Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)CC2C=CC(OC)=CC=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1.CCN(CC)CC.[O:48]1[CH2:51][C:50](=[CH:52][C:53]#[N:54])[CH2:49]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>CO.C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([C:50]3([CH2:52][C:53]#[N:54])[CH2:51][O:48][CH2:49]3)[CH2:12][CH2:13]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:33]2[CH2:34][CH2:35]2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(C4CCNCC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: N#CC=C1COC1
Solvent: COc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: N#CCC1(N2CCC(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CC2)COC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 208D) (30 mg, 0.054 mmol) in a mixture solvent {CH2Cl2 (1 ml)/MeOH (0.5 mL)} was added Et3N (0.011 ml, 0.081 mmol) followed by 2-(oxetan-3-ylidene)acetonitrile (36.0 mg, 0.379 mmol). The reaction mixture was heated at 50° C. for 2 days. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, removal of the solvent and the crude PMB-protected product was purified by silica gel chromatography, eluting with DCM containing 0 to 2% MeOH. The PMB-protected product was dissolved in DCE (2 ml), and added anisole (0.059 ml, 0.541 mmol), followed by TFA (0.5 ml). The resulting mixture was stirred at rt overnight. Removal of the solvent, and the crude material was purified by prep. HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; solvent B=90% Methanol, 10% H2O, 0.1% TFA, Flow rate 42 ml permin, 20-100% B, over 20 min). The HPLC fractions containing the product were applied onto a cartridges of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with large amount of 2 N solution of ammonia in methanol/DCM (1:1). Removal of the solvents left 2-((2-chloro-5-cyano-3-(1-(3-(cyanomethyl)oxetan-3-yl)piperidin-4-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (10.6 mg) as a solid.
Reaction SMILES: O[C@@H]([C@@H:4]1[C@@H:7]([C@@H:8](C)[C:9](=O)[C:10](=[N+]=[N-])[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[NH:6][C:5]1=[O:21])C.[C:22]1([CH3:28])[CH:27]=[CH:26]C=CC=1>C(OCC)(=O)C>[C:5]([NH:6][C:9]1[CH2:8][C@@H:7]2[CH2:4][C:5](=[O:21])[N:6]2[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:26][CH:27]=[CH:22][CH:28]=1)=[O:12])(=[O:21])[CH3:4]
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O
Reactant: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of crystalline diazo keto ester 4 (45 mg, 0.152 mmol) rhodium octanoate (1.2 mg, 0.00154 mmol) and anhydrous toluene (3.0 ml) was heated in an oil bath at 80° and under a nitrogen atmosphere for 15 minutes. (Note: gas evolution occurred at room temperature before heating). After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (3 ml), dried over magnesium sulfate, filtered, evaporated under vacuum and stripped with methylene chloride to afford 5 as a pale green oil (41 mg, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[NH:41])[NH2:40])=[CH:35][CH:34]=1.[OH-].[Na+]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:40])[NH2:41])=[CH:37][CH:38]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)cc(CCc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CCc2ccc(C(=N)N)cc2)cc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 3 from 1-methyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sul-phonylamino]-indole and sodium hydroxide solution.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:21][CH:22]=[CH2:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19].CN(C)C=O.S(Cl)([Cl:31])=O>C1C=CC=CC=1>[Cl:31][CH2:2][CH2:3][N:4]([CH2:21][CH:22]=[CH2:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: C=CCN(CCO)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: C=CCN(CCCl)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
16.7 parts by weight of N-hydroxyethyl-N-allyl-2,6-dinitro-4-trifluoromethylaniline is dissolved in 50 parts by weight of benzene. After adding 1 part by weight of dimethylformamide and dripping in 30 parts by weight of thionyl chloride at room temperature the whole is boiled for two hours under reflux. The volatile constituents are distilled off from the reaction mixture at 20 mm Hg, the residue is taken up in ethyl acetate, the solution is washed with ice-water, then with 10% sodium bicarbonate solution and finally again with water and the organic phase is dried over sodium sulfate.
Reaction SMILES: N#N.C([NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]1([F:25])[F:24])C1C=CC=CC=1>CO.[Pd]>[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][C:12]1([F:25])[F:24]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)(F)C1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)C(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), tert-butyl 4-(benzylamino)-3,3-difluoropiperidine-1-carboxylate (0.186 g, 0.57 mmol) was dissolved in MeOH (5 mL) and wet Pd/C 10% (50 mg) was added. The flask was purged with H2 gas and the reaction mixture stirred under an H2 atmosphere for 2 h at rt. The reaction mixture was filtered over celite and the cake was washed with MeOH and EA. The filtrate was concentrated under reduced pressure to give tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate as a colorless oil. LC-MS-conditions 08: tR=0.49 min; [M-CH3+H]+=222.32.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)[CH:16]=[CH:15][N:14]=2)[CH:6]=1)C.C(OC(=O)C1C=CC(NC2N=C(C3C=NC=CC=3)C=CN=2)=CC=1)C>>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:25])=[O:3])=[CH:6][C:7]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CCOC(=O)c1ccc(C)c(Nc2nccc(Nc3nccs3)n2)c1
Agent: CCOC(=O)c1ccc(Nc2nccc(-c3cccnc3)n2)cc1
Product: Cc1ccc(C(=O)O)cc1Nc1nccc(Nc2nccs2)n1

Procedure:
4-methyl-3-[4-(thiazol-2-ylamino)-pyrimidin-2-ylamino]-benzoic acid ethyl ester prepared in Preparation 15 was used instead of 4-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid ethyl ester according to the similar procedure to Preparation 19 to give the titled compound as yellow solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9]OC>>[CH3:9][C:3]1[CH:4]=[C:5]([OH:6])[CH:7]=[CH:8][C:1]=1[OH:2]
Reactant: COC
Reactant: Oc1ccc(O)cc1
Product: Cc1cc(O)ccc1O
Yield: 45 %

Procedure:
In the same microreactor with the previous procedures there are charged 8.0 g amorphous BPO4 calcined at 170° C., 8.0 g hydroquinone and 7.9 g dimethylether, at a weight ratio 1/1/1. The hydroquinone conversion is 52% by moles, the yield to methyl hydroquinone 45% by moles and the selectivity to methyl hydroquinone 87% by moles. The gas-chromatographic analysis of the products gave the following result:
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:11][C:12](=[O:15])[CH2:13][CH3:14]>>[O:15]=[C:12]([CH2:13][CH3:14])[CH2:11][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CCC(=O)CBr
Reactant: NC(=O)C1CCNCC1
Product: CCC(=O)CN1CCC(C(N)=O)CC1

Procedure:
The title compound was prepared according to the procedure described in the step 5 of Example 4 from isonipecotamide and 1-bromobutan-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([CH2:8][CH2:9][C:10]([CH3:12])=[O:11])[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.P([O-])(O)(O)=O.[K+].[Cl:21][O-].[Na+].C(O)(=O)C>C(Cl)Cl.O>[Cl:21][CH:3]1[CH2:4][CH2:5][C:6]([CH3:14])([CH3:13])[CH:7]([CH2:8][CH2:9][C:10](=[O:11])[CH3:12])[C:2]1=[CH2:1]
Reactant: CC(=O)CCC1C(C)=CCCC1(C)C
Reactant: [O-]Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: C=C1C(Cl)CCC(C)(C)C1CCC(C)=O
Temperature: 25 °C

Procedure:
388 g (2 mol) of dihydro-α-ionone was placed in 2.2 l of methylene chloride in a 10 l four-necked flask fitted with a stirrer, thermometer, condenser and dropping funnel. Then, 660 g (4.6 mol) of potassium dihydrogen phosphate dissolved in 3 l of water was added and the resulting emulsion was cooled in an ice bath. 1.6 (2.3 mol) of sodium hypochlorite solution (~12%) was added at about 10° within 1.5 hours and, after about 3 hours at 15°, a further 350 ml (0.5 mol) was added. The pH value of the mixture was adjusted to ~5.5 with acetic acid and it was stirred at room temperature. After a total reaction time of 27 hours the phases were separated and the aqueous phase was extracted 4 times with methylene chloride. The combined organic phases were washed neutral once with water, twice with saturated NaHCO3 solution and a further 3 times with water, dried over MgSO4, filtered and evaporated (bath temperature=room temperature). 407.45 g 4-(3-chloro-2-methylidene-6,6-dimethyl-cyclohex-1-yl)-butan-2-one was obtained as a yellow liquid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:18])[CH2:12][NH:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)=[CH:5][C:4]=1[Cl:19]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:18])[CH2:12][NH:13][CH:14]2[CH2:15][CH2:16][CH2:17]2)=[CH:5][C:4]=1[Cl:19]
Reactant: N#Cc1cc(C(=O)CNC2CCC2)cc(Cl)c1N
Agent: Cl
Product: N#Cc1cc(C(O)CNC2CCC2)cc(Cl)c1N

Procedure:
m.p. of the hydrochloride: 178°-180° C. (decomp.), was prepared from 4'-amino-3'-chloro-5'-cyano-2-cyclobutylaminoacetophenone analogous to Example 48.
Reaction SMILES: O.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([NH:21][CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](O)=[O:24])=[O:20])=[CH:13]2>C(OCC)(=O)C>[CH2:26]([CH:22]([NH:21][C:19]([C:14]1[NH:15][C:16]2[C:12]([CH:13]=1)=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=2)=[O:20])[C:23](=[O:24])[N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1CCNCC1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
4-Piperidone monohydrate (2.0 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (1.0 mmol) were coupled according to procedure A (0-25° C. reaction temperature) substituting the following workup: the reaction mixture was diluted with ethyl acetate, the resulting solution washed with 2 N NaOH and 2 N HCl, the suspension filtered and the solids dried: Yield 111 mg, 26%; HPLC (60/40) 8.88 minutes (92%); PBMS 424/426 (MH+, 100%); mp 258-261° C.; PBMS 424/426 (MH+, 100%);
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[F:31][C:32]([F:47])([F:46])[S:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>O1CCCC1.O>[C:1]1([C:7]2[N:11]([S:42]([C:39]3[CH:38]=[CH:37][C:36]([S:33]([C:32]([F:47])([F:31])[F:46])(=[O:35])=[O:34])=[CH:41][CH:40]=3)(=[O:44])=[O:43])[CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(S(=O)(=O)C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 60 mg) was added, and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (0.30 mL) was added and the mixture was further stirred at the same temperature for 15 min. 4-[(Trifluoromethyl)sulfonyl]benzenesulfonyl chloride (432 mg) was added and the reaction mixture was stirred at room temperature for 30 min. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give 5-phenyl-1-({4-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrole-3-carbaldehyde (191 mg) as an orange solid. The obtained 5-phenyl-1-({4-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrole-3-carbaldehyde (191 mg) was subjected to a similar operation as in the synthesis of Example 179 to give the title compound as a solid (yield 86 mg, 40%).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC=CC=3Cl)C=2)=[O:7])=[CH:4][N:3]=1.C[C@H]1CNC[C@@H](C)N1>>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:26]=[CH:27][CH:2]=[N:3][CH:4]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2Cl)c1)c1ccc(Cl)nc1
Agent: C[C@@H]1CNC[C@H](C)N1
Product: NC(=O)c1cccnc1

Procedure:
6-chloro-N-(4-chloro-3-(2-chlorobenzamido)phenyl)nicotinamide (0.2 mmol) was used in general procedure 3 with cis-2,6-dimethylpiperazine (0.8 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(2-chlorobenzamido)phenyl))-6-(3S,5R)-3-5-dimethylpiperazine-1-yl)-nicotin-amide. MS (Q1) 498.1 (M)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:15][N:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=[N:17]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][N:16]1[C:20]([C:2]2[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[S:5][C:6]=2[C:7]([F:10])([F:9])[F:8])=[CH:19][CH:18]=[N:17]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(C(F)(F)F)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(C(F)(F)F)s1
Temperature: 70 °C
Reaction time: 12 h
Yield: 77.6 %

Procedure:
A mixture of methyl 4-bromo-5-(trifluoromethyl)-2-thiophenecarboxylate (0.8 g, 40% purity, 1.11 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.299 g, 1.434 mmol), tetrakis (0.128 g, 0.11 mmol) and K2CO3 (0.459 g, 3.32 mmol) in dioxane/H2O (5 mL/1 mL) was heated to 70° C. in a sealed tube. After 12 h, the reaction mixture was concentrated under vacuum and purified on silica (EtOAc/Hex, 40-60%) to afford the title compound (0.25 g, 70%) as a light yellow solid: LC-MS (ES) m/z 291 (M+H)+.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)O.C(N(CC)CC)C>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[Cl:27])[C:36]1[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=1)=[O:11])[CH2:3]2
Reactant: OC(c1ccc(Cl)cc1)c1ccccc1Cl
Reactant: O=C(O)C1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(OC(c1ccc(Cl)cc1)c1ccccc1Cl)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (0.1 g, 0.52 mmol), EDC (150 mg, 0.78 mmol), and HOBT (120 mg, 0.78 mmol) were dissolved in dry THF (3 ml). (2-Chlorophenyl)(4-chlorophenyl)methanol (145 mg, 0.57 mmol) was dissolved in dry THF (2 ml) and then added to the reaction mixture. Triethylamine (253 μl, 1.83 mmol) was added, and the resulting reaction was stirred at room temperature overnight. The mixture was evaporated, and the crude was taken up with EtOAc and washed with water and brine. The organic phase was separated, dried (sodium sulfate), filtered, and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH=95/5) to afford (2-chlorophenyl)(4-chlorophenyl)methyl quinuclidine-3-carboxylate (40 mg, mixture of diastereoisomers). The compound was used as such in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2.[CH3:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[NH2:33].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C1(C)C=CC=CC=1>[CH3:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[NH:33][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[CH:8]=[CH:7]2
Reactant: Cc1ccc2ccccc2c1N
Reactant: Brc1cccc2ccc(-c3cccc4ccccc34)nc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2ccccc2c1Nc1cccc2ccc(-c3cccc4ccccc34)nc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 8-bromo-2-(1-naphthyl)quinoline (3.25 g, 9.7 mmol), 2-methyl-1-naphthalenamine (1.76 g, 11.2 mmol), Pd(dba)2 (0.12 g, 0.2 mmol), L=(N-[2′-(dicyclohexylphosphino)[1,1′-biphenyl]-2-yl]-N,N-dimethylamine (0.15 g, 0.4 mmol), NaOtBu (1.15 g, 12 mmol) and toluene (20 mL) is stirred for 8 h under an argon atmosphere at 100° C. in oil bath. The mixture is then poured into water and extracted with benzene (3×40 mL). The combined organic phases are washed with water and brine and then concentrated. The residue is purified by column chromatography (silica gel 40, hexane/toluene 4:1). Yield 3.1 g (78%).
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:16]=1)[C:14]#[N:15].[F:17][C:18]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][Si](C)(C)C)=[CH:26][C:19]=1[CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[Br-].[Zn+2].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:13]1[CH:16]=[C:9]([C:31]#[C:30][C:27]2[CH:28]=[CH:29][C:18]([F:17])=[C:19]([CH:26]=2)[CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:10]=[N:11][CH:12]=1)#[N:15]
Reactant: N#Cc1cncc(Br)c1
Reactant: C[Si](C)(C)C#Cc1ccc(F)c(CNS(C)(=O)=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
Dissolve zinc (II) bromide (94 mg, 0.36 mmol) in tetrahydrofuran (0.75 mL) and treat with triethylamine (0.20 mL, 1.4 mmol). After 4 min add 5-bromonicotinonitrile (55 mg, 0.30 mmol), N-(2-fluoro-5-trimethylsilanylethynylbenzyl) -methanesulfonamide, (prepared as described in PREPARATION 34), (100 mg, 0.33 mmol) and tetrakis(triphenylphosphine)palladium (0) (17 mg, 0.015 mmol) to the reddish solution. Heat to 60° C. and add a 1 M solution of tetrabutylammonium fluoride (0.36 mL) in tetrahydrofuran. After 1 h add additional 1 M tetrabutylammonium fluoride (0.3 mL) in tetrahydrofuran and stir an additional 30 min. Cool to room temperature and filter through diatomaceous earth washing with ethyl acetate. Purify by silica gel chromatography, eluting with a gradient from 60:40 to 40:60 (7:30 hexanes:dichloromethane):ethyl acetate, to give the title compound as a white crystalline solid (50 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=O)=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([N:21](CC)[CH2:22]C)C.ClC(OCC)=O.CNC.[OH-].[Na+]>C1(C)C=CC=CC=1.CO.Cl.O>[CH3:19][N:21]([CH3:22])[C:16]([C:10]1[C:11](=[O:15])[CH:12]=[C:13]([CH3:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:18]
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CNC
Agent: Cl
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(=O)c(C(=O)N(C)C)nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.7 %

Procedure:
To an ice cooled suspension of 2.65 g (0.01 mol) 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic Acid (see Example 12) and 1.01 g (0.01 mol) of triethylamine in 50 ml of toluene there is added dropwise 1.09 g (0.01 mol) of ethyl chloroformate. The mixture is stirred at room temperature for 15 min. and is cooled to 5° C. To the mixture there is added 3.375 g (0.03 mol) of 40% dimethylamine (aqueous). The solution formed is stirred at room temperature for 18 hrs. and to it there is added 100 ml of water. The mixture is stirred at room temperature for 1 hr. and the aqueous layer is isolated. The aqueous layer is made basic with 50% sodium hydroxide and extracted with toluene. The toluene extract is dried over magnesium sulfate and concentrated in vacuo to afford 1.8 g of colorless tar. The tar is dissolved in 30 ml of methanol, saturated with anhydrous hydrogen chloride and concentrated in vacuo. The concentrate is slurried in 100 ml of ether for 1 hr. and vacuum filtered. The filter cake is air dried to afford 1.45 g (44% yield) of product, mp 125°-135° C. decomp.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].O=[C:17]1[CH2:22][CH2:21][N:20]([C@H:23]([CH3:27])[CH2:24][C:25]#[N:26])[CH2:19][CH2:18]1>>[NH2:26][CH2:25][CH2:24][C@H:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:15])[CH3:14])=[CH:12][CH:11]=2)[CH2:18][CH2:19]1)[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Product: C[C@H](CCN)N1CCC(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1

Procedure:
Using general procedure A with 4-(tert-butyl-dimethyl-silanyloxy)-phenylamine (Swenton, John S.; et al., J. Org. Chem., 54, 1, 1989, 51-58) (1.28 g, 5.73 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (1.05 g, 6.32 mmol) followed by general procedure J gave [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-amine as a yellow oil (1.81 g, 84% over 2 steps).