Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.CN.C(Cl)CCl.C1C=CC2N(O)N=[N:27][C:25]=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:27][CH3:25])=[O:8]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To the mixture of 5-fluoro-2-nitrobenzoic acid (371 mg, 2.0 mmol), methylamine hydrogen chloride (162 mg, 1.2 eq), EDC (575 mg, 1.5 eq), HOBt (324 mg, 1.2 eq) in DMF (10 mL) was added DIEA (1.8 mL, 5.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3 solution. The solvent was removed and the crude was purified by silica gel chromatography (0%˜20% MeOH/DCM) to obtain the desired product 5-fluoro-N-methyl-2-nitrobenzamide (356 mg, isolated yield 90%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:64]=[CH:63][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:57]=[CH:58][C:59]([CH3:62])=[CH:60][CH:61]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1ccc(CCNCc2ccc(C(C)(C)C)cc2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 89 mg (0.3 mmol) (4-tert-butyl-benzyl)-(2-p-tolyl-ethyl)-amine in 1 ml DMF was added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The yellow residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 111 mg (86%) of a white solid. MS (ISP) 425.3 (M+H)+.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[CH:29]1[C:38]2[C:33](=[C:34]([NH:39][NH2:40])[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1>>[CH:29]1[C:38]2[C:33](=[C:34]([N:39]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]6[CH2:27][CH2:26][CH2:25][CH2:24]6)(=[O:21])=[O:22])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:40]3)[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Reactant: NNc1cccc2cnccc12
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1cccc2cnccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and isoquinolin-5-yl-hydrazine according to the method described for example 91. MS: M=499.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([Cl:17])=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:23].N1C=CC=CC=1.[CH3:30][C:31]1[S:32][CH:33]=[C:34]([C:36](Cl)=[O:37])[N:35]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:17][C:14]1[N:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]3[C:3]([CH:4]=[N:5][N:6]3[CH3:23])=[C:2]([NH:1][C:36]([C:34]3[N:35]=[C:31]([CH3:30])[S:32][CH:33]=3)=[O:37])[CH:10]=2)=[CH:12][C:13]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: Cn1ncc2c(N)cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc21
Reactant: Cc1nc(C(=O)Cl)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)cc3c2cnn3C)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.5 %

Procedure:
N-[5-(4-Amino-1-methyl-1H-indazol-6-yl)-2-chloro-3-pyridinyl]methanesulfonamide (75 mg) was dissolved in DCM (2 ml) and pyridine (0.052 ml) was added followed by 2-methyl-1,3-thiazole-4-carbonyl chloride (52 mg) in DCM (1 ml) as a suspension. The reaction was stirred at RT for 1 h. Saturated sodium bicarbonate solution was added followed by DCM (3 ml) and the reaction was stirred vigorously. The reaction was passed through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DMSO:MeOH (1:1, v/v, 1 ml) and purified by MDAP (method E) to give the title compound (1.5 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(OC)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:14]1C=C(Cl)C=C(Cl)[C:15]=1O.C([Zn]CC)C.C(I)I.BrC1C=CC(C(=C)CC)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC1(c2ccc(Br)cc2)CC1
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Agent: C=C(CC)c1ccc(Br)cc1
Agent: CC[Zn]CC
Solvent: ICI
Product: CCC1(c2ccc(Br)cc2)CC1
Yield: 85 %

Procedure:
The title compound was synthesized in analogy to 1-bromo-4-(1-methoxycyclopropyl)-benzene (described in example S89) using 2,4,6-trichlorophenol (580 mg, 2.94 mmol), diethyl zinc (2.94 ml, 1M solution in hexane, 2.94 mmol), CH2I2 (237 μl, 2.94 mmol) and 1-bromo-4-(1-methylenepropyl)-benzene (310 mg, 1.47 mmol). The isolated residue was purified by flash column chromatography (100% pentane) to give 1-bromo-4-(1-ethylcyclopropyl)-benzene (280 mg, 85%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.39 (d, J=8.5 Hz, 2H), 7.16 (d, J=8.5 Hz, 2H), 1.55 (q, J=7.5 Hz, 2H), 0.82 (t, J=7.5 Hz, 3H), 0.75-0.71(m, 2H), 0.68-0.64 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1(O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.Cl>>[ClH:1].[CH:30]1([O:24][C:23]([C:18]2([C:20]([O:22][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: OC1CCCCC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OC1CCCCC1)(C(=O)OC1CCCCC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclohexanol according to the procedure of Example 1 as a yellow gum: 1H NMR (300 MHz, CDCl3): δ 1.10-1.40 (complex m, 7H), 1.45-1.60 (brm, 4H), 1.63-1.81 (brm, 8H), 1.82-1.95 (brm, 4H), 2.72-2.90 (brm, 1H), 3.10-3.30 (brm, 2H), 3.37-3.55 (m, 2H), 4.90-5.03 (m, 2H), 5.37-5.52 (brs, 1H), 6.71-6.90 (complex m, 4H), 7.20-7.32 (m, 2H), 7.44 (s, 1H), 8.55-8.80 (brs, 1H), 9.90-10.20 (brs, 1H); MS (ES) m/z (relative intensity): 585 (M+ -HCl), 532 (10).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=3[CH:25]=2)=[CH:5][CH:4]=1)[CH3:2].Cl>COCCOC>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=3[CH:25]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Solvent: COCCOC
Product: CCc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of methyl 7-(4-ethylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (600 mg) in 1,2-dimethoxyethane (20 ml) was added 6N hydrochloric acid (10 ml), and the mixture was refluxed for 24 hours, cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration. The crystals were washed with hexane to give pale yellow crystals of 7-(4-ethylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (501.2 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[BH3-]C#[N:15].[Na+]>C(O)(C)C>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:15])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: Cc1c(Cl)ccc2c1C(=O)CC2
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(Cl)ccc2c1C(N)CC2

Procedure:
6-Chloro-7-methyl-1-indanone (2.50 g, 14.00 mmol), NaBH3CN (6.00 g, 95.48 mmol) and NH4OAc (32.04 g, 0.42 mol) in isopropanol were reacted according to the protocols as outlined in general procedure C to give the title indanamine. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 1.5 (br s, 2H), 1.84-1.93 (m, 1H), 2.30-2.45 (m, 4H), 2.72-2.88 (m, 1H), 3.02-3.16 (m, 1H), 4.40-4.50 (m, 1H), 7.0 (d, 1H, J=7.9 Hz), 7.2 (d, 1H, J=8.2 Hz).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].O=[C:27]1[CH:31]=[N:30][S:29][NH:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:25][C:27]1[CH:31]=[N:30][S:29][N:28]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=c1cns[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cnsn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
Diisopropyl azodicarboxylate (1.1 ml, 5.5 mmol) was added dropwise to a solution of 2-(t-butoxycarbonylamino)ethanol (850 μl, 5.5 mmol), 3-oxo-2,3-dihydro-1,2,5-thiadiazole (Method 75; 510 mg, 5 mmol) and triphenylphosphine (1.44 g, 5.5 mmol) in THF (20 ml) and the mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel eluting with iso-hexane: EtOAc (100:0 increasing in polarity to 4:1) to give the title compound (1.17 g, 95%) as a white solid. NMR 1.38 (s, 9H), 3.31 (m, 2H), 4.16 (t, 2H), 6.96 (m, 1H), 8.35 (s, 1H); m/z 246.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:18]1C=CC=C[CH:19]=1>>[CH:5]1[C:6]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:2]([C:19]#[N:18])=[CH:3][CH:4]=1
Reactant: c1ccncc1
Reactant: Clc1cccc2c1CCCCc1ccccc1-2
Product: N#Cc1cccc2c1CCCCc1ccccc1-2

Procedure:
The reaction of 4-chloro-5,6,7,8-tetrahydrodibenzo[a,c]cyclooctene (3.3 g, 0.014 mole), cuprous cyanide (2.44 g, 0.027 mole) and pyridine (2.5 g, 0.027 mole) produced 5,6,7,8-tetrahydrodibenzo[a,c]cycloocten-4-carbonitrile as an oil (60% product, 40% starting material by gas chromatography). The IR spectrum possessed an adsorption at 4.45μ indicating a CN group.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[NH:26][C:25]2([CH3:33])[CH3:32].[C@H]1(N)CCCC[C@@H]1N.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([N:26]3[C:27](=[O:31])[C:28]4[C:24](=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=4)[C:25]3([CH3:33])[CH3:32])[N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cncc(Cl)n2)C1
Reactant: CC1(C)NC(=O)c2ccc(Cl)cc21
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC(c2cncc(N3C(=O)c4ccc(Cl)cc4C3(C)C)n2)C1
Yield: 32.8 %

Procedure:
A mixture of 3-(6-chloro-pyrazin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (892.5 mg, 3.0 mmol), 5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediate A-12, 586.5 mg, 3.0 mmol), CuI (171.4 mg, 0.9 mmol), (1S,2S) -cyclohexane-1,2-diamine (205.2 mg, 1.8 mmol) and Cs2CO3 (1.956 g, 6.0 mmol) were dissolved in dioxane (15 mL). The reaction mixture was subjected to microwave reaction at 150° C. for 2.5 hours before it was poured into H2O (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by flash chromatography to afford the title compound (450 mg, 33%) as a white solid. MS: 457.2 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(Cl)(Cl)Cl>[Cl:11][C:12]1[N:13]=[N:14][C:15]([C:7]([C:8]#[N:9])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:10])=[CH:16][CH:17]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C#N)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C#N)(c1ccccc1)c1ccc(Cl)nn1
Yield: 42.7 %

Procedure:
Triethyl benzyl ammonium chloride (0.25 g.) was added to a well stirred mixture of 2-phenyl propionitrile (7.2 g.) [prepared as described by a Hauser & Brasen, J.A.C.S. 78, 494 (1956], 3,6-dichloropyridazine (7.45 g.) [prepared as described by Jackiewiez et al, Acta. Polon. Pharm. 17, 355 (1960)] and 50% aqueous sodium hydroxide solution (7.5 ml.). After stirring for 30 minutes, a further quantity of triethyl benzyl ammonium chloride (0.2 g.) was added and the temperature of the mixture rose to 77° C. The viscous mixture was stirred for 4 hours until ambient temperature had been regained, when it was diluted with chloroform (150 ml.). The solution thus obtained was washed with water (4 × 50 ml.), dried over magnesium sulphate, filtered and evaporated to give a brown gum. Repeated crystallisation of the gum from cyclohexane gave 3-chloro-6-(1-cyano-1-phenylethyl)pyridazine (5.2 g.), m.p. 116.5°-117.5° C., as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10]CC)=[O:9].[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1cnn(C)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1ncc(C(=O)O)c1Cl

Procedure:
5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid, ethyl ester (13 grams, 0.07 mole) and potassium hydroxide (7.8 grams, 0.14 mole) were combined in 75 ml. of ethanol and refluxed for six hours. The solution was cooled, poured over water, acidified with concentrated hydrochloric acid, and the precipitated solid collected, dried, and recrystallized from water. The resulting 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid was obtained in the amount of 5.4 grams and melted at 195°-197° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.O>CS(C)=O>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:6]#[N:7]
Reactant: Cc1cc(C#N)ccc1F
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)ccc1N1CCNCC1
Temperature: 140 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
To a solution of 4-fluoro-3-methylbenzonitrile (2.5 g, 18.50 mmol) in DMSO (Volume: 10.0 mL) was added piperazine (7.97 g, 92 mmol) at 23° C. The reaction was stirred at 140° C. for 16 hr. The reaction mixture was poured into H2O (100 mL) and the reaction vessel was rinsed with H2O (50 mL). The resulting suspension was filtered, rinsed with H2O (3×10 mL) and the resulting solid was dried in vacuo to provide 3-methyl-4-(piperazin-1-yl)benzonitrile (2.593 g, 12.88 mmol, 69.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.21-2.30 (m, 3 H) 2.57-2.70 (m, 1 H) 2.83 (s, 8 H) 7.03-7.09 (m, 1 H) 7.55-7.62 (m, 2 H). ESI-MS: m/z 202.1 (M+H)+. mp=214.1-231.2° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=O)([O-:3])=[O:2].B>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)([O-:3])=[O:2]
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])N1CCOCC1
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1CCN1CCOCC1
Reaction time: 1 h
Yield: 120.8 %

Procedure:
To a solution of 4-[(2-nitrophenyl)acetyl]morpholine (10 g, 40 mmol) in THF (250 ml) was added borane. THF (1.0M, 60 ml, 60 mmol) and the mixture heated at reflux for 1 h. A further portion of borane. THF (1.0M, 80 ml, 80 mmol) was added and reflux continued for 1 h. The cooled reaction was quenched by addition of hydrochloric acid (concentrated, 8 ml) and left at room temperature for 18 h. The mixture was concentrated under vacuum, basified with aqueous sodium hydroxide (2N) and extracted with ether (3×100 ml). The combined extracts were dried (magnesium sulphate) and the solvent evaporated under vacuum to give a crude sample of 4-[(2-nitrophenyl)ethyl]morpholine (11.42 g), which was used without further purification. Microanalysis: calculated C 61.007, H 6.83, N 11.86; found C 62.38; H, 8.02; N, 9.54.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].[N:18]1([CH2:23][CH2:24][CH:25](O)[CH3:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:25]([CH3:26])[CH2:24][CH2:23][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC(O)CCN1CCCC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CCN1CCCC1)Oc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 9.9 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1.03 g, 4.40 mmol), 4-pyrrolidin-1-yl-butan-2-ol (0.5 g, 3.50 mmol), PPh3 (1.15 g, 4.40 mmol), THF (10 ml) and DIAD (0.86 ml, 4.40 mmol) were reacted together according to general procedure C. The crude product was purified by preparative HPLC, eluting with acetonitrile/water/0.1% TFA as a gradient, to give the title compound as a yellow oil (125 mg, 10%). 1H NMR (400 MHz, CDCl3) δ7.19 (d, 2H), 6.86 (d, 2H), 4.43 (m, 1H), 3.75 (dt, 2H), 3.60-3.51 (m, 2H), 2.67-2.46 (m, 6H), 2.40 (s, 2H), 2.14-2.04 (m, 2H), 1.97 (s, 6H), 1.93-1.73 (m, 8H), 1.31 (d, 3H).
Reaction SMILES: Cl.[CH2:2]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=N)=[CH:13][CH:12]=1)CCCCCCC.[CH2:20]([O:28][C:29]1[CH:34]=CC(C#N)=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C1(C)C=CC=CC=1>[CH3:2][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]2[CH:31]=[CH:30][C:29]([O:28][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:34][N:17]=2)=[CH:18][CH:19]=1
Reactant: CCCCCCCCOc1ccc(C#N)cc1
Reactant: CCCCCCCCOc1ccc(C(=N)N)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(OC)cc2)nc1

Procedure:
To a flask outfitted with a reflux condenser was added 6B (300 mg), 6A (600 mg), and palladium tetrakis(triphenylphosphine) (62 mg). To this mixture was added toluene (4 ml) and a sodium carbonate solution (2M, 4.5 ml). This solution was refluxed for 16 hrs, at which time it was acidified with hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate and potassium carbonate. The solvent was removed in vacuo. The product purified by flash chromatography using 20% ethyl acetate in hexanes as the eluent to give a yellow liquid.
Reaction SMILES: [N+](=[CH2:3])=[N-].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:17][CH:16]3[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]3)[CH:12]2[CH:20]=[N:21][OH:22])=[CH:7][CH:6]=1.C(OCC)(=O)C>CO.C(O)C>[CH3:3][O:22][N:21]=[CH:20][CH:12]1[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=2)[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]1[CH2:14][CH2:15]2
Reactant: C=[N+]=[N-]
Reactant: CN1C2CCC1C(C=NO)C(c1ccc(F)cc1)C2
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: CON=CC1C(c2ccc(F)cc2)CC2CCC1N2C

Procedure:
The carbaldehyde-oxime obtained above is converted to an alkyl oxime by treatment with a diazoalkane such as diazomethane. Thus 3-(4-fluoro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]octane-2-carbaldehyde oxime is dissolved in an appropriate alcohol such as methanol or ethanol or an organic solvent such as ethyl acetate and then this solution is cooled in an ice/water bath and then a solution of diazomethane. (excess 1.1-20 equivalents) is added. The reaction mixture should be stirred until the reaction is complete (TLC) and then the desired product isolated by solvent evaporation. The pure product is obtained by crystallization or flash column chromatography.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[C:14]3[CH:13]=[C:12]([F:16])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[C:6](=[O:20])[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=1.[C-:27]#[N:28].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[F:16][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:17][O:18][CH3:19])[C:7]3[C:6](=[O:20])[N:5]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:4]=[C:3]([CH2:2][C:27]#[N:28])[C:15]=3[C:14]=2[CH:13]=1
Reactant: COCn1c2ccc(F)cc2c2c(CBr)nn(-c3ccccc3)c(=O)c21
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCn1c2ccc(F)cc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Yield: 86.6 %

Procedure:
A two-phase mixture of 2.8 g (6.7 mmol) of 1-(bromomethyl)-8-fluoro-5-(methoxymethyl)-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one, of 1.3 g (26 mmol) of sodium cyanide and of 0.23 g (0.7 mmol) of tetrabutylammonium bromide in 100 ml of dichloromethane and 100 ml of water is stirred vigorously for 12 h. The organic phase is separated, washed several times with water, dried over magnesium sulphate and concentrated under reduced pressure. Diethyl ether is added and the precipitate is collected by filtration and dried under reduced pressure. 2.1 g (5.8 mmol) of solid are isolated, which solid is used as is in the following stage.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH:13]2[CH:9]1[CH2:10][N:11]([C:14]1[N:38]=[CH:37][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)=[C:25]([CH3:36])[CH:24]=4)[C:16]=3[CH:15]=1)[CH2:12]2)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:7][CH:8]1[CH:9]2[CH:13]1[CH2:12][N:11]([C:14]1[N:38]=[CH:37][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)=[C:25]([CH3:36])[CH:24]=4)[C:16]=3[CH:15]=1)[CH2:10]2
Reactant: Cc1cc(Nc2ncnc3cnc(N4CC5C(C4)C5NC(=O)OC(C)(C)C)cc23)ccc1Oc1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2ncnc3cnc(N4CC5C(N)C5C4)cc23)ccc1Oc1cccnc1
Yield: 98.8 %

Procedure:
A sample (0.26 g, 0.49 mmol) of (3-{4-[3-Methyl-4-(pyridin-3-yloxy)-phenylamino]-pyrido[3,4-d]pyrimidin-6-yl}-3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester was treated with 0.5 mL of trifluoroacetic acid and immediately concentrated in vacuo. The residue was dissolved in chloroform and washed with saturated sodium bicarbonate. The aqueous layer was back extracted several times with chloroform. The organics were dried over sodium sulfate and evaporated to afford 206 mg of the title compound. A pure sample was obtained by crystallization from methanol and isopropyl ether. 1H NMR (CDCl3): δ 8.96 (s, 1), 8.53 (s, 1), 8.33 (m, 2), 7.65 (m, 1), 7.55 (m, 1), 7.21 (m, 2), 6.96 (d, 1), 615 (s, 1), 3.76 (d, 2), 3.54 (m, 2), 2.26 (s, 3), 2.24 (m, 1), 1.76 (m, 2). M.S. (m+1): 426. HPLC retention time (minutes): 3.919.