Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:10]=[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[N:21]=2)=[N:13][C:14]=1Br.[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)#[CH:31].O>CN(C=O)C.CC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:9]1[N:10]=[C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[N:21]=2)=[N:13][C:14]=1[C:31]#[C:30][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C#Cc1ccccc1
Reactant: Cn1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(-c2nc(C#Cc3ccccc3)c(N)nc2-c2ccccc2)ccc1=O
Reaction time: 2 h

Procedure:
In the presence of copper(I) iodide (4.3 mg) and dichlorobis(triphenylphosphine)palladium(II) (15.7 mg), triethylamine (0.0685 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-methyl-3(2H)-pyridazinone (150 mg) and ethynylbenzene (0.0054 ml) in DMF (1.5 ml) at 75-80° C. The mixture was stirred at the same temperature for 2 hours. To the reaction mixture, water was added to give a solid. The solid was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give a solid. The solid was suspended in acetone to give 6-[5-amino-3-phenyl-6-(phenylethynyl)-2-pyrazinyl]-2-methyl-3(2H)-pyridazinone (96 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[C@@H:22]12[O:29][C@@H:26]([CH2:27][CH2:28]1)[CH2:25][NH:24][CH2:23]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:24]3[CH2:23][C@@H:22]4[O:29][C@@H:26]([CH2:27][CH2:28]4)[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1C[C@H]2CNC[C@@H]1O2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1C[C@H]2CC[C@@H](C1)O2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (54745-74-3) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=380.5 [MH+].
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: C1CCNCC1
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCCCC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 20.4 mg (0.24 mmol) piperidine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 33 mg (53.3%) product as an orange powder. MS (ESI) m/z 516.25 (M+1).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](O)=[O:6].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([NH2:46])[CH:44]=2)[N:39]([CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[N:38]=1>CN(C=O)C>[NH:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:28]=[C:29]1[C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([NH:46][C:5]([CH:3]3[CH2:4][C:2]3([F:8])[F:1])=[O:6])[CH:44]=2)[N:39]([CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][O:48]2)[N:38]=1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: O=C(O)C1CC1(F)F
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
2,2-Difluorocyclopropanecarboxylic acid (8 mg, 0.065 mmol), HOBt (12 mg, 0.089 mmol), EDC (17 mg, 0.089 mmol) and sodium bicarbonate (56 mg, 0.059 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.059 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound as a solid in a 50% yield. 1H NMR (400 MHz, CD3OD): δ 8.51 (s, 1H), 7.77 (m, 1H), 7.67 (m, 3H), 7.27 (m, 2H), 5.86 (d, 1H, J=7.6 Hz), 4.00 (m, 1H), 3.81 (m, 1H), 2.74-2.61 (m, 2H), 2.13 (m, 3H), 1.84 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[ClH:27].[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[CH:14][CH:15]=2)=[O:28])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2CCNC2)cc1)c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 166.2 %

Procedure:
To a stirred solution of (RS)-3-[4-(4-chloro-benzoylamino)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (2.36 g) in THF (30 ml) was added dropwise a solution of hydrogen chloride in dioxane (22 ml, 4 M solution) and the mixture was heated at 60° C. overnight. The mixture was then cooled to 0° C. and the ensuing crystals were collected by filtration, washing with diethyl ether, and then dried in vacuo at 60° C. to afford (RS)-4-chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide hydrochloride (1.65 g, 83%) as a white crystalline solid. MS (ISP): 303.2 ([{37Cl}M+H]+), 301.3 ([{35Cl}M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9][C:10](OCC)=[O:11])=[C:6]([Cl:15])[N:5]=[C:4](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:15][C:6]1[C:7]([CH2:8][CH2:9][CH2:10][OH:11])=[C:2]([Cl:1])[N:3]=[C:4](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]=1
Reactant: CCOC(=O)CCc1c(Cl)nc(/C=C/c2ccccc2)nc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1c(Cl)nc(/C=C/c2ccccc2)nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To Ethyl 3-{4,6-dichloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanoate (0.35 g, 1.04 mmol) in THF (10 mL) at −78° C. was added a 1N solution of lithium aluminium hydride in THF (2.0 mL, 2.0 mmol). The reaction was allowed to stir under nitrogen for 1 h and allowed to warm to 0° C. After 2 h at 0° C. the reaction was quenched by addition of 5 mL of methanol and 2 mL of water. The reaction was concentrated under vacuum and the residue was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc (3×), dried over Na2SO4, filtered and concentrated under vacuum to give the product as a yellow solid (275 mg, 86%) to be used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[N:6][C:5]=1Cl.[C:13]([Cu])#[N:14]>CN1C(=O)CCC1.O.Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[N:6][C:5]=1[C:13]#[N:14]
Reactant: COC(=O)c1c(C)ccnc1Cl
Reactant: N#C[Cu]
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1c(C)ccnc1C#N
Temperature: 180 °C
Reaction time: 16 h

Procedure:
A suspension of 2-chloro-4-methyl-nicotinic acid methyl ester (2.64 g, 14.3 mmol) and CuCN (6.4 g, 71 mmol) in NMP (5.3 mL) was heated to 180° C. for 30 min. The reaction mixture was then cooled to room temperature and diluted with water (80 mL). After vigorous stirring for 16 h, the suspension was centrifuged and the precipitate suspended in a solution of FeCl3.6H2O (5.8 g, 21 mmol) in aqueous HCl (4 M, 80 mL). After vigorous stirring for 1 h, the suspension was extracted with DCM (3×70 mL). The organic layer was dried over Na2SO4/Na2CO3, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with EA/DCM 1:10) to give the title compound. MS (m/z): 177.0 [M+H+].
Reaction SMILES: [Cl-:1].[Mn+2:2].[Cl-:3].[CH2:4]([CH:22]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][NH:23]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO>[Cl:1][C:22]1([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:36][NH:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][N:23]1[Cl:3].[Mn+2:2]
Reactant: [Cl-]
Reactant: CCCCCCCCCCCCCCCCCCC1CNCCNCCNCCNCCN1
Agent: [Mn+2]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCC1(Cl)CNCCNCCNCCNCCN1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a refluxing solution of anhydrous manganese(II) chloride (0.18 g, 1.4 mmol) in anhydrous methanol (50 ml) was added 2-octadecyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in example 28I (0.65 g, 1.4 mmol). The resulting solution was refluxed under a dry nitrogen atmosphere for 2 h and then stirred at room temperature overnight. The solvent was removed in vacuo, the oily residue redissolved in hot THF (20 ml) and filtered. The solution was concentrated and hot. ethyl ether was added with stirring to give 0.62 g (75% yield) of the product as a white solid: FAB mass spectrum (NBA) m/z (relative intensity) 556/558 [(M-Cl)+, 100/34]; Exact mass (M-Cl)+ : calcd., 557.3996; found, 557.4058 (C26H61N5MnCl).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=[O:14])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[C-]#N.[Na+].C#N.Cl>CS(C)=O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=[O:14])[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15]
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Agent: C#N
Agent: Cl
Agent: [C-]#N
Solvent: CS(C)=O
Product: Cc1cc2c(cc1O)C(C)(C)CCC2=O
Temperature: 25 °C

Procedure:
A solution of 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (described in U.S. 2003/0166932, published Sep. 4, 2003, incorporated herein by reference; 5.5 g, 25.6 mmol) and sodium cyanide (6.25 g, 127 mmol) in anhydrous dimethylsulfoxide (100 mL) was heated at 230° C. for 48 h under argon. The reaction mixture was then cooled to ambient temperature, poured into ice and acidified (Caution! Hydrogen cyanide evolution!) with dilute hydrochloric acid and extracted with ethyl acetate (×2). The combined organic extract was washed with brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound, which was used as such for the next step (5.2 g, ˜100%).
Reaction SMILES: Cl.Cl[CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH3:4].C(#N)C.CS(C)=O.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>O>[N:23]1([CH:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[CH3:4])[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: c1c[nH]cn1
Reactant: CC(Cl)c1ccc2c(c1)CCC(=O)N2
Agent: Cl
Solvent: CC#N
Solvent: CS(C)=O
Solvent: O
Product: CC(c1ccc2c(c1)CCC(=O)N2)n1ccnc1
Reaction time: 8 h
Yield: 53.5 %

Procedure:
A mixture of 2.3 parts of 6-(1-chloroethyl)-3,4-dihydro-2 (1H)-quinolinone hydrochloride, 24 parts of acetonitrile, 7.7 parts of dimethyl sulfoxide and 3.8 parts of 1H-imidazole was stirred overnight at 60°-70° C. The reaction mixture was poured into water, extracted and further purified according similar procedures as described in example 12, yielding 1.2 parts (53.5%) of 3,4-dihydro-6-[1-(1H-imidazol-1-yl)ethyl]-2(1H)-quinolinone; mp. 184.8° C. (compound 21).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][C:22]([O:26]C)=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH2:11][CH:12]=1.Cl.N1C=CC=CC=1>>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[CH2:11][CH:12]=1
Reactant: COc1ccc2c(CCCCN3CC=C(c4cccs4)CC3)c[nH]c2c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(CCCCN3CC=C(c4cccs4)CC3)c[nH]c2c1
Reaction time: 3 h

Procedure:
A mixture of 4.03 g of 3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-methoxyindole hydrochloride and 3.5 g of pyridine hydrochloride is stirred at 160° for 3 hours. After the usual work-up, 3-[4-(4-(2-thienyl)-1,2,3,6-tetrahydropyridyl)butyl]-6-hydroxyindole of m.p. 181° is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]#[N:16])=[C:10]([O:17][CH3:18])[C:9]=2[F:19])[N:5]=[C:4]([C:20]([OH:22])=[O:21])[C:3]=1[Cl:23].[CH3:24][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]#[N:16])=[C:10]([O:17][CH3:18])[C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:24])=[O:21])[C:3]=1[Cl:23]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1c(C#N)cc(F)c(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2c(F)cc(C#N)c(OC)c2F)cc(N)c1Cl

Procedure:
A slurry of 4-amino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxlic acid in tetrahydrofuran (10 mL) and methanol (3 mL) was treated with trimethylsilyldiazomethane (0.64 g, 0.28 mL of a 2M solution in hexanes) at ambient temperature. After 1 hour the reaction mixture was quenched with acetic acid (2 mL) and water (10 mL). The mixture was extracted with ethyl acetate (2×20 mL) and the combined extracts dried (Na2SO4), and concentrated. The residue was purified by chromatography (30-100% ethyl acetate in hexanes) to give 4-amino-3-chloro-6-(4-cyano-2,6-difluoro-3-methoxyphenyl)pyridine-2-carboxylic acid, methyl ester (0.083 g, 0.24 mmol): 1H NMR (CDCl3) δ 7.15 (dd, 1H), 6.85 (s, 1H), 4.98 (bs, 2H), 4.08 (d, 3h), 3.98 (s, 3H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([S:23]([N:26]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=3[O:42][CH3:43])[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[C:18]([F:44])[CH:17]=2)[C@@H:11]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:22][C:21]1[C:16]([O:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([OH:8])[CH2:10][C@@H:11]2[C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)=[CH:17][C:18]([F:44])=[C:19]([S:23]([N:26]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:20]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC[C@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 96.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 120c by using the 4-{[(1S*,2R*,4S*)-4-{[tert-butyl(dimethyl) silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (81.5 mg, 0.109 mmol) prepared in Example 162g, tetrabutyl ammonium fluoride (1.0 M solution in THF; 0.218 mL, 0.218 mmol) and THF (5.0 mL), to yield the title compound (66.5 mg, 89%) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[I:10].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O>[N:11]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[I:10])=[N+:12]=[N-:13]
Reactant: Fc1ccc(CBr)c(I)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(F)cc1I
Temperature: 50 °C
Yield: 99.8 %

Procedure:
A solution of 1-(bromomethyl)-4-fluoro-2-iodobenzene (M. Protiva et al., Collect. Czech. Chem. Comm., 44, 1979, 2108–2123) (17.9 g, 56.8 mmol) in N,N-dimethylformamide (35 ml) was treated with sodium azide (5.0 g, 76.7 mmol) and the resulting mixture was heated to 50° C. for 4 h. The cooled mixture was filtered, the filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (elution hexane) to give 15.7 g (97% yield) of the title azide as a clear oil. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 4.53 (2H, s, CH2), 7.32 (1H, m, aromatic), 7.54 (1H, dd, J=6 Hz and J=8.6 Hz, aromatic), 7.83 (1H, dd, J=3 Hz and J=8 Hz, aromatic).
Reaction SMILES: [BH4-].[Na+].[C:3]([Si:7]([CH3:38])([CH3:37])[O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[N:31][C:30]=23)=[O:25])[CH2:11][CH2:10]1)([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O>[C:3]([Si:7]([CH3:38])([CH3:37])[O:8][CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:27]=[N:28][N:29]3[CH:34]=[C:33]([CH2:35][OH:36])[CH:32]=[N:31][C:30]=23)=[O:25])[CH2:11][CH2:10]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(Oc2ccc(Cl)cc2NC(=O)c2cnn3cc(C=O)cnc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCC(Oc2ccc(Cl)cc2NC(=O)c2cnn3cc(CO)cnc23)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium borohydride (30 mg, 0.079 mmol) was added to a solution of 6-formyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-amide (20 mg, 0.038 mmol) in a mixture of tetrahydrofuran (1.5 mL) and water (0.1 mL) and the resulting mixture was stirred at room temperature for 2.5 hours. The solvent was evaporated under reduced pressure to give 6-hydroxymethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-amide as an oily residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:22]1([CH:28]([N:35]=[C:36]=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[CH:28]([NH:35][C:36]([N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1)=[O:37])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=NC(c1ccccc1)c1ccccc1
Reactant: CN1CCC(C(c2ccc(F)cc2)N2CCNCC2)CC1
Solvent: ClCCl
Product: CN1CCC(C(c2ccc(F)cc2)N2CCN(C(=O)NC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 1-((4-fluorophenyl)(1-methylpiperidin-4-yl)methyl)piperazine 0.1 g (0.343 mmol) dissolved in methylene chloride (20 ml) was added diphenylmethyl isocyanate 0.073 g (0.343 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated. The residue was applied to flash column chromatography using methylene chloride and methanol (100:10) as eluents to give 0.13 g of desired product.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:22]([Cl:23])=[C:21]([Cl:24])[C:20]([Cl:25])=[C:19]([Cl:26])[C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:27])[CH3:2].[CH2:28]([N:30]([CH2:42][CH3:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:32]=1)[CH3:29]>C(OC(=O)C)(=O)C>[CH2:38]([N:37]([CH2:40][CH3:41])[C:33]1[CH:32]=[C:31]([N:30]([CH2:28][CH3:29])[CH2:42][CH3:43])[CH:36]=[CH:35][C:34]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:27])[C:14]2[C:15](=[C:19]([Cl:26])[C:20]([Cl:25])=[C:21]([Cl:24])[C:22]=2[Cl:23])[C:16](=[O:18])[O:17]1)[CH3:39]
Reactant: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(CC)CC)c1

Procedure:
Following a procedure similar to that described in part B of Example 2 above, 4.45 g (0.01 mole) of 2-(1-ethyl-2-methyl-3-indolyl)carbonyl-3,4,5,6-tetrachlorobenzoic acid and 2.20 g (0.01 mole) of N,N,N',N'-tetraethyl-m-phenylenediamine were interacted in the presence of ten ml of acetic anhydride to obtain 3-[2,4-bis(diethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-4,5,6,7-tetrachlorophthalide (Formula III: R0 =R1 =R2 =R3 =Cl; R=R6 =CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3 ; Y1 =H) melting at 100°-103° C. and showing a significant infrared absorption maxima at 1770 cm-1 (C=O; s). A toluene solution of this compound developed an intense blue color when spotted on silica gel.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.[CH:22]1([CH:25]=[O:26])[CH2:24][CH2:23]1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH:22]1([CH:25]([C:15]2[C:14]([F:13])=[CH:19][N:18]=[C:17]([O:20][CH3:21])[CH:16]=2)[OH:26])[CH2:24][CH2:23]1
Reactant: COc1ccc(F)cn1
Reactant: O=CC1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COc1cc(C(O)C2CC2)c(F)cn1
Temperature: -15 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, a hexane solution (1.6 M, 29.5 mL) of n-butyllithium was added to a solution of diisopropylamine (6.60 mL) in THF (80 mL) at −15° C., and the mixture was stirred at −15° C. for 5 min. A solution of 5-fluoro-2-methoxypyridine (5.00 g) in THF (30 mL) was added dropwise to the reaction mixture at −78° C. over 15 min, and the mixture was stirred at −78° C. for 1.5 hr. A solution of cyclopropanecarbaldehyde (3.53 mL) in THF (15 mL) was added dropwise to the reaction mixture at −78° C. over 20 min, and the mixture was stirred at −78° C. for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product (8.87 g) of the title compound as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=O)C>Cl>[NH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Agent: Cl
Product: Nc1ccc2c(c1)CCCC2=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Concentrated hydrochloric acid (250 ml) was added to 6-acetamido-1-tetralone (20.0 g, 98.4 mmol), which was stirred at 100° C. for 1 hour. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The residue was powdered with ethyl acetate and isopropyl ether, to give the titled compound (14.5 g).