Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:24][C:25]2[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[N:27]([CH3:33])[CH:26]=2)[C:9]2[C:10]([C:20]([F:23])([F:22])[F:21])=[N:11][N:12]([CH:17]3[CH2:19][CH2:18]3)[C:13]=2[C:14](O)=[O:15])=[CH:4][CH:3]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10]([C:20]([F:21])([F:22])[F:23])=[N:11][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:13]=3[C:14](=[O:15])[N:24]2[C:25]2[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[N:27]([CH3:33])[CH:26]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2c(C(F)(F)F)nn(C3CC3)c2C(=O)O)cn(C)c1=O
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3c(c(C(F)(F)F)nn3C3CC3)C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (Step 45.2). tR: 1.13 min (LC-MS 2); ESI-MS: 463 [M+H]+ (LC-MS 2); Rf=0.61 (CH2Cl2/5% MeOH); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.17 (m, 2H) 1.27-1.40 (m, 2H) 1.89 (s, 3H) 3.32 (s, 3H) 3.95-4.05 (m, 1H) 6.24 (s, 1H) 7.21-7.40 (m, 5H) 7.69 (d, J=2.7 Hz, 1H).
Reaction SMILES: [C:1]1([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:51][CH3:52])[CH2:24][N:23]3[C@H:9]([C:10](=[O:50])[NH:11][C@:12]4([C:47](O)=[O:48])[CH2:46][C@H:13]4[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][N:19]([S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH2:20][C@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:22]3=[O:25])[CH2:8]2)=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:71]1([S:74]([NH2:77])(=[O:76])=[O:75])[CH2:73][CH2:72]1.C1CCN2C(=NCCC2)CC1.Cl>O1CCCC1.O>[C:1]1([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:51][CH3:52])[CH2:24][N:23]3[C@H:9]([C:10](=[O:50])[NH:11][C@:12]4([C:47](=[O:48])[NH:77][S:74]([CH:71]5[CH2:73][CH2:72]5)(=[O:76])=[O:75])[CH2:46][C@H:13]4[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][N:19]([S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH2:20][C@H:21]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])[C:22]3=[O:25])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3C=CCCCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3/C=C\CCCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3/C=C\CCCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3C=CCCCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-methoxy-8-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[n]pyrrolo[2,1-c][1,4,8]triazacyclopentadecine-14a-carboxylic acid (13 mg, 0.016 mmol) and CDI (3.61 mg, 0.022 mmol) in tetrahydrofuran (2 mL) was refluxed for 1 h. It was then cooled to rt and cyclopropanesulfonamide (2.70 mg, 0.022 mmol) was added followed by DBU (8.39 μL, 0.056 mmol). The reaction mixture was stirred at rt 18 h, and then it was concentrated in vacuo to yield a light yellow oil. To this oil was added 5 mL of water, adjusting to pH=4 using 1N HCl. The white precipitate was collected by filtration and washed with water to give 15 mg of the crude product as a white solid. Purification by flash chromatography eluting with 2% MeOH/CH2Cl2 gave 8 mg of tert-butyl (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-14a-(cyclopropylsulfonylcarbamoyl)-2-methoxy-8-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[n]pyrrolo[2,1-c][1,4,8]triazacyclopentadecin-6-ylcarbamate as a white solid. LC-MS: MS m/z 889(M+1-MeOH). (This product was contaminated with an equal portion of the P1 methyl ester by-product.)
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][S:4]1(=[O:21])=[O:20])[CH3:2].O.NN>CCO>[CH2:1]([N:3]1[CH2:7][CH:6]([CH2:8][NH2:9])[CH2:5][S:4]1(=[O:21])=[O:20])[CH3:2]
Reactant: CCN1CC(CN2C(=O)c3ccccc3C2=O)CS1(=O)=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCN1CC(CN)CS1(=O)=O
Yield: 53.5 %

Procedure:
To a solution of 2-(2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-ylmethyl)-isoindole-1,3-dione (261 mg, 0.85 mmol) in EtOH (4 ml) was added hydrazine monohydrate (0.165 ml, 4 equiv). The reaction mixture was then refluxed overnight and a white gum formed. The reaction mixture was filtered (rinsing several times with EtOH) and the filtrate was evaporated to afford 81 mg of the expected amine contaminated by 10% of 2,3-Dihydro-phthalazine-1,4-dione. It was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CN(C)C=O>[Cl:1][C:2]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Temperature: 70 °C

Procedure:
A mixture of 60 parts of 2-chloro-1H-benzimidazole, 58 parts of 1-(chloromethyl)-4-fluorobenzene, 42.5 parts of sodium carbonate, 0.1 parts of potassium iodide and 135 parts of N,N-dimethylformamide was stirred and heated overnight at 70° C. The reaction mixture was poured into water. The precipitated product was filtered off and dissolved in trichloromethane. The solution was dried, filtered and evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 62.5 parts of 2-chloro-1-(4-fluorophenylmethyl)-1H-benzimidazole (61).
Reaction SMILES: C1([C:4]2[N:5]=[C:6]3[C:12]([C:13]([OH:15])=O)=[CH:11][N:10](COCC[Si](C)(C)C)[C:7]3=[N:8][CH:9]=2)CC1.C([N:31]1CCC(C)(C)C(N)C1)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:5]1[CH:4]=[CH:9][N:8]=[C:7]2[NH:10][CH:11]=[C:12]([C:13]([NH2:31])=[O:15])[C:6]=12
Reactant: CC1(C)CCN(Cc2ccccc2)CC1N
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1c[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 25 mL flask were combined 2-cyclopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 0.45 mmol), 1-benzyl-4,4-dimethylpiperidin-3-amine (147 mg, 0.68 mmol), and HATU (188 mg, 0.50 mmol). Then added DMF (3 mL) followed by N,N-diisopropylethylamine (0.24 mL 1.35 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then quenched with H2O and extracted with EtOAc (3×). The combined organics were washed with H2O (3×), dried over MgSO4 and concentrated. The crude residue was purified by SiO2 chromatography (30% to 80% EtOAc/hexanes) to afford 197 mg (82%) of N-(1-benzyl-4,4-dimethylpiperidin-3-yl)-2-cyclopropyl-5-(2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as a white foam.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[C:27]([CH3:28])=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:28][C:27]1[C:22]([O:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[N:23][CH:24]=[C:25]([N+:29]([O-:31])=[O:30])[CH:26]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1OC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc([N+](=O)[O-])cnc1OC1CCNCC1
Temperature: 22 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Add trifluoroacetic acid (150 mL) to a cold solution of 4-(3-methyl-5-nitro-pyridin-2-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (10.12 g, 30 mmol) in dichloromethane (450 mL). Stir the reaction mixture at 22° C. for 60 min. After removal of solvent, treat the residue with 1 N sodium hydroxide (150 mL) and extract with dichloromethane and ethyl acetate. Dry the combined organic phases over sodium sulfate. Removal of solvent provides 3-methyl-5-nitro-2-(piperidin-4-yloxy)-pyridine as a yellow solid (6.9 g, 97% yield). MS(ES): m/z=238.2 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Li+]>C(O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3cccc(OC)c3)oc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 4-({1-[5-(3-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)benzoic acid (197 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give ethyl 3-[{[4-({1-[5-(3-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate. The obtained ethyl 3-[{[4-({1-[5-(3-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL), 1N lithium hydroxide (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (216 mg, 91%).
Reaction SMILES: C([NH:4][CH2:5][C:6]1[O:20][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH:7]=1)[NH:14][C:13](=[O:19])[CH:12]=[CH:11]3)(=O)C.[OH-].[K+]>CO.O>[NH2:4][CH2:5][C:6]1[O:20][C:9]2=[C:10]3[C:15](=[C:16]([CH3:18])[CH:17]=[C:8]2[CH:7]=1)[NH:14][C:13](=[O:19])[CH:12]=[CH:11]3
Reactant: CC(=O)NCc1cc2cc(C)c3[nH]c(=O)ccc3c2o1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2cc(CN)oc2c2ccc(=O)[nH]c12
Temperature: 90 °C
Reaction time: 11 h
Yield: 76.3 %

Procedure:
2-(N-Acetylaminomethyl)-6,7-dihydro-5-methylfuro[2,3-f]quinoline-7-one (475 mg) was suspended in methanol (4 mg), to which KOH (1.16 g) in water (1 ml) was added. The mixture was stirred at 90° C. for 11 hours. After completion of the reaction, the solvent was removed under reduced pressure, and water (50 ml) was added. The resulting mixture was made into acidic with 2N-HCl. The aqueous phase was washed with chloroform. Potassium carbonate was added thereto up to definite alkaline pH, followed by extraction with chloroform. The chloroform phase was washed with aqueous NaCl solution, and dried. After the solvent was removed under reduced pressure, 306 mg of 2-aminomethyl-6,7-dihydro-5-methylfuro[2,3-f]quinoline-7-one (76.3%) was obtained. This product was converted into a hydrochloride, and recrystallized from methanol. As a result, a hydrochloric acid salt of 2-aminomethyl-6,7-dihydro-5-methylfuro[2,3-f]quinoline-7-one was obtained as pale yellow prisms (mp.: higher than 300° C.).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[NH2:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.Cl>C(#N)C>[C:1]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:10][C:22]2[C:31]3[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CN1CCN(c2ccc(N)cc2CNC(C)(C)C)CC1
Agent: Cl
Solvent: CC#N
Product: CN1CCN(c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2CNC(C)(C)C)CC1
Yield: 47.3 %

Procedure:
3-[(tert-butylamino)methyl]-4-(4-methylpiperazin-1-yl)aniline (60 mg, 0.22 mmol) and 4,7-dichloroquinoline (43 mg, 1 eq) were refluxed overnight in 10 mL of acetonitrile with 0.43 mL of HCl 1M. The reaction mixture was then evaporated and purified by preparative thin-layer chromatography (DCM/MeOH/NH4OH/18/210.1) to yield expected compound as a pale yellow solid (45 mg, 47% yield). m/z (ESI) 438.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C:15]([C:19]1[CH:20]=[C:21]([C:25]2[C:26]3[N:27]([N:31]=[C:32]([NH2:34])[N:33]=3)[CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:23][CH:24]=1)([CH3:18])([CH3:17])[CH3:16].NC1C=CC=C(Br)N=1.C(C1C=C(B(O)O)C=CC=1)(C)(C)C>>[C:15]([C:19]1[CH:20]=[C:21]([C:25]2[C:26]3[N:27]([N:31]=[C:32]([NH:34][CH:11]4[CH2:12][CH2:13][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=5)[CH2:9][CH2:10]4)[N:33]=3)[CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:23][CH:24]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C1CCN(c2ccnc(Cl)c2)CC1
Reactant: CC(C)(C)c1cccc(-c2cccn3nc(N)nc23)c1
Agent: CC(C)(C)c1cccc(B(O)O)c1
Agent: Nc1cccc(Br)n1
Product: CC(C)(C)c1cccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)c5)CC4)nc23)c1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(2-chloropyridin-4-yl)piperidin-4-one (see example 232b) and 8-(3-tert-butylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine. The latter compound can be prepared in analogy to example 1 steps d-f) starting from 2-amino-6-bromo-pyridine and 3-tert-butylphenylboronic acid (EP2243785A1). The title compound was obtained as a colourless foam. MS ISP (m/e): 461.2 [(M+H)+].
Reaction SMILES: [Br-:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[C:11]2[CH:16]3[CH2:17][CH2:18][N+:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH2:14][CH2:15]3)[CH2:12]2)=[CH:5][CH:4]=1.C(O)(=O)C>[Pd].O>[Br-:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[CH:16]3[CH2:15][CH2:14][N+:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:17]3)[CH2:12]2)=[CH:5][CH:4]=1
Reactant: CCCCCCC[N+]12CCC(CC1)C(=CCc1ccc(Cl)cc1)C2
Agent: [Pd]
Agent: [Br-]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCC[N+]12CCC(CC1)C(CCc1ccc(Cl)cc1)C2

Procedure:
Combine 2.47 g (0.08 mole) of 3-[2-(4-Chlorophenyl)ethylidene]-1-heptyl-1-azoniabicyclo[2.2.2]octane bromide, 50 ml of acetic acid, 0.26 g of 10% palladium on carbon and 5 ml of water in a Parr bottle and place the mixture on a Parr hydrogenation apparatus. Pressurize the system to 40 p.s.i. and follow the reaction by the pressure drop in the system. Filter the catalyst, remove the solvent in vacuo and triturate the residue with several portions of diethyl ether. Suspend the crude solid in 100 ml of water and adjust the mixture with 10% sodium hydroxide solution to pH 10. Extract the mixture with three 50 ml portions of ether. Adjust the mixture to pH 2 with hydrobromic acid and extract with four 75 ml portions of methylene chloride. Dry the combined organic extracts over anhydrous sodium sulfate. Filter the drying agent and remove the solvent in vacuo. Recrystallize the residue from acetone to obtain the title compound.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.C(OCC)(=O)C>[C:9]1([CH:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1cccnc1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccnc1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
To a stirring solution of nicotinaldehyde 75 (0.876 mL, 9.34 mmol) in THF (20 mL) at 0° C. was slowly added a 1M phenylmagnesium bromide solution (9.34 mL, 9.34 mmol) and the reaction mixture was allowed to warm to room temperature over 30 minutes. The crude solution was diluted with ethyl acetate and washed with water, dried over Na2SO4, filtered and concentrated to afford compound 76 (1.7 g, 98% yield) after purification by flash chromatography (50 to 100% EtOAc in hexanes).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1CCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(CCc2ccccc2)c1
Temperature: 77.5 °C
Yield: 84.9 %

Procedure:
To a solution of 42 (80.0 mg; 0.17 mmol) in tetrahydrofuran (3 mL) and methanol (1 mL) was added aqueous sodium hydroxide (4 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a clear oil (64.0 mg).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][N:37]1[C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:39]=[N:38]1.I[C:52]1[CH:53]=[C:54]([C:70]([OH:72])=[O:71])[C:55](=[O:69])[N:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=2)[C:57]=1[CH3:58]>O.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:58][C:57]1[N:56]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:67])([F:68])[F:66])[CH:60]=2)[C:55](=[O:69])[C:54]([C:70]([OH:72])=[O:71])=[CH:53][C:52]=1[C:41]1[N:37]([CH3:36])[N:38]=[CH:39][CH:40]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2ccnn2C)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
Acetonitrile (30.3 L, 3 rel vol) was charged, followed by palladium(II) acetate (260 g, 0.05 mol eq) and 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (980 g, 0.1 mol eq). The mixture was stirred for 15 minutes. A solution of potassium carbonate (10.0 kg, 3.0 mol eq) in water (60.6 L, 6 rel vol) was added to the reaction. 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (31.8% w/w, 20.3 kg, 1.3 mol eq) as a solution in acetonitrile was added, followed by 5-iodo-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (10.1 kg, 1 mol eq, limiting reagent). The reaction mixture was heated to reflux and stirred until the reaction was complete as judged by HPLC analysis. The reaction mixture was cooled and filtered. The cake was washed with acetonitrile (10.1 L, 1 rel vol) and the cake discarded. The filtrate was heated to 50° C. 6 M Hydrochloric acid (60.6 L, 6 rel vol) was added carefully to the reaction. The reaction mixture was stirred at 50° C. for 60 minutes, cooled to 5° C. and stirred overnight. The solid was collected by filtration, washed twice with water (2×20.2 L, 2×2 rel vol) and with cold (around 5° C.) acetonitrile (10.1 L, 1 rel vol). The solid was dried to constant weight to yield the title compound (8.1 kg, 21.5 mol, 77%); 1H NMR (d6-DMSO): δ 1.87 (s, 3H); 3.73 (s, 3H); 6.35-6.37 (m, 1H); 7.54-7.55 (m, 1H); 7.83-7.91 (m, 2H); 7.95-7.97 (m, 1H); 8.07 (s, 1H); 8.25 (s, 1H); 13.80 (s, 1H); LCMS: m/z 378.3 (MH+).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Cl:9][C:10]([Cl:16])=[CH:11][CH:12]=[C:13]([CH3:15])[CH3:14].O.[Cl-].[Li+].C([O-])(=O)C.[K+].ClCl>C(#N)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:12]([CH:11]=[C:10]([Cl:16])[Cl:9])[C:13]1([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)=CC=C(Cl)Cl
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: ClCl
Agent: [Cl-]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C

Procedure:
A mixture of ethyl cyanoacetate (12.44 parts), 1,1-dichloro-4-methylpenta-1,3diene (15.1 parts), lithium chloride monohydrate (6.26 parts), cupric acetate monohydrate, and in one case potassium acetate, as indicated in the table below, in acetonitrile (100 parts by volume), is heated and chlorine is added at a uniform rate, heating being continued for a further period. After cooling the reaction mixture the acetonitrile is removed by distillation under reduced pressure and the ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate is isolated as described for Examples 41 to 48. The yield, strength and composition of the product, together with other preparative details, are given in the table below.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:24])=[N:19][C:20]=1[CH:21]([CH3:23])[CH3:22]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:24][C:18]2[CH:17]=[CH:16][C:15]([F:14])=[C:20]([CH:21]([CH3:23])[CH3:22])[N:19]=2)[CH:7]=1
Reactant: CC(C)c1nc(N)ccc1F
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(F)c(C(C)C)n1
Temperature: 130 °C

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (674 mg, 3.05 mmol) in acetonitrile (10 mL) was added 5-fluoro-6-isopropylpyridin-2-amine (470 mg, 3.05 mmol) and heated at 130° C. in a sealed tube for 18 h. Upon completion, the mixture was concentrated on to silica gel and purified by chromatography (silica. 10% to 33% EtOAc in hexanes) to give recovered aniline (300 mg) and ethyl 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxylate (150 mg, 22%). 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 10.72 (s, 1H), 9.23 (s, 1H), 7.38 (t, J=8.4 Hz, 1H), 6.79 (dd, J=8.5, 2.8 Hz, 1H), 4.57 (m, 2H), 3.45 (m, 1H), 1.53 (m, 3H), 1.36 (d, J=6.9 Hz, 6H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>ClCCl.O>[N:26]([CH2:2][CH2:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCc1cc2ccccc2cn1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a ice-bath cooled solution of 3-(2-hydroxyethyl)isoquinoline (Description 111; 4.85 g, 28 mmol) and triethylamine (5.07 ml, 36.4 mmol) in anhydrous dichloromethane (100 ml) was added slowly methanesulfonyl chloride (2.49 ml, 32.2 mmol), and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water (200 ml), sat NaCl (100 ml), dried over Na2SO4, filtered and evaporated. The residue was dissolved in anhydrous N,N-dimethylformamide (100 ml) and sodium azide (2.00 g, 30.8 mmol) added and the resulting mixture stirred at room temperature for 4 days. The mixture was poured into water (400 ml), and extracted with EtOAc (3×100 ml). The combined EtOAc layers were washed with water (3×200 ml), saturated aqueous NaCl (100 ml), dried over Na2SO4, filtered and evaporated to give the title compound (5.6 g, 100%).