Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([N:15]([CH3:17])[CH3:16])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C1([O:24][C:25](=O)[NH:26][CH:27]([CH3:38])[CH2:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)C=CC=CC=1.[OH-].[Na+]>O1CCOCC1>[CH3:16][N:15]([CH3:17])[C:6]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:25]([NH:26][CH:27]([CH3:38])[CH2:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)=[O:24])[CH2:8][CH2:7]1
Reactant: CC(Cc1c[nH]c2ccccc12)NC(=O)Oc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(Cc1c[nH]c2ccccc12)NC(=O)NCC1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 0 °C

Procedure:
The more nonpolar diastereoisomer of (4-aminomethyl-1-phenyl-cyclohexyl)-dimethylamine (162.7 mg, 0.7 mmole) was added to a solution of [2-(1H-indol-3-yl)-1-methyl-ethyl]-carbamic acid phenyl ester (206 mg, 0.7 mmole) in dioxane (7 ml). The batch was then refluxed for 14 h. Working up was performed by pouring the reaction mixture into ice water (15 ml), adjusting the pH to 11 with 5M NaOH and extracting with ether (3×20 ml). The organic phase was dried with Na2SO4 and then evaporated. The residue was purified by flash chromatography on silica gel (30 g). Ethanol/EE (1:2, 400 ml) was used as eluent. The more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexylmethyl)-3-[2-(1H-indol-3-yl)-1-methyl-ethyl]-urea was obtained in this manner as a colorless solid with a melting point of 89-92° C. in a yield of 185 mg (61%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=[O:10].[CH:18]([O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:20])[CH3:19]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])[CH:4]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1cc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(OC(C)C)cc2)ccn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 4-isopropoxy-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 9.94 (s, 1H) 8.61 (d, J=5 Hz, 1H) 7.78 (d, J=8.8, 1H) 7.61 (d, J=8 Hz, 1H) 7.50 (dd, J=11 Hz, 2 Hz, 2H) 7.27 (d, J=2.4 Hz, 1H) 7.07 (s, 1H) 6.96 (d, J=4 Hz, 1H) 6.75 (d, J=8.8 Hz, 2H) 4.47 (m, 1H) 2.63 (s, 3H) 1.27 (s, 6H). MS (ES) m/z=445.0 (M++1).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([N:13]1[C:17](=O)[CH2:16][C@H:15]([OH:19])[C:14]1=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.B.[Na].Cl>COCCOC.C1(C)C=CC=CC=1.O.CO>[CH2:6]([N:13]1[CH2:17][CH2:16][C@H:15]([OH:19])[CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1C[C@H](O)C(=O)N1Cc1ccccc1
Agent: B
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A solution of 13.4 ml (0.25 mole) sulfuric acid in 40 ml DME was added dropwise to a suspension of 25.6 g (0.125 mole) (S)-1-benzyl-3-hydroxy-2,5-pyrrolidine dione (IIa) and 19 g (0.5 mole) sodium boron hydride in 150 ml DME within 1.5 h at 35° C. The mixture was subsequently agitated 2 h at 70° C. After cooling off, 40 ml MeOH were added and the batch was evaporated to dryness. The residue was taken up in 120 ml water and agitated overnight at room temperature with 30 ml conc. hydrochloric acid and 150 ml toluene. After alkalization with 45 ml 50% sodium hydroxide solution the toluene phase was separated off at 70° C. and the aqueous phase subsequently extracted [re-extracted] with 100 ml toluene. The toluene phases were evaporated to dryness after drying over sodium sulfate, during which 22.7 g oil were obtained. It was taken up in 150 ml toluene, 100 ml water and 15 ml conc. hydrochloric acid and agitated overnight at room temperature. After repetition of the described workup 21.7 g (97.9%) (S)-1-benzyl-3-hydroxypyrrolidine (IIIa) were obtained as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][S:13]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:5].[N:34]1([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([NH:22][CH2:23][C:24](=[O:26])[N:44]2[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[CH2:46][CH2:45]2)=[O:21])=[CH:27][CH:28]=1)(=[O:14])=[O:15])=[O:5]
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: C1CCN(CCN2CCNCC2)C1
Product: O=C(NCC(=O)N1CCN(CCN2CCCC2)CC1)c1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from {4-[2-(2,4-dichloro-benzoyl)-phenylsulfamoyl]-benzoylamino}-acetic acid and 1-(2-pyrrolidin-1-yl-ethyl)-piperazine (EMKA-Chemie) according to the method described in Example 1.1/f. MS (EI) 673.2 (MH+).
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>CO.[Pd]>[C:4]1([CH2:3][CH2:2][C:1]([O:11][CH2:12][CH3:13])=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccccc1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A 500 mL 3-necked round bottom flask was added a solution of ethyl cinnamate (10 g, 56.75 mmol) in methanol (200 mL). To the mixture was added Pd/C (2 g) followed by addition of hydrogen gas. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 35° C. in a bath of oil. A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 10 g (99%) of ethyl 3-phenylpropanoate as a colorless oil.
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1)=O.N[C:16]1[CH:20]=C[NH:18][N:17]=1>C(O)(=O)C>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:18]3[N:17]=[CH:16][CH:20]=[C:14]3[N:2]=[CH:3][CH:4]=2)=[N:8][CH:9]=1
Reactant: Nc1cc[nH]n1
Reactant: Cc1ccc(C(=O)C=CN(C)C)nc1
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccnc3ccnn23)nc1

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-1-(5-methyl-2-pyridyl)-2-propen-1-one and 0.01 mole of 3-aminopyrazole in glacial acetic acid is refluxed for 8 hours and worked up as for Example 53 to give the product of the example.
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].N#N.[CH2:9]([O:16][CH2:17][CH2:18][CH:19]1[CH2:24]CC(=O)C[CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH2:1]=[C:2]1[CH2:4][CH2:20][CH:19]([CH2:18][CH2:17][O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:24][CH2:3]1
Reactant: O=C1CCC(CCOCc2ccccc2)CC1
Reactant: CC(C)(C)[O-]
Agent: N#N
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCC(CCOCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a cooled (−78° C.) mixture of Ph3PCH2Br (5.42 g, 14.88 mmol) in THF (25 mL) was added KOtBu (1M in THF, 17.05 mL, 17.05 mmol) dropwise under N2. The resulting mixture was stirred at 0° C. for 1 h and warmed to rt for another 1.5 h. The reaction mixture was then cooled to −40° C., added a solution of 4-(2-(benzyloxy)ethyl)cyclohexanone (1.8 g, 7.75 mmol) in THF (15 mL) dropwise. The mixture was then stirred at rt overnight and quenched by brine, extracted with EtOAc, dried over Na2SO4. Purification by flash column chromatography (eluent: 20% EtOAc in hexanes to 30%) gave the titled product (1.77 g, 99%). LC/MC: 231.1 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH3:13][C:7]1([CH3:14])[O:8][CH2:9][C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][C:2]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)=[CH:15][C:6]1=2
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1ccc(F)cc1
Product: CC1(C)OCC(=O)Nc2ccc(-c3ccc(F)cc3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 4-fluoro benzeneboronic acid generally according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 9.92 (s, 1H), 7.64-7.67 (m, 2H), 7.41-7.46 (m, 2H), 7.17-7.25 (m, 2H), 7.12 (s, J=2.26 Hz, 1H), 4.21 (s, 2H), 1.57 (s, 6H); MS (ESI) m/z 286 ([M+H]+); MS (ESI) m/z 284 ([M−H]−).
Reaction SMILES: C([O:8][C@H:9]1[CH2:12][C@H:11]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH2:10]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[OH:8][C@H:9]1[CH2:12][C@H:11]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH2:10]1
Reactant: O=C(Nc1ccccn1)[C@H]1C[C@H](OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1ccccn1)[C@H]1C[C@H](O)C1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
trans-3-(benzyloxy)-N-(pyridin-2-yl)cyclobutanecarboxamide (0.394 g, 1.40 mmol) and palladium hydroxide (0.098 g, 0.14 mmol, 20 weight % on carbon) were mixed in ethanol (5 mL). The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at 70° C. for 20 h. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated, and the resulting crude product was purified via silica gel chromatography to give trans-3-hydroxy-N-(pyridin-2-yl)cyclobutanecarboxamide as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH2:8][C@@H:9]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[NH:10][CH2:11][C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH2:8][C@H:9]([NH:10][CH2:11][C:12]1[C:17]([NH2:18])=[CH:16][N:15]=[C:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]=1)[CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC[C@H](NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CC[C@H](NCc1cc(Oc2ccccc2)ncc1N)C1CCCCC1
Reaction time: 2 h

Procedure:
To a solution of 4-(S)-cyclohexyl-4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-butyric acid tert-butyl ester (4.8 g, 10.2 mmol) in MeOH (50 mL) was added 10% Pd on activated carbon (0.8 g) under N2. The resulting mixture was subjected to hydrogenation at 5 psi for 2 hours. The catalyst was removed by filtration, and the MeOH was evaporated in vacuo to yield 4-[(5-amino-2-phenoxy-pyridin-4-ylmethyl)-amino]-4-(S)-cyclohexyl-butyric acid tert-butyl ester as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[C:18]3[N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)[N:10]=1)C1C=CC=CC=1>[Pd].CCO.CCOC(C)=O>[O:8]=[C:9]1[NH:10][C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[C:18]3[N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:12][CH:13]=[CH:14]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3ccc(-c4nccc(OCc5ccccc5)n4)cc23)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3ccc(-c4nccc(=O)[nH]4)cc23)C1
Reaction time: 12 h
Yield: 87 %

Procedure:
To a solution of (S)-tert-butyl 1-(6-(4-(benzyloxy)pyrimidin-2-yl)quinolin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.) in 4:1 EtOH/EtOAc (0.6 M), was added 10% palladium on carbon (0.2 eq.). The resulting heterogeneous solution was stirred for 12 hours under an atmosphere of hydrogen. The mixture was then filtered through a pad of celite eluting with EtOAc. The volatiles were removed in vacuo yielding (S)-tert-butyl 1-(6-(6-oxo-1,6-dihydropyrimidin-2-yl)quinolin-4-yl)piperidin-3-ylcarbamate (87%). LCMS (m/z): 422.1 (MH+); LC Rt=2.14 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Mg].[CH:26]([C:28]([CH3:30])=[O:29])=[CH2:27].Cl>O1CCCC1>[CH2:18]([O:17][C:3]1[CH:4]=[C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:7][C:2]=1[CH2:27][CH2:26][C:28](=[O:29])[CH3:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Reactant: C=CC(C)=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(OCc2ccccc2)c1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
A solution of 3.89 g. (0.010 mol.) of 1-bromo-2-benzyloxy-4-(1,1-dimethylheptyl)benzene in 15 ml. of tetrahydrofuran is slowly added to 0.36 g. (0.015 mol.) of 70-80 mesh magnesium metal. The resultant mixture is refluxed for 20 minutes and is then cooled to -10° C. Cuprous iodide (0.115 g., 0.006 mol.) is added and stirring continued for 10 minutes. To the resultant mixture is slowly added a solution of 0.701 g. (0.010 mol.) of methyl vinyl ketone in 5 ml. of tetrahydrofuran at such a rate that the reaction temperature could be maintained below 0° C. The reaction mixture is stirred for 30 minutes longer (t<0° C.) and is then added to 100 ml. of 1 N hydrochloric acid and 100 g. of ice. The quenched reaction is extracted three times with 150 ml. portions of ether. The combined ether extract is washed twice with 100 ml. portions of water, twice with 100 ml. portions of saturated sodium chloride, dried over magnesium sulfate and evaporated to an oil. The oil was purified via column chromatography on 180 g. of silica gel eluted with 20% ether-cyclohexane to yield 1.07 g. (28%) of the title compound as an oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5](Br)=[C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)Br)C.Cl.[NH2:21][OH:22].[OH-].[Na+]>>[OH:3][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[O:22][N:21]=1
Reactant: NO
Reactant: CCOC(=O)C(Br)=C(Br)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(-c2cccc3ccccc23)on1
Yield: 78.8 %

Procedure:
α,β-Dibromo-1-naphthylacrylic acid ethyl ester (6.0 g), hydroxylamine hydrochloride (1.3 g) and sodium hydroxide (7.2 g) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(c) to obtain the title compound (2.6 g, 78%) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[C:6]2[N:7]([C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=2)[N:8]=1.N1C=CC=CC=1.[CH3:36][O:37][C:38](Cl)=[O:39]>ClCCl>[CH2:12]([C:9]1[N:7]2[N:8]=[C:3]([CH2:2][NH:1][C:38]([O:37][CH3:36])=[O:39])[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:5]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=3)[C:6]2=[CH:11][CH:10]=1)[CH3:13]
Reactant: CCOC(=O)CCCCc1c(CN)nn2c(CC)ccc2c1-c1cncc(C)c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCCc1c(CNC(=O)OC)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a solution of ethyl 5-[2-(aminomethyl)-7-ethyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate (80 mg) and pyridine (1 mL) in dichloromethane (2 mL) was added methyl chloridocarbonate (34.8 mg) under ice-water cooling and the mixture was stirred at ambient temperature for 2 hours. After evaporation of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by preparative silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1) to give ethyl 5-[7-ethyl-2-{[(methoxycarbonyl)amino]methyl}-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]pentanoate as yellow oil (70 mg).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][CH2:57][C@H:58]2[CH2:62][O:61][C:60]3([CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]3)[O:59]2)[N:53]=[C:52]([S:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[C:71]=2[F:77])[N:51]=1>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:77][C:71]1[C:72]([F:76])=[CH:73][CH:74]=[CH:75][C:70]=1[CH2:69][S:68][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][CH2:57][C@H:58]2[CH2:62][O:61][C:60]3([CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]3)[O:59]2)[N:53]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: Fc1cccc(CSc2nc(Cl)cc(OC[C@H]3COC4(CCCCC4)O3)n2)c1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(OC[C@H]2COC3(CCCCC3)O2)nc(SCc2cccc(F)c2F)n1)N1CCC1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iv) using a mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.25 g), tris(dibenzylideneacetone)dipalladium (0) (83 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (43 mg), cesium carbonate (0.44 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2S)-1,4-dioxaspiro[4.5]dec-2-ylmethoxy]-pyrimidine (0.40 g) in dioxane (8 mL). Purification was by column chromatography on silica gel using EtOAC/isohexane (1:9 to 1:2 gradient) as eluent to give the subtitle compound as a pale yellow oil. Yield: 0.34 g
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.COC1C=CC([Br:30])=CC=1C=O>>[Br:30][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1ccc(Br)cc1C(O)C#Cc1ccccc1
Yield: 69 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2-methoxy-5-bromobenzaldehyde was reacted to give the title compound as a colourless oil (440 mg, 69%). LCMS (Method B): RT=4.47 min, [M−OH+H]+=299/301.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:30](=[CH:31][CH:32]=1)[O:29][C:7]1([CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]4[C:17](=[C:18]([O:27][CH3:28])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:33].[Cl:34][C:35]([O:37][CH3:38])=[O:36].CC(OC(C)=O)=O.Cl>>[ClH:34].[CH3:26][O:25][C:23]1[C:22]2[C:17](=[C:18]([O:27][CH3:28])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:13]([N:10]2[CH2:11][CH2:12][C:7]3([CH2:6][C:5](=[O:33])[C:4]4[C:30](=[CH:31][CH:32]=[C:2]([NH:1][C:35]([O:37][CH3:38])=[O:36])[CH:3]=4)[O:29]3)[CH2:8][CH2:9]2)=[O:14])[CH:24]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(N)ccc2O3)nc2c(OC)cccc12
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3cc(OC)c4cccc(OC)c4n3)CC1)O2

Procedure:
The free form of the compound was prepared according to the procedure described in Example 30 but using 6-amino-1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]spiro[chroman-2,4′-piperidin]-4-one and methyl chloroformate instead of 6-(piperazin-1-yl)-1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]spiro[chroman-2,4′-piperidin]-4-one and Ac2O. Then the material was converted to HCl salt according to the procedure described in Example 2. 1H-NMR (400 MHz, DMSO-d6) δ: 9.65 (1H, s), 7.84 (1H, s), 7.73-7.53 (3H, m), 7.36-7.25 (2H, m), 7.06 (1H, d, J=9.0 Hz), 4.34-4.18 (1H, m), 4.10 (3H, s), 3.97 (3H, s), 3.69-3.26 (3H, m), 3.64 (3H, s), 2.86 (2H, s), 2.10-1.71 (4H, m). MS [M+H]+=506.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32](=[O:33])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])([C:12]2=[N:11][C:10]=1[C:34]([OH:36])=O)[CH2:17][CH2:16]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:44][CH2:45][C:46](=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[NH:21][C:18]12[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:32](=[O:33])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([C:34](=[O:36])[NH:44][CH2:45][C:46](=[O:55])[CH2:47][C:48]3[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=3)[N:11]=[C:12]21)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)O)c(OCc2ccccc2)c1=O)OCc1ccccc1
Reactant: NCC(=O)Cc1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 3-(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylic acid, Intermediate 4 (1 g, 2.043 mmol) in CH2Cl2 (20 mL) was added oxalyl chloride (0.286 mL, 3.27 mmol). A few drops of DMF was then added and the mixture stirred at room temperature for 2 h. Solvent was removed under reduced pressure and the crude acid chloride was diluted with dichloromethane (10 mL) and added to a stirred solution of 1-amino-3-(4-fluorophenyl)propan-2-one HCl (0.458 g, 2.247 mmol) and triethylamine (1.139 mL, 8.17 mmol) in CH2Cl2 (20 mL). The resulting solution was stirred at room temperature for 16 h then poured into sat. NaHCO3 and extracted with dichloromethane (50 mL×3), dried (Na2SO4), filtered and concentrated to give a yellow oil. The crude product was then purified by silica gel chromatography (50-100% EtOAc/hexane) to afford the title compound (770 mg, 1.206 mmol, 59.0% yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 7.99 (1H, br. s.), 7.49 (2H, d, J=5.80 Hz), 7.28-7.37 (8H, m), 7.15 (2H, dd, J=8.55, 5.49 Hz), 7.01-7.04 (2H, m), 6.79 (1H, br. s.), 5.32 (2H, s), 5.06 (2H, s), 4.17 (2H, d, J=4.88 Hz), 4.12 (2H, d, J=3.66 Hz), 3.69 (2H, s), 2.67-2.78 (2H, m), 2.47 (1H, br. s.), 1.89-2.01 (4H, m), 1.64-1.72 (2H, m). LCMS (M+H)=640.04.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].B(F)(F)F.CCOCC.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:33])([F:32])[F:34])=[CH:26][CH:25]=1)([CH3:22])[CH2:6][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccc(OC(F)(F)F)cc1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(4-Benzyloxyphenyl)-3-hydroxy-2-(4-trifluoromethoxyphenoxy)-2-methylpropionic acid ethyl ester (9.5 mmol) in anhydrous CH2Cl2 (30 mL) was cooled to 0° C. and treated with BF3-Et2O (1.16 mL, 9.5 mmol) and triethylsilane (1.51 mL, 9.5 mmol). The mixture was stirred for 2 h and gradually warmed to ambient temperature. Saturated aqueous Na2CO3 (15 mL) was added and the mixture was stirred vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 3-(4-benzyloxyphenyl)-2-(4-trifluoromethoxyphenoxy)-2-methylpropionic acid ethyl ester as an oil.