added to a dry flask through which argon was purged. 3.0 mL dry dioxane was added and argon was bubbled through the solution for 5 minutes. The reaction was stirred and heated to 105° C. After 12 hours, the reaction mixture was poured into 100 mL ethyl acetate, 100 mL water, and 25 mL saturated ammonium chloride. The organic layer was separated, dried with magnesium sulfate, filtered, concentrated, and purified by reverse phase HPLC (20-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)[CH:12]([F:14])[F:13]>C1CCCCC1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][C:11]([F:10])([F:24])[CH:12]([F:13])[F:14])[CH:17]=1
Reactant: Nc1cc(F)ccc1F
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Solvent: C1CCCCC1
Product: Fc1ccc(F)c(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 0 °C
Yield: 85 %

Procedure:
EX-661A) A mixture of 2,5-difluoroaniline (2.58 g, 20 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (4.44 g, 20 mmol) in cyclohexane (50 mL) was heated under reflux for 5 h using a Dean-Stark trap to remove water. The solvent was removed in vacuo, and the residue was dissolved in methanol (30 mL). The solution was stirred and cooled to 0° C., then sodium borohydride was added (1.32 g, 35 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h, then acidified with 1 N HCl. After neutralizing to pH 7.5 with 2.5 N sodium hydroxide, the mixture was extracted with diethyl ether (3×20 mL). The organic layer was washed with brine and water, then dried over anhydrous MgSO4, and evaporated to give 5.7 g (86%) of the desired N-(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amine product as a brown oil, which was greater than 90% pure by reverse phase HPLC analysis. MS m/z=336 [M+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:19](=[O:22])[CH2:20][CH3:21])[C:15](=[O:18])[CH2:16][CH3:17])=[CH:4][CH:3]=1.[CH2:23]([O:25][CH2:26][CH2:27]Br)[CH3:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:23]([O:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:15](=[O:18])[CH2:16][CH3:17])[C:19](=[O:22])[CH2:20][CH3:21])=[CH:6][CH:7]=1)[CH3:24]
Reactant: CCC(=O)C(CCCCCCc1ccc(O)cc1)C(=O)CC
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCCOc1ccc(CCCCCCC(C(=O)CC)C(=O)CC)cc1
Reaction time: 72 h

Procedure:
A mixture of 3.9 g. of 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione, 12 g. of 2-bromoethyl ethyl ether, 4 g. of potassium carbonate and 1 g. of potassium iodide in 40 ml. of acetone was heated at reflux for 48 hours and then allowed to stand at room temperature for three days. The reaction mixture was then filtered and concentrated to remove the solvent. The residue was distilled at 200°-205° C. (0.001 mm.) to give 4-{6-[4-(2-ethoxyethoxy)phenyl]hexyl}-3,5-heptanedione as a light yellow oil.