Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:20]([CH3:21])=[CH:19][NH:18][N:17]=2)=[C:12]([CH3:22])[CH:11]=1.[CH3:23]C1C(C2C=CC=CC=2)=NNC=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:20]([CH3:21])=[CH:19][N:18]([CH:2]([CH2:8][CH3:23])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[N:17]=2)=[C:12]([CH3:22])[CH:11]=1
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: Cc1cc(Cl)ccc1-c1n[nH]cc1C
Reactant: CC(Cl)C(=O)N(C)C
Product: CCC(C(=O)N(C)C)n1cc(C)c(-c2ccc(Cl)cc2C)n1

Procedure:
Using the procedure of Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 3-(4-chloro-2-methylphenyl)-4-methylpyrazole for 4-methyl-3-phenylpyrazole there is obtained 3-(4-chloro-2-methylphenyl)-α-ethyl-N,N,4-trimethylpyrazole-1-acetamide, m.p. 89°-92° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[N:15]=[C:14]([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[N:17]2)[CH:13]=[C:12]([N+:30]([O-])=O)[CH:11]=1.O.O.[Sn](Cl)Cl.NO.[Sn](Cl)Cl>CCOC(C)=O.[Pd].O.CN(C=O)C>[NH2:30][C:12]1[CH:11]=[C:10]([C:4]2[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:15]=[C:14]([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[N:17]2)[CH:13]=1
Reactant: CCOC(=O)c1cnn(-c2cc([N+](=O)[O-])cc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Agent: [Pd]
Agent: Cl[Sn]Cl
Agent: NO
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2cc(N)cc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Temperature: 70 °C

Procedure:
A mixture of the title compound from Example 19 Step D (1.2 g, 2.7 mmol), DMF (15 mL), water (1.5 mL) and tin (II) chloride dihydrate (1.8 g, 7.9 mmol) was heated at 70° C. for 1.5 h, leading to reduction of the nitro group to the corresponding hydroxylamine. A second addition of tin (II) chloride dehydrate (2.4 g, 10.6 mmol) followed by heating at 100° C. overnight led to little progress. Water was added, and the reaction mixture was extracted with hexanes-EtOAc. The organic phase was separated and passed through a pad of silica gel. Hydrogenation using Pd-black (450 mg, 4.2 mmol) in EtOAc:EtOH (100 mL, 1:1 v/v) under 50 psi H2, followed by filtration and concentration, provided the title compound: LCMS m/z 421.6 [M+H]+; 1H NMR (400 MHz, acetone-d6) δ 8.09 (s, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.45 (d, J=1.9 Hz, 1H), 7.13 (dd, J=8.4 Hz, 2.1 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.84 (d, J=1.9 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 2.26 (s, 3H), 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:10])=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:31]>C(OCC)(=O)C>[CH:9]([O-:11])=[O:10].[CH:9]([O-:11])=[O:10].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][CH:8]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:16][CH2:15][N+:14]([CH2:29][C:30](=[O:31])[C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)([CH2:19][CH2:18]3)[CH2:13]2)=[O:10])=[CH:26][CH:27]=1.[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][CH:8]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]([O:11][C@@H:12]2[CH:17]3[CH2:16][CH2:15][N+:14]([CH2:29][C:30]([C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)=[O:31])([CH2:19][CH2:18]3)[CH2:13]2)=[O:10])=[CH:26][CH:27]=1
Reactant: O=C(CCl)c1cccs1
Reactant: Cc1ccc(CNC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(CNC(C(=O)O[C@H]2C[N+]3(CC(=O)c4cccs4)CCC2CC3)c2ccccc2)cc1
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
(R)-Quinuclidin-3-yl 2-(4-methylbenzylamino)-2-phenylacetate (C77) (73 mg, 0.20 mmol) is dissolved in ethyl acetate (2.00 mL) and 2-chloro-1-(thiophen-2-yl)ethanone (35.4 mg, 0.22 mmol) is added. The colorless solution is stirred at RT overnight. Solvent is evaporated and the residue is first purified by flash chromatography (DCM/MeOH=9/1 to 85/15) and then by preparative LC/MS. Organic solvent is evaporated and then the aqueous solution is freeze-dried overnight to afford the title compound as a pale yellow oil (42 mg, 36% yield, formate formate anion, mixture of diastereoisomers).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([C:27]2[NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH:13]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.O.[OH-].[Na+]>ClCCl>[NH:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[CH:18]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:14]1[CH:13]=[C:12]([S:11][CH2:10][CH2:9][NH2:8])[CH:17]=[CH:16][CH:15]=1
Reactant: CN1CCC(OC(c2cccc(SCCNC(=O)OC(C)(C)C)c2)c2nc3ccccc3[nH]2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(OC(c2cccc(SCCN)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-tert-butoxycarbonyl-2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine in dichloromethane (2 mL) is added trifluoroacetic acid (0.5 ml) at room temperature. The mixture is stirred at room temperature for 24 h. Water is added and the mixture is basified by adding a solution of sodium hydroxide. The aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated. The residue is triturated in diisopropylether to give 2-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:10]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11]1.C(OCC)C>CCCCCCC>[CH2:7]([O:6][C:4](=[O:5])[C:3]([C:14](=[S:15])[NH:13][CH:10]1[CH2:12][CH2:11]1)=[C:2]([NH2:1])[CH3:9])[CH3:8]
Reactant: S=C=NC1CC1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCCCCCC
Solvent: CCOCC
Product: CCOC(=O)C(C(=S)NC1CC1)=C(C)N
Temperature: 100 °C
Yield: 44.9 %

Procedure:
A mixture of 2.03 ml of ethyl 3-aminocrotonate (16 mmol) and 1.59 g of cyclopropyl iso-thiocyanate (16 mmol) was heated to 100° C. for 5 h. The reaction mixture was then cooled to 0° C. and diethyl ether (5 ml) and a small amount of heptane were added. An oily precipitate formed and after 5 min the solvents were decanted off. The remaining residue was triturated with a small amount of diethyl ether at 0° C. The precipitate was then filtered off and dried to give 1.64 g (45%) of 3-amino-2-cyclopropylthiocarbamoyl-but-2-enoic acid ethyl ester as a yellow solid. 1HNMR (DMSO-d6, 300 MHz): δ 0.60 (m, 2H), 0.76 (m, 2H), 1.11 (t, J=7.1 Hz, 3H), 1.90 (s, 3H), 3.28 (m, 1H), 3.97 (q, J=7.1 Hz, 2H), 7.24 (br s, 1H), 8.21 (br s, 1H), 9.79 (d, J=5.5 Hz, 1H).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)(=[O:35])[CH3:34]
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A165) and acetyl chloride the title compound is obtained as colorless MS (ESI): m/z=426 (MH+, 100%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]([CH2:13]O)=[CH:11][C:10]2[CH:9]=[C:8]3[O:15][CH2:16][O:17][C:7]3=[CH:6][C:5]=2[N:4]=1.O=S(Cl)[Cl:20]>C(Cl)Cl>[ClH:20].[Cl:20][CH2:13][C:12]1[C:3]([NH:2][CH3:1])=[N:4][C:5]2[CH:6]=[C:7]3[O:17][CH2:16][O:15][C:8]3=[CH:9][C:10]=2[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: CNc1nc2cc3c(cc2cc1CO)OCO3
Solvent: ClCCl
Product: CNc1nc2cc3c(cc2cc1CCl)OCO3
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of (6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methanol CCH 34158-2 (1.00 g, 4.31 mmol) in dry CH2Cl2 (20 mL) in a 50 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (5.0 mL, 68.9 mmol). The mixture was stirred for 2 h at RT then concentrated to dryness at 40° C. under vacuum. The residue was then taken up in CH2Cl2 (15 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 7-(chloromethyl)-N-methyl-[1,3]dioxolo[4,5-g]quinolin-6-amine hydrochloride CCH 34158B as a yellow solid (1.24 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]1)=[O:20])=[N:5]2
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)c(Cl)cc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 61 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 176 to obtain the titled compound (yield, 61%). 1H NMR (300 MHz, CDCl3) δ 3.31-3.30 (m, 4H), 3.75-3.76 (m, 4H), 4.15 (s, 3H), 6.80-6.82 (m, 1H), 6.90-6.91 (m, 2H), 7.18-7.23 (m, 1H), 7.32 (br s, 1H), 7.85 (s, 1H), 7.91 (s, 1H).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CN(C)CCN(C)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>C1COCC1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:29][CH:28]=1
Reactant: CCCCCCCCCC(Br)CCCCC
Reactant: COc1ccc([Mg]Br)cc1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCC(CCCCC)c1ccc(OC)cc1

Procedure:
The title compound (34.8 g) was prepared from 6-bromo-pentadecane (Example 12, 34 g), N,N,N′,N′-tetramethyletane-1,2-diamine (14.92 g), THF (35 ml) and (4-methoxyphenyl)magnesium bromide (0.5M in THF, 226.5 ml) using the procedure of Example 7.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C@H](C2C=CC=CC=2)C)[C@@H:3]1[C:15]([NH2:17])=[O:16]>CO.[Pd]>[CH3:1][C@@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:15]([NH2:17])=[O:16]
Reactant: C[C@@H]1CCN([C@@H](C)c2ccccc2)[C@@H]1C(N)=O
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CCN[C@@H]1C(N)=O
Reaction time: 46 h

Procedure:
(2S,3R)-3-Methyl-1-((S)-1-phenyl-ethyl)-pyrrolidine-2-carboxylic acid amide (Stage P.1, 1.1 g, 4.76 mmol) and Pd on charcoal 10% (0.101 g, 0.947 mmol) in MeOH (20 mL) was shaken under a H2 atm. for 46 h at rt. The RM was then filtered through a Fluoropore Membrane Filter (0.2 μm FG) and evaporated. The residue was dissolved in DCM and evaporated to dryness to give the title compound as white crystals MS: M+H=129.0. 1H-NMR (d6-DMSO, 600 MHz): 7.34 (s, br,1H), 7.10 (s, br,1H), 3.48 (d, 1H), 3.0.2-2.97 (m, 1H), 2.80-2.75 (m, 1H), 2.35-2.28 (m, 1H), 1.88-1.81 (m, 1H), 1.39-1.32 (m, 1H), 0.83 (d, 3H).
Reaction SMILES: [Cl:1][C:2]([Cl:12])([Cl:11])[CH2:3][CH:4]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5]1=O.[C:13]([OH:16])(=[O:15])C.[OH:17]O>[Fe](Cl)(Cl)Cl.O>[CH3:9][C:7]([CH3:8])([CH:4]([OH:17])[CH2:3][C:2]([Cl:1])([Cl:11])[Cl:12])[CH2:6][CH2:5][C:13]([OH:16])=[O:15]
Reactant: OO
Reactant: CC(=O)O
Reactant: CC1(C)CC(=O)C1CC(Cl)(Cl)Cl
Agent: Cl[Fe](Cl)Cl
Solvent: O
Product: CC(C)(CCC(=O)O)C(O)CC(Cl)(Cl)Cl
Temperature: 35 °C
Reaction time: 3.5 h

Procedure:
15.3 g (0.067 mol) of 2-(2',2',2'-trichloroethyl)-3,3-dimethylcyclobutanone, 75 ml of glacial acetic acid and 7.6 g of a 30% aqueous H2O2 solution are placed together and stirred at 35° C. for 3.5 hours. The mixture is then vigorously stirred up with water containing iron(III)chloride until no further peroxide is detectable. The resulting mixture is extracted with n-hexane. The extract is dried over magnesium sulphate and concentrated by evaporation. The residue (13.4 g) is distilled to yield the lactone of 3,3-dimethyl-4-hydroxy-6,6,6-trichlorohexanecarboxylic acid as a clear liquid; b.p. 108°-111° C./0.3 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:10][O:11][C:12](=[O:44])[C@H:13]([CH2:40][CH2:41][S:42][CH3:43])[NH:14][C:15](=[O:39])[C:16]1[CH:21]=[CH:20][C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:18][C:17]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[CH3:45]S(C)=O>O.C(OCC)(=O)C>[CH3:10][O:11][C:12](=[O:44])[C@H:13]([CH2:40][CH2:41][S:42][CH3:43])[NH:14][C:15](=[O:39])[C:16]1[CH:21]=[CH:20][C:19](=[CH:45][O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:18][C:17]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CS(C)=O
Reactant: Oc1cccnc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)C1=C(c2ccccc2)CC(=COc2cccnc2)C=C1

Procedure:
3-Hydroxypyridine (1.0 equivalent) is treated with sodium hydride (1.0 equivalent) in DMSO, then the resultant compound from Example 27A (1.0 equivalent) is added. When judged complete by TLC analysis, the reaction is diluted with water and ethyl acetate, the organic layer is dried and concentrated, and the crude title compound is purified by chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:5]([NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:22])=[O:6].[C:27](#[N:30])[CH:28]=[CH2:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:5]([NH:7][C:8]1([CH2:29][CH2:28][C:27]#[N:30])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:22])=[O:6]
Reactant: C=CC#N
Reactant: CCCCCN1C(=O)C(NC(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCN1C(=O)C(CCC#N)(NC(=O)c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Under argon atmosphere, a mixture of 2.70 g of 3,4-dichloro-N-(2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl)benzamide, 1.30 g of acrylonitrile, 30 ml of acetone and 1.46 g of potassium carbonate was stirred at room temperature for 1 hour. After removal of solvent, the residue was treated with water and extracted with ethyl acetate. After the ethyl acetate extract was washed and dried, the solvent was removed by evaporation. The residue was crystallized from ethyl acetate-hexane to afford 2.28 g of 3,4-dichloro-N-[3-(2-cyanoethyl)-2,3-dihydro-2-oxo-1-pentyl-1H-indol-3-yl]-benzamide as colorless crystals. Melting point: 79° to 84° C., IR (Nujol) (cm-1): 3340, 2325, 1700, 1655, 1610, MS (m/z): 445 & 443 (M+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:14]#[N:15])[C:11]([NH2:13])=[NH:12].[F:16][C:17]([F:28])([F:27])[C:18](=O)[CH2:19][C:20](=O)[C:21]([CH3:24])([CH3:23])[CH3:22].[O-]CC.[Na+]>CS(C)=O.CC(=O)OCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:11]1[N:13]=[C:20]([C:21]([CH3:22])([CH3:23])[CH3:24])[CH:19]=[C:18]([C:17]([F:16])([F:27])[F:28])[N:12]=1)[C:14]#[N:15]
Reactant: N#CC(C(=N)N)=C1Nc2ccccc2S1
Reactant: CC(C)(C)C(=O)CC(=O)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C(F)(F)F)nc(C(C#N)=C2Nc3ccccc3S2)n1
Temperature: 180 °C

Procedure:
2-[Benzothiazol-2(3H)-ylidene]-2-cyanoacetamidine (0.2 g, 0.92 mmol) was dissolved in dimethylsulfoxide (1 mL), and 1,1,1-trifluoro-5,5,-dimethyl-2,4-hexanedione (320 μL, 1.84 mmol) and sodium ethoxide (0.6 mL of 21 wt % solution in ethanol, 1.84 mmol) were added. The solution was heated to 180° C. under microwave irradiation for 20 min, dissolved in EA, and washed with 1N hydrochloric acid and then water. Removal of the solvent gave 2-[benzothiazol-2(3H)-ylidene]-2-[4-tert-butyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile as a beige solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.O.[C:14]([OH:18])(=O)[CH:15]=O.O.[NH2:20][NH2:21]>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3[C:7](=[CH:15][C:14](=[O:18])[NH:20][N:21]=3)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: NN
Reactant: O=CC(=O)O
Solvent: O
Product: O=c1cc2c(n[nH]1)-c1ccc(O)cc1CC2

Procedure:
In a manner similar to that given in Preparation 3, 6-hydroxy-1-tetralone was treated with glyoxylic acid monohydrate and hydrazine hydrate to give 5,6-dihydro-8-hydroxybenzo[h]cinnolin-3[2H]-one (m.p. 300°, from dimethylformamide/ethanol); ν(Nujol mull) 3400-2000, 1652, 1594, and 1582cm-1 ; δ(DMSO-d6) 2.77 (4H,s,5,6-H2), 6.65 (2H,m, 4,7-H), 6.74 (1H,m,9-H), 7.73 (1H,d,10-H), 9.93 (1H,d(br),OH), 12.7 (1H,d(br)NH).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[C:31]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:30])[CH:6]=1)[CH2:25][C:26]([F:29])([F:27])[F:28])(=[O:33])[CH3:32]
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1
Reactant: CC(=O)Cl
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(CC(F)(F)F)C(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 6 and Step 7, using the following starting materials: {6-methoxy-2′-[(2,2,2-trifluoro-ethylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C1(C)C=CC(S([CH2:24][N+:25]#[C-])(=O)=O)=CC=1.O.[Cl-].[Na+]>COCCOC.C(O)C>[C:24]([CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)#[N:25]
Reactant: Nc1ccc(C2CCC(=O)CC2)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: N#CC1CCC(c2ccc(N)cc2)CC1
Yield: 54.9 %

Procedure:
392 mg (3.5 mmol) of potassium t-butylate were added portionwise at -10° to a suspension of 278 mg (1.5 mmol) of 4-(4-oxo-cyclohexyl)-aniline and 370 mg (1.9 mmol) of toluene-4-sulfonylmethylisocyanide in 5 ml of 1,2-dimethoxyethane and 0.15 ml of ethanol. After stirring at -5° for 1 hour and at room temperature for a further 70 hours 25 ml of water and 10 ml of saturated sodium chloride solution were added and the mixture was extracted three times with 40 ml of dichloromethane each time. The organic phase was dried with sodium sulfate and concentrated. Chormatography over silica gel with ethyl acetate/hexane 1:2 gave 165 mg (56%) of 4-(4-cyano-cyclohexyl)-aniline with m.p. 132°-140°.
Reaction SMILES: [CH3:1]C(O)(C#CC1C=CC=C(Br)C=1)C.CC(O)(C)C#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#CC(O)(C)C)[CH:19]=1>>[C:18]1([CH3:17])[CH:19]=[C:20]([CH3:24])[CH:21]=[C:22]([CH3:1])[CH:23]=1
Reactant: CC(C)(O)C#Cc1cccc(Br)c1
Reactant: CC(C)(O)C#Cc1cccc(C#CC(C)(C)O)c1
Product: Cc1cc(C)cc(C)c1

Procedure:
Referring to Table 1 above, the Conversion ("Conv.") was a weight percent conversion and was calculated by: ##EQU1## Selectivity ("Selec.") in Table 1 means, as appropriate: ##EQU2## The Yield means, as appropriate, the yield of 2-methyl-4-(3-bromophenyl)-3-butyn-2-ol: ##STR15## or 1,3-di(3-methyl-3-hydroxy-1-butynyl)benzene: ##STR16## and was calculated as the product of Conversion times Selectivity. Selectivities and yields were calculated only on isolated crude products by gas chromatography with an appropriate internal standard (mesitylene).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][N:20]2[CH:24]=[CH:23][N:22]=[C:21]2[CH3:25])[N:16]=[N:17][CH:18]=1>>[ClH:12].[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[C:15]([CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[C:21]3[CH3:25])[N:16]=[N:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccc(F)c(F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=287.2 (M+H+), was prepared from 3,4-difluorobenzeneboronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[C:28]3[C:23](=[CH:24][C:25]([O:29]C)=[CH:26][CH:27]=3)[CH2:22][CH2:21][N:20]2[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[CH:15][CH:14]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[F:35][C:32]([F:33])([F:34])[C:31]([N:20]1[CH2:21][CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[CH:19]1[C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1)=[O:36]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OCc2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(N1CCc2cc(O)ccc2C1c1ccc(O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 9.9 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (6.0 ml, 6.0 mmol) was added slowly to a solution of 1-[1-(4-benzyloxyphenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoroethanone (1.054 g, 2.4 mmol) in anhydrous CH2Cl2 (100 ml) at 0° C. under N2. The reaction mixture was warmed to rt and stirred at rt for 17 hr. MeOH (50 ml) was slowly added with stirring and the resulting solution was concentrated in vacuo to a red oil. This was dissolved in MeOH (20 ml) and 1M HCl (20 ml), and the resulting solution was stirred at rt for 4 hr, then neutralized with saturated NaHCO3 solution (60 ml). The resulting suspension was concentrated in vacuo and the remaining material was extracted with EtOAc (4×30 ml). The combined extracts were dried over MgSO4 and evaporated in vacuo to give 0.775 g of crude brown solid. Purification by flash chromatography, eluting with hexane:EtOAc (1:1) gave 0.080 g (10% yield) of white solid.