Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[F:23][CH2:24][CH2:25][N:26]1[C:35]2[C:30](=[CH:31][C:32]([F:38])=[C:33](F)[C:34]=2[F:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]1>C(#N)C>[F:38][C:32]1[CH:31]=[C:30]2[C:35](=[C:34]([F:36])[C:33]=1[N:9]1[CH2:10][CH2:11][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8]1)[N:26]([CH2:25][CH2:24][F:23])[CH:27]=[C:28]([C:40]([OH:42])=[O:41])[C:29]2=[O:39]
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1cn(C2CCNC2)nn1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(CCF)c2c(F)c(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Yield: 34.4 %

Procedure:
3-(1,2,3-triazol-1-yl)pyrrolidinehydrochloride (87 mg) and DBU (76 mg) were added to a suspension of 1-(2-fluoroethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (72 mg, 0.25 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed for 21 hrs, concentrated and the residue was diluted with water. The separated solid was filtered, washed with water and acetonitrile to give 35 mg of the title product. m.p. 240°-243° C. (dec). 1H NMR (TFA) δ: 9.76 (s, 1H), 9.08 (s, 1H), 8.73 (s, 1H), 8.12 (d, 13.7Hz, 1H), 5.8-5.6 (m, 1H), 5.4-4.1 (m, 9H), 3.0-2.65 (m, 2H). Anal. Calcd. for C18H16F3N5O3 . 1/2 H2O; C, 51.93; H, 4.12; N, 16.32.Found: C, 51.77; H, 3.84; N, 15.6.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[N:5]1[C:9](=[O:10])CCC1=O.[N:12]1([C:18]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[C:21](C(N)=O)=[CH:20][N:19]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.Cl>ClCCl>[CH3:1][O:2][C:9](=[O:10])[NH:5][C:21]1[CH:20]=[N:19][C:18]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:26][C:25]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[O-]
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1C(N)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)Nc1cnc(N2CCOCC2)cc1-c1ccccc1C
Temperature: -5 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
9.9 ml (53.7 mMol) Sodium methoxide solution (5.4 M in MeOH) were added over 15 minutes to a solution of 3.9 g (21.5 mMol) N-bromosuccinimide in 22.5 ml dichloromethane cooled to −5° C. The milky suspension was stirred at −5° C. for 18 hours, then, at the same temperature, a solution of 4.5 g (14 mMol) 6-morpholin-4-yl-4-o-tolyl-nicotinamide in 22.5 ml dichloromethane was added over 15 minutes. After 5 hours at −5° C., 33 ml (33 mMol) aqueous HCl 1N were added, the phases were separated, the organic phase washed with water and the aqueous phases extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and evaporated. The residue was treated with basic Alox (1:1 weight) in ethyl acetate/heptane 1:1 for 30 minutes at room temperature. After filtration and removal of the solvents, the residue was crystallized from di-iso-propylether/n-heptane 1:2 at 0° C. to yield 3.4 g (72.5%) (6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-carbamic acid methyl ester as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CS(O[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.O>[O:23]1[CH2:24][CH2:25][CH:20]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][CH2:22]1
Reactant: CS(=O)(=O)OC1CCOCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(c2cnn(C3CCOCC3)c2)OC1(C)C
Temperature: 100 °C
Yield: 16.4 %

Procedure:
In 8 mL of N,N-dimethylformamide were combined 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.75 g, 3.87 mmol), tetrahydro-2H-pyran-4-yl methanesulfonate (1.04 g, 5.80 mmol), and Cs2CO3 (2.01 g, 6.18 mmol) in a glass bomb and then sealed under nitrogen and heated to 100° C. After one hour the reaction was cooled and water was added to dissolve all solids. The solution was diluted with water and then extracted with EtOAc (250 mL). The organic layer was then washed with water and brine. The combined aqueous layer was then extracted with EtOAc (200 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was dried overnight on high vacuum. The crude was purified by way of silica gel chromatography eluting with a gradient of 15-25% EtOAc in DCM to afford 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.176 g, 0.633 mmol, 16.4% yield). MS (apci) m/z=279.2 (M+H).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH:28]3[CH2:40][O:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[O:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>CO>[ClH:1].[ClH:1].[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH:28]3[CH2:40][O:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[O:26])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc3c(c2)CCC3)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1ccc2c(c1)CCC2)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 65 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2,3-dihydro-1H-inden-5-ylcarbamoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (62.6 mg, 0.110 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and treated with 4 M HCl in 1,4-dioxane (6 mL). The mixture was concentrated under reduced pressure to give 30.7 mg (65%) of the title compound. LC-MS: RT=4.79 min, [M+H]+=353.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=1[C:23](=[O:25])[CH3:24]>CN(C=O)C>[CH2:7]([O:22][C:20]1[CH:19]=[CH:18][C:17]([C:23](=[O:25])[CH3:24])=[C:16]([OH:15])[CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1O
Reaction time: 2 h
Yield: 60.7 %

Procedure:
Potassium carbonate (27.2 g, 0.2 mol) followed by benzyl bromide (7.04 mL, 59.2 mmol) were added to a solution of 1-(2,4-dihydroxy-phenyl)-ethanone (10 g, 66 mmol) in DMF (90 mL). The mixture was stirred for 2 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) followed by recrystallization gave the title compound as a white solid (8.7 g, 55%). 1H NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 5.09 (s, 2H), 6.50 (s, 1H), 6.51 (dd, J=9.1, 3.9 Hz, 1H), 7.34-7.43 (m, 5H), 7.64 (d, J=9.1 Hz, 1H), 12.73 (s, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:10]1([CH2:16][CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:20]=O>ClCCl>[N:1]1([CH2:20][NH:19][CH2:18][CH2:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: NCCCc1ccccc1
Reactant: C=O
Solvent: ClCCl
Product: c1ccc(CCCNCn2nnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To the mixture of 8.8 g (0.74 mole) benzotriazole and 10 g (0.74 mole) of phenylpropylamine in 200 mL of dichloromethane was added dropwise 6.0 mL (0.74 mole) of 37% aqueous formaldehyde. The reaction mixture was stirred at room temperature overnight. The solution was dried over calcium chloride, filtered and concentrated under pressure. Hexane was added under ice-cooled bath and the resulting solid was collected by filtration and washed with hexane dried to give 21.0 g of benzotriazol-1-ylmethyl-(3-phenyl-propyl)-amine as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([C:24]1[S:28][C:27]([CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:30]([CH2:29][C:27]1[S:28][C:24]([CH2:22][CH3:23])=[CH:25][CH:26]=1)[C:31]1[CH:32]=[CH:33][C:34]([CH:37]([CH3:38])[CH3:39])=[CH:35][CH:36]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(CNc2ccc(C(C)C)cc2)s1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: CCc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)s1
Yield: 48.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.13 g) and [(5-ethylthiophen-2-yl)methyl](4-isopropylphenyl)amine (1.04 g) as starting materials, 5-benzyloxy-N-[(5-ethylthiophen-2-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.01 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])[CH:14]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)c2cccc(N)c2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(3-amino-benzoylamino)-benzoic acid ethyl ester (50.0 mg, 0.18 mmol) in pyridine (0.40 ml) was treated with a solution of benzensulfonyl chloride (31.0 mg, 0.18 mmol) in pyridine (0.10 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated, yielding crude 4-(3-benzenesulfonylamino-benzoylamino)-benzoic acid ethyl ester, MS (ISP): m/e=425.1 (M+H+), which was used as such in the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[C-:23]#[N:24].[Na+].[I-].[Na+]>CN(C)C=O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][C:23]#[N:24])=[CH:4][CH:5]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(N2CCN(Cc3ccc(CCl)cc3)CC2)cc1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1
Temperature: 0 °C
Yield: 67 %

Procedure:
A solution of 4-((4-chloromethylphenyl)methyl)-1-(4-fluorophenyl)piperazine (10.0 g), sodium cyanide (1.72 g) and a catalytic amount of sodium iodide in dimethylformamide (50 ml) was stirred at 70° C. for 3 hr, and poured into ice water (200 ml) and extracted with ethyl acetate (300 ml×2). The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:2) and recrystallized from ethyl acetate-hexane to give the title compound (6.50 g) as pale-yellow crystals.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1B(O)O>CS(C)=O>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)c(B(O)O)c1
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Solvent: CS(C)=O
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cc(C)ccc4O)n3)n2)c1
Yield: 50 %

Procedure:
6-(2-Hydroxy-5-methoxyphenyl)-6′-(2-hydroxy-5-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-5-methylphenylboronic acid in 50% yield using method F; δH [2H6]]-DMSO 13.27,(1H, b), 12.64,(1H, b), 8.37,(1H, d), 8.33,(1H, d), 8.21,(2H, t), 8.14,(2H, d), 7.93,(1H, s), 7.64,(1H, s), 7.17,(1H, d), 7.00,(1H, d), 6.93,(1H, d), 6.89,(1H, d), 3.82,(3H, s), 2.34,(3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1/[CH:17]=[CH:18]\[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:13][C@H:12]1/[CH:17]=[CH:18]\[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1/C=C\c1cccnc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](/C=C\c2cccnc2)N(C(=O)OCc2ccccc2)C1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-4-hydroxy-2-[(Z)-2-(pyridin-3-yl)vinyl]pyrrolidine (5.2 g) in a mixture of ethyl acetate (50 ml) and triethylamine (2.90 ml) was added dropwise methanesulfonyl chloride (1.24 ml) under ice-cooling with stirring and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added ethyl acetate (50 ml) and water (30 ml). The organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of n-hexane and ethyl acetate (1:2, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(Z)-2-(pyridin-3-yl)vinyl]pyrrolidine (4.14 g).
Reaction SMILES: BrBr.[C:3]([NH:7][NH:8][C:9]1([C:18]#[N:19])[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1)([CH3:6])([CH3:5])[CH3:4]>>[C:3]([N:7]=[N:8][C:9]1([C:18]#[N:19])[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1)([CH3:5])([CH3:4])[CH3:6]
Reactant: CC1CC(C)(C)CC(C#N)(NNC(C)(C)C)C1
Agent: BrBr
Product: CC1CC(C)(C)CC(C#N)(N=NC(C)(C)C)C1

Procedure:
1-tert.-butylazo-1-cyano-3,3,5-trimethylcyclohexane was prepared by bromine oxidation of the above 1-tert.-butylhydrazo-1-cyano-3,3,5-trimethylcyclohexane in the same way that 4-tert.-butylhydrazo-4-cyano2,6-dimethylheptane was oxidized in Example VII C. The yield of liquid product was 8.2 g. (63%) and the infrared spectrum was consistent with the structure of the proposed compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]=1[CH:21]=O.N1CCCCC1>C(O)C>[CH3:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]=1[CH:21]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1c(C=O)[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccccc32)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-oxindole (133 mg), 3-methylindole-2-carbaldehyde (190 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydroindole-2-one.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[CH3:17].[CH3:18]I.O>CS(C)=O>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10](=[O:14])[N:11]2[CH3:18])=[CH:6][C:5]=1[CH3:17]
Reactant: CI
Reactant: Cc1cc2c(cc1Br)NC(=O)CC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2c(cc1Br)N(C)C(=O)CC2(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 101.3 %

Procedure:
A mixture of powdered KOH (14.06 g, 0.250 mol) in DMSO (150 mL) was stirred at 0° C. for 10 min. 7-Bromo-4,4,6-trimethyl-3,4- dihydro-1H-quinoline-2-one (33.59 g, 0.125 mol) was added cautiously, followed immediately by the addition of methyl iodide (39 mL, 0.625 mol). The reaction mixture was kept at 0° C. for 30 min then slowly warmed up to room temperature and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane washed with water and brine, dried (MgSO4), filtered and evaporated to give 35.74 g of 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (99%) and used without further purification in the Suzuki coupling (step a). 1H NMR (300 MHz; CDCl3): 1.27 (s, 6 H), 2.37 (s, 3 H), 2.48 (s, 2 H), 3.35 (s, 3 H), 7.12 (s, 1 H), 7.16 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[S:37][CH3:38]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[S:37][CH3:38])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CSc1cc(C(C)=O)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.88 g, 8.5 mmol), K2CO3 (1.8 g) and 1-[4-(3-bromopropoxy)-3-methylmercaptophenyl]ethanone (2.3 g, 7.6 mmol) in acetonitrile (100 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was concentrated, then diluted with dichloromethane (250 ml). The insolubles were filtered off. The dichloromethane solution was concentrated to dryness as an oil. Purification was effected by flash chromatography on a silica gel column (SiO2, 54 g, eluted with dichloromethane, 500 ml; 1% methanol-dichloromethane, 1.1 l). The purest fractions were combined to give a colorless oil which solidified to an off-white solid (2.4 g). Recrystallization from ethanol (100 ml) yielded 1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl]-1-piperidinyl]propoxy]-3-methylmercaptophenyl]ethanone as off-white needle crystals, 2.15 g, m.p.=150°-152° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:18]=[C:17]2[C@@H:7]([CH2:8][C:9]3[C:19]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]2=4)[NH:11][CH:10]=3)[N:5]([CH3:6])[CH2:4]1>C(O)(C)(C)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[C:3]([N:11]1[C:12]2[C:19]3[C:9]([CH2:8][C@@H:7]4[C:17]([C:16]=3[CH:15]=[CH:14][CH:13]=2)=[CH:18][C@@H:3]([CH2:2][OH:1])[CH2:4][N:5]4[CH3:6])=[CH:10]1)([CH3:18])([CH3:4])[CH3:2]
Reactant: CN1C[C@H](CO)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Solvent: CC(C)(C)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN1C[C@H](CO)C=C2c3cccc4c3c(cn4C(C)(C)C)C[C@H]21
Reaction time: 90 h
Yield: 122.9 %

Procedure:
To a mixture of 8 g of lysergol in 150 ml of t-butanol, 200 ml of trifluoroacetic anhydride were added dropwise with vigorous stirring. After the solution had been left at room temperature for 90 hours, it was evaporated. The residue was dissolved in water, made alkaline with ammonium hydroxide and the aqueous layer was extracted with ethyl acetate. After removal of the ethyl acetate, the residue was purified by silica gel column chromatography using 1:1 cyclohexane:ethyl acetate for elution to give 6 g of the title compound melting at 181° to 183° C.
Reaction SMILES: CNC(=O)O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:12]C1C=CC=CC=1.C([N+](CC)(CC)CC)C.[OH:28][C:29]1C=CC([N+]([O-])=O)=[CH:31][N:30]=1>C(O)C>[CH3:31][N:30]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:29]([NH2:12])=[O:28]
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: Nc1ccccc1
Reactant: CNC(=O)Oc1ccccc1
Agent: CC[N+](CC)(CC)CC
Solvent: CCO
Product: CN(C(N)=O)c1ccccc1
Yield: 91 %

Procedure:
15.1 g. of phenyl N-methylcarbamate, 9.3 g. of aniline and 5.4 g. of the tetraethylammonium salt of 2-hydroxy-5-nitro-pyridine are refluxed in 200 ml. of ethanol for 5 hours. The reaction solution is concentrated, and the residue is dissolved in 100 ml. of chloroform, washed successively with 50 ml. of 1N sodium carbonate, 50 ml. of 1N hydrochloric acid and 100 ml. of water, and dried. By concentrating to dryness and recrystallizing from 120 ml. of ethanol, crystals of N-methyl-N-phenylurea having a m.p. of 150° - 151°C. are obtained in 91% yield.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]1=O)(=O)[CH3:5]>CCO>[CH3:5][C:4]1[C:7]2[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]=2[NH:3][N:2]=1
Reactant: CC(=O)C1C(=O)CCCC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
According to Scheme 4 Step 3: Hydrazine monohydrate (7.59 mmol, 0.37 mL) was added to a solution of 2-acetylcyclohexane-1,3-dione (7.59 mmol, 1.17 g) in EtOH (19 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. After evaporation, the crude residue was purified by flash chromatography over silica gel using DCM/AcOEt (70:30 to 50:50) as eluent to yield 3-methyl-6,7-dihydro-1H-indazol-4(5H)-one (1.76 mmol, 265 mg, 23%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(N(CC)CC)C.[Cl:18][CH:19]([Cl:23])[C:20](Cl)=[O:21].O>C(Cl)Cl>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:20](=[O:21])[CH:19]([Cl:23])[Cl:18])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)C(Cl)Cl)n[nH]1
Yield: 67 %

Procedure:
4.2 g (0.03 mole) of 3-amino-5-t-butylpyrazole prepared in Example 1 and 3.1 g of triethylamine were dissolved in 30 ml of methylene chloride, and 4.4 g of dichloroacetyl chloride was added dropwise thereto at about 30° C. The resulting mixture was allowed to stand over night. Thereafter, water was added thereto whereby crystals were precipitated. The crystals were collected by filtration and washed with water to obtain 5.0 g of 5-t-butyl-3-dichloroacetylaminopyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:8]=1)[NH2:7].[C:10](OCC)(=[O:13])[CH:11]=[CH2:12].CC(N=NC(C#N)(C)C)(C#N)C>CS(C)=O.O>[Cl:1][C:2]1[CH:8]=[C:6]2[C:5]([CH2:12][CH2:11][C:10](=[O:13])[NH:7]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)ccc1I
Reactant: C=CC(=O)OCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCc2ccc(Cl)cc2N1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of 5-chloro-2-iodoaniline (14.0 g, 0.0552 mol) in dimethyl sulphoxide, ethyl acrylate (30.38 mL, 0.276 mol) and n-tributyltinhydride (22.3 mL, 0.0828 mol), AIBN (3.6 g, 0.022 mol) was added at room temperature. The reaction mixture was heated to 120° C. and stirred for 16 h. The reaction mixture was cooled to room temperature; the reaction mixture was diluted with water. The aqueous phase was extracted with ethyl acetate (3×500 mL), the combined organic layer was washed with cold water, saturated aqueous sodium chloride solution and dried over sodium sulphate, the solvent was evaporated under vacuum and the residue was purified with silica gel (60-120 mesh) silica gel column chromatography by 0-20% ethyl acetate in hexane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.17-7.15 (d, J=7.6 Hz, 1H), 6.93-6.91 (d, J=8.0 Hz, 1H), 6.85 (s, 1H), 2.85-2.81 (t, J=7.2 Hz, 2H), 2.44-2.41 (t, J=8 Hz, 2H); MS (M+1): 181.9.