Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)nc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(F)nc3)c2cc1OC
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 75.3 %

Procedure:
6-Fluoro-3-hydroxypyridine (10 mg), 4-chloro-6,7-dimethoxyquinoline (59 mg), and 4-dimethylaminopyridine (32 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 3.5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (20 mg, yield 76%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:12]=2)=[O:9])=[C:6]([Cl:26])[CH:5]=1.[NH:27]1[CH2:31][CH2:30][N:29]=[C:28]1N1C(C)=CC(C)=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:26][C:6]1[CH:5]=[C:4]([CH2:3][NH:2][C:28]2[NH:29][CH2:30][CH2:31][N:27]=2)[CH:25]=[CH:24][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9]
Reactant: Cc1cc(C)n(C2=NCCN2)n1
Reactant: NCc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CNC2=NCCN2)cc1Cl

Procedure:
100 mg of the crude HCl salt of 4-(aminomethyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 72 mg of 1-(4,5-dihydro-1H-imidazol-2-yl)-3,5-dimethyl-1H-pyrazole and 100 μL of DIPEA in 500 μL of DMF in the microwave at 150° C. for 5 minutes. The crude product was concentrated to dryness and purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4,5-dihydro-1H-imidazol-2-ylamino)methyl)benzamide. MS (Q1) 440 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][CH2:7]2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1)[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: O=C1OCc2cccc(Cl)c21
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(OC)nc(C2(c3nc(OC)nc(OC)n3)OC(=O)c3c(Cl)cccc32)n1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
1.48 g of 7-chlorophthalide are dissolved in 80 ml of THF. The solution is cooled to -70° C. and 1.5M IDA in THF (6 ml) is syringed in at -70° C. over 3 min. Stirring is continued for 15 min at -70°, 1.54 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine in 50 ml of THF added dropwise and the mixture is then allowed to warm to -20°. The mixture is again cooled to -70°, and 1 ml of conc. HCl in 10 ml of water is added. The mixture is stirred for 25 min and allowed to warm to RT and the THF is removed by evaporation. The residue is partitioned between CH2Cl2 and water (50 ml each) and the aqueous phase extracted with an additional 30 ml of CH2Cl2. The combined organic phases are washed with 30 ml of water and concentrated to give a yellow gum. This is flash chromatographed on silica gel using 60/40 hexane/ethyl acetate (1000 ml), ethyl acetate (400 ml), 80/20 acetone/methanol (500 ml) (30 fractions×50 ml, 1×200 ml). Fractions 21 and 22 yielded a yellow gum which upon recrystallization from hexane yielded title product m.p. 126°-127° as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([O:12][CH3:13])=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17].OC1C2C=NC(S(C)(=O)=O)=NC=2N(C)C(=O)C=1C(NCC(OC(C)(C)C)=O)=O.N.CO>C1COCC1>[OH:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([O:12][CH3:13])=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: COc1ncc2c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n(C)c2n1
Agent: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cnc(S(C)(=O)=O)nc21
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: COc1ncc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c2n1
Temperature: 0 °C

Procedure:
tert-Butyl 2-(5-hydroxy-2-methoxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamido)acetate. To a mixture of tert-butyl 2-(5-hydroxy-8-methyl-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamido)acetate (141 mg, 0.34 mmol) and THF (10 mL) was added ammonia, 2.0M methyl alcohol (3 mL, 5.1 mmol) at 0° C. under N2. The mixture was then stirred at 0° C. and warmed to room temperature overnight. LCMS showed no starting material was left and two peaks corresponding to the 7-amino and to the 7-OMe product (ca. 1:1). The white solid was filtered off and discarded. The filtrate was concentrated under reduced pressure to give the title compound. MS m/z: Calculated: 364.35. Observed: 365.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][CH2:10][CH:9]2[CH:7]([O:8]2)[CH2:6]1)(=[O:4])=[O:3].[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C)C=O>[N:12]([CH:9]1[CH2:10][CH2:11][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]1[OH:8])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)N1CCC2OC2C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(N=[N+]=[N-])C(O)C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a stirred solution of rac-3-methanesulfonyl-7-oxa-3-aza-bicyclo[4.1.0]heptane (0.92 g, 5.19 mmol, Example 303) in dimethylformamide (20 mL), sodium azide (550 mg, 8.46 mmol) was added and the mixture was stirred at 80° C. for 6 hours. The mixture was cooled and poured into water and extracted with ethyl acetate (3×10 mL). The extracts were combined, washed with water, brine and dried with MgSO4. The solvent was removed to give the desired product as colorless oil. 304 mg, 30.4%. The compound was used directly for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]2[CH2:33][O:34][CH2:35][CH:29]2[CH2:28]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]5[CH2:33][O:34][CH2:35][CH:29]5[CH2:28]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCCN1CCC2COCC2C1
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCN1CCC2COCC2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of 4-((4-bromo-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (225 mg, 0.62 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (151 mg, 0.74 mmol, 1.2 eq) and K2CO3 (171 mg, 1.24 mmol, 2 eq) in DMF (10 mL) was stirred at 80° C. overnight and cooled to room temperature. To this, CH2Cl2 (50 mL) was added. The mixture was washed with brine (20 mL×3) and water (20 mL×2), then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (199 mg, 60.50%), HPLC: 98.32%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 531.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.69-1.73 (2H, m), 2.41-2.46 (3H, m), 2.64-2.66 (2H, m), 2.68-2.70 (3H, m), 2.75-2.82 (2H, m), 3.00-3.03 (3H, m), 3.06-3.10 (2H, m), 3.81-3.85 (2H, m), 4.23-4.27 (2H, m), 7.06-7.12 (1H, m), 7.21 (1H, s), 7.68-7.79 (2H, m), 7.87 (1H, s), 8.06-8.11 (1H, m), 8.65 (1H, s) ppm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:17]([NH2:31])[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30]>O>[NH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][CH2:17][NH:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCCOCCOCCOCCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: O
Product: NCCCOCCOCCOCCCNc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 52.7 %

Procedure:
1.41 g (0.01 mol) of 1-fluoro-4-nitrobenzene and 1.62 ml (0.02 mol) of pyridine were introduced into a three-necked flask under nitrogen. 8.75 ml (0.04 mol) of 4,7,10-trioxatridecane-1,13-diamine were added dropwise with stirring. The mixture was heated to 70° C. After reaction for 24 hours, the reaction mixture was cooled and 40 ml of distilled water were then added with vigorous stirring. Next, the reaction mixture was extracted with dichloromethane, washed twice with water, dried over MgSO4 and then evaporated under vacuum. The crude product, isolated in the form of a yellow oil comprising about 90% of expected mono-nitro derivative, was purified on a column of silica, eluting with ethyl acetate (to separate out the dinitro derivative), and then with methanol (to recover the expected mono-nitro derivative). 1.8 g of expected product (19) were obtained in the form of a dark yellow oil.
Reaction SMILES: [C:1]1(=[O:8])[CH:7]=[CH:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH2:21][CH2:22][CH2:23][NH2:24])[O:20][CH2:19][CH2:18][O:17]2)=[CH:12][CH:11]=1>CO>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([CH2:21][CH2:22][CH2:23][N:24]3[CH:6]4[CH2:5][CH2:4][CH:3]3[CH2:2][C:1](=[O:8])[CH2:7]4)[O:17][CH2:18][CH2:19][O:20]2)=[CH:14][CH:15]=1
Reactant: O=C1C=CCCC=C1
Reactant: NCCCC1(c2ccc(F)cc2)OCCO1
Solvent: CO
Product: O=C1CC2CCC(C1)N2CCCC1(c2ccc(F)cc2)OCCO1

Procedure:
To a flask equipped with a nitrogen gas inlet, addition funnel and magnetic stirrer is charged 2.7 g. (0.025 mol) of 2,6-cycloheptadienone and 90 ml. of methanol. The solution is stirred and 5.63 g. (0.025 mol) of 2-(4-fluorophenyl)-1,3-dioxolane-2-propanamine in 90 ml. of methanol is added over 30 minutes. After the addition, the reaction is allowed to stir for 20 hrs. The solution is then concentrated in vacuo to afford an oil. Chromatography on 500 g. of silica gel gives, after evaporation of solvent, 8-{3-[2-(4-fluorophenyl)1,3-dioxolan-2-yl]-propyl}-8-azabicyclo-[3.2.1]octan-3-one as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[H][H]>N.CO.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[CH2:30][NH2:31])=[CH:32][CH:33]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(CN)c1
Yield: 14.6 %

Procedure:
To tert-Butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (1.09 g, 2.22 mmol) in 6 ml of 7 N ammonia in methanol at ambient temperature was added Raney-Ni (0.019 g) and the reaction was stirred under a balloon of hydrogen gas at ambient temperature. The reaction was filtered and concentrated to give tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-(aminomethyl)phenyl)acetate (0.160 g, 15%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37]>C(Cl)Cl>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][CH2:35][CH:36]([CH3:38])[CH3:37])[N:7]=2)=[C:9]([C:17]2[CH:18]=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)CN
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Solvent: ClCCl
Product: CC(C)CNc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.288 mmol) and isobutylamine (1 mL, 10.06 mmol) was stirred at rt overnight. The reaction mixture was diluted with DCM and washed with dilute aqueous HCl. The DCM extract was dried over MgSO4, filtered, evaporated onto silica gel and chromatographed (0-20% MeOH in DCM). The title compound was obtained as a yellow solid (75 mg, 44% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 7.96 (d, J=5.2 Hz, 1H), 7.40-7.62 (m, 3H), 7.23-7.33 (m, 2H), 7.20 (s, 1H), 7.14 (d, J=7.7 Hz, 2H), 6.00 (br. s., 1H), 2.85-3.11 (m, 2H), 1.67-1.87 (m, 1H), 1.36 (s, 9H), 0.82 (d, J=6.4 Hz, 6H). MS (ESI): 558.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2([CH2:37][CH2:36][CH2:35]2)[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[N:26]1([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[CH:18]=2)=[O:25])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2([CH2:37][CH2:36][CH2:35]2)[CH2:27]1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: c1ccc2c(c1)NCC21CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CC2(CCC2)c2ccccc21

Procedure:
214 mg (0.63 mmol) 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 100 mg (0.628 mmol) spiro[cyclobutane-1,3′-indoline], 212 mg (0.66 mmol) TBTU and 168 μL (1.20 mmol) triethylamine in 4 mL DMF were stirred overnight at RT. The mixture was separated by preparative HPLC. The product fractions were combined and the acetonitrile was removed using the rotary evaporator. The precipitated substance was suction filtered, washed with 20 mL water and dried in the CAD at 50° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:31]([NH:3][CH:4]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(C(N)C(=O)O[C@H]2CN3CCC2CC3)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NC(=O)c2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-(4-methoxyphenyl)acetate dihydrochloride (I106) (325 mg, 0.89 mmol) in DCM (10 ml), were added triethylamine (374 μl, 2.68 mmol) and benzoyl chloride (125 μl, 1.07 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with Na2CO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-(4-methoxyphenyl)acetate (145 mg; 41% yield). The product was used in the next step without any further purification.
Reaction SMILES: [C:1]([O:14][CH:15]1[CH:20]([CH3:21])[CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:18][CH:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:16]1[CH3:34])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC1(C)O[O:37]1>>[C:1]([O:14][CH:15]1[CH:16]([CH3:34])[CH:17]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:18]([OH:37])[CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]1[CH3:21])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC1C(C)C(c2ccccc2)NC(c2ccccc2)C1C
Reactant: CC1(C)OO1
Product: CCCCCCCCCCCC(=O)OC1C(C)C(c2ccccc2)N(O)C(c2ccccc2)C1C
Yield: 99.5 %

Procedure:
The general procedure of Example 2 is repeated using 29.9 g (64.5 mmol) of 2,6-diphenyl-3,5-dimethylpiperidin-4-yl laurate and 1.24 L (64.5 mmol) of dimethyldioxirane (0.050M in acetone). 30.8 g (98% yield) of the title compound is isolated: mp 108°-112° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C([Li])CCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17].[Cl-].[NH4+]>C1COCC1>[CH3:9][C:4]1[CH:3]=[C:2]([Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:7]=[CH:6][C:5]=1[O:8][Si:16]([CH3:18])([CH3:17])[CH3:15]
Reactant: Cc1cc(Br)ccc1O
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc([Si](C)(C)C)ccc1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 4-bromo-2-methylphenol (1.5 g, 8.02 mmol) in THF (16 mL) at −78° C. was added n-butyl lithium (12.5 mL, 1.6 M solution in hexanes, 20.05 mmol) and the reaction was stirred at this temperature for 30 minutes. Trimethylsilyl chloride (2.5 mL, 20.05 mmol) was then added and the resulting mixture was stirred at −78° C. for a further 1.5 hours. The reaction was allowed to warm to room temperature and saturated ammonium chloride solution (10 mL) was added. The mixture was extracted with diethyl ether (2×20 mL) and the combined organic extracts were dried (magnesium sulphate) and concentrated under reduced pressure to give the intermediate 2-methyl-4-(trimethylsilyl)phenoxytrimethylsilane as a pale yellow oil (1.6 g). This intermediate was then diluted with THF (3 mL) and treated with TBAF (6.3 mL, 1.0 M solution in THF, 6.33 mmol) at room temperature. The reaction was stirred at this temperature for 5 minutes and poured into water (10 mL). The aqueous portion was then extracted with ether (3×5 mL) and the combined organic extracts were washed (saturated brine), dried (magnesium sulphate) and concentrated under reduced pressure. The resulting oily residue was pre-adsorbed onto silica and the 2-methyl-4-(trimethylsilyl)phenol isolated by column chromatography (SiO2; light petroleum to 7:3 light petroleum-diethyl ether) as a pale yellow oil (0.78 g, 68%). Rf=0.65 (7:3 light petroleum-diethyl ether, silica). 1H NMR (DMSO-d6): δH 0.17 (9 H, s), 2.1 (3 H, s), 6.77 (1 H, d, J=7.8 Hz), 7.12 (1 H, d, J=7.8 Hz), 7.17 (1 H, s), 9.36 (1 H, s).
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[C:13]2[C:5]([CH2:6][CH2:7][C:8]3([O:12]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][C:3]=1[OH:16].[CH3:17][C:18](=[CH:20][CH2:21][CH2:22]/[C:23](=[CH:25]/[CH2:26]O)/[CH3:24])[CH3:19].O>O1CCOCC1>[CH3:24][C:23]([CH2:22][CH2:21][CH:20]=[C:18]([CH3:19])[CH3:17])=[CH:25][CH2:26][C:4]1[C:3]([OH:16])=[C:2]([CH3:1])[C:14]([CH3:15])=[C:13]2[C:5]=1[CH2:6][CH2:7][C:8]1([O:12]2)[CH2:9][CH2:10][CH2:11]1
Reactant: Cc1c(O)cc2c(c1C)OC1(CCC1)CC2
Reactant: CC(C)=CCC/C(C)=C/CO
Solvent: C1COCCO1
Solvent: O
Product: CC(C)=CCCC(C)=CCc1c(O)c(C)c(C)c2c1CCC1(CCC1)O2
Reaction time: 8 h

Procedure:
To a solution of 7,8-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (0.5 g) in 20 mL of dioxane under argon, was added borontrifluoride-diethyl etherate (0.72 mL) followed by geraniol (0.4 mL) and the reaction was stirred overnight. After addition of water, the solution was extracted with EtOAc, washed with brine, dried over Na2SO4, and evaporated. The residue was purified on a silica column eluting with 1:8 EtOAc/hexane to give 5-(3,7-dimethylocta-2,6-dienyl)-7,8-dimethylspiro[chroman-2,1′-cyclobutan]-6-ol (104 mg ) as an amber oil. 1H-NMR (300 MHz, CDCl3) δ=1.65-1.99 (m, 10H), 2.01-2.28 (m, 17H), 2.74-2.79 (t, 2H), 3.35-3.37 (d, H), 4.78 (s, 1H), 5.10-5.12 (t, 1H), 5.17-5.21 (t, 1H) ppm. 13C-NMR (75 MHz, CDCl3) δ=11.93, 12.15, 12.61, 16.21, 17.80, 20.47, 25.55, 25.80, 26.45, 29.58, 34.05, 39.74, 76.23, 117.15, 121.87, 121.97, 122.48, 123.62, 123.89, 132.02, 138.03, 145.52, 145.89 ppm. MS (m/z)=354 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)O)=[CH:9][N:10]=2)[N:7]=1.II.[PH2](=O)O.ClC1C=CC2N(C(C(C3C(F)=C4C(=CC=3F)N(C)N=C4)C)=CN=2)N=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:13]3[C:14]([F:24])=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2c(F)c(C(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Agent: CC(c1c(F)cc2c(cnn2C)c1F)c1cnc2ccc(Cl)nn12
Agent: II
Agent: O=[PH2]O
Product: Cn1ncc2c(F)c(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Yield: 77.5 %

Procedure:
The title compound as a light yellow solid (370 mg, 78%) was synthesized from (6-chloroimidazo[1,2-b]pyridazin-3-yl)(4,6-difluoro-1-methyl-1H-indazol-5-yl)methanol (500 mg, 1.43 mmol), iodine (907 mg, 3.57 mmol) and phosphinic acid (50%, 0.55 mL) using the same procedure as described in the synthesis of compound 51.2. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.07 (s, 1H), 8.01 (d, 1H), 7.44 (s, 1H), 7.29 (d, 1H), 7.27 (d, 1H), 4.46 (s, 2H), 4.04 (s, 3H). LCMS (method B): [MH]+=333.9, IR=2.68 min.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][CH2:8][C@H:9]([NH:13][C:14](=[O:33])[C@@H:15]([NH:26][C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][CH:18]=1)[C:10]([OH:12])=O)(C)(C)C.[ClH:35].[NH2:36][C@@H:37]([CH2:49][C:50]([NH2:52])=[O:51])[C:38]([NH:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C>CN(C=O)C>[ClH:35].[CH2:30]([O:29][C:27]([NH:26][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][CH:18]=1)[C:14]([NH:13][C@H:9]([C:10](=[O:12])[NH:36][C@H:37]([C:38](=[O:39])[NH:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:49][C:50](=[O:51])[NH2:52])[CH2:8][CH2:7][C:6]([OH:5])=[O:34])=[O:33])=[O:28])[CH:31]=[CH2:32]
Reactant: NC(=O)C[C@H](N)C(=O)NCCc1ccccc1
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: C=CCOC(=O)N[C@@H](Cc1ccc(C(=N)N)cc1)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-(S)-[2-(S)-allyloxycarbonylamino-3-(4-carbamimidoyl-phenyl)-propionylamino]-pentanedioic acid 5-tert-butyl ester (48 mg, 0.1 mmol) and 2-(S)-amino-N1-phenylethyl-succinamide hydrochloride (27 mg, 0.1 mmol) in 5 ml of DMF were added at 0° C. HATU (39 mg, 0.1 mmol) and collidine (24.2 mg, 0.2 mmol). The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation the residue was purified by chromatography on Sephadex LH20 employing n-butanol/glacial acetic acid/water (17/1/2) as eluent. Pure fractions were combined. The solvent was evaporated, the residue was taken up in water and the aqueous solution was freeze-dried. Yield: 45 mg (66%). MS: m/z=638.4 (M+H)+.