Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:14]1[C:15]([O:33][CH3:34])=[C:16]([CH:22]2[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]2)[C:17]([Cl:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO.CCOC(C)=O>[NH:24]1[CH2:25][CH:22]([C:16]2[C:15]([O:33][CH3:34])=[C:14]([CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH3:13])[CH:19]=[C:18]([Cl:20])[C:17]=2[Cl:21])[CH2:23]1
Reactant: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(Cl)c1C1CNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.8 %

Procedure:
A solution of tert-butyl 3-[3-(1-{[(benzyloxy)carbonyl]amino}ethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate (200 mg, 0.39 mmol, from Example 194, Step 6) in methylene chloride (10 mL) was treated with trifluoroacetic acid (5 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to give a residue that was dissolved in methanol (˜20 mL) and treated with saturated sodium bicarbonate solution (pH˜8). The methanol was then removed in vacuo to give an aqueous suspension that was diluted with EtOAc. The organic layer was separated and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product (180 mg, 98%) that was used without further purification. LCMS for C20H23Cl2N2O3 (M+H)+: m/z=409.1, 411.1. Found: 409.1, 411.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O:34]C)=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([C@@H:36]([CH3:39])[CH2:37][CH3:38])[O:11][N:10]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([C@@H:36]([CH3:39])[CH2:37][CH3:38])[O:11][N:10]=1
Reactant: CC[C@H](C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)OC)ccc3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 80 °C
Yield: 100 %

Procedure:
To a solution of methyl 6-{4-[({3-(2,6-dichlorophenyl)-5-[(1S)-1-methylpropyl]-4-isoxazolyl}methyl)oxy]phenyl}-2-quinolinecarboxylate (50 mg, 0.089 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.13 mL, 0.13 mmol). The solution was heated in a microwave reactor at 80° C. for 10 minutes and then 1 N hydrochloric acid (0.13 mL, 0.13 mmol) was added. The solution was concentrated and the residue was taken up with ethyl acetate and water. The layers were separated and the organic layer was dried over magnesium sulfate and concentrated to afford 50 mg of 6-{4-[({3-(2,6-dichlorophenyl)-5-[(1S)-1-methylpropyl]-4-isoxazolyl}methyl)oxy]phenyl}-2-quinolinecarboxylic acid as a yellow solid (0.089 mmol, 100%). 1H-NMR (400 MHz, DMSO-d6) δ 13.37 (br s, 1H), 8.53 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.18-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.63-7.51 (m, 3H), 6.99 (d, J=9 Hz, 2H), 4.88 (app q, J=12 Hz, 2H), 3.31-3.22 (m, 1H), 1.73-1.66 (m, 2H), 3.32 (d, J=7 Hz, 3H), 0.83 (t, J=7 Hz, 3H). HRMS (ESI) C30H24Cl2N2O4 calculated: 547.1186 (M+H)+, found: 547.1182 (M+H)+.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:28]=[CH:27][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH:55]2[CH2:57][O:56]2)=[CH:49][CH:48]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH:22]1([CH2:21][NH:20][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:57][C@H:55]([OH:56])[CH2:54][O:53][C:50]4[CH:51]=[CH:52][C:47]([OH:46])=[CH:48][CH:49]=4)=[CH:28][CH:27]=3)[CH2:13][CH2:14]2)=[O:19])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCC3CCCC3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCC1CCCC1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 39 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(cyclopentylmethyl)-1-piperidinecarboxamide formate (0.38 g, 0.818 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.32 g, 0.792 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give the title compound (0.24 g, 0.309 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.S(OC)(O[CH3:21])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:21][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
A mixture of 4'-hydroxy-2-nitrobiphenyl (10.4 g), dimethyl sulphate (9.15 g) in acetone (350 ml) and anhydrous potassium carbonate (22 g) was heated at reflux for 10 hours to get an oil which was purified by column chromatography on silica gel (150 g, 100-200 mesh) eluted with hexane to give 4'-methoxy-2-nitrobiphenyl (m.p. 55°-56° C.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:11]=O.[C:13](/[CH:15]=[C:16](\[O-:18])/[CH3:17])#[N:14].[Na+]>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:11]=[C:15](/[C:16](=[O:18])[CH3:17])\[C:13]#[N:14]
Reactant: O=Cc1cc2cn[nH]c2cc1F
Reactant: C/C([O-])=C/C#N
Agent: [Na+]
Product: CC(=O)/C(C#N)=C/c1cc2cn[nH]c2cc1F

Procedure:
The title compound was prepared from 3.7 g (80% purity, 18.0 mmol) 6-fluoro-1H-indazole-5-carbaldehyde (Example 13A) and 2.08 g (19.84 mmol) sodium (1Z)-1-cyanoprop-1-en-2-olate in analogy to the procedure described in Example 9A yielding 2.5 g (61% of th.) of product which was used in subsequent steps without further purification.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([CH2:9][C:10]([OH:12])=[O:11])[CH2:3]1.Cl.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][N:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)N)=[CH:17][CH:16]=1>C(O)(C)(C)C>[F:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:20]([CH2:19][C:18]1[CH:29]=[CH:30][C:15]([Cl:14])=[CH:16][CH:17]=1)[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([CH2:9][C:10]([OH:12])=[O:11])[C:3]2=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: O=C(O)CC1CCCCC(=O)C1
Agent: Cl
Solvent: CC(C)(C)O
Product: O=C(O)CC1CCCCc2c1c1cc(F)ccc1n2Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To 1.10 g of 3-oxo-cycloheptaneacetic acid in 35 mL tert-butanol was added 2.13 g of 1-(p-chlorobenzyl)-1-(p-fluorophenyl) hydrazine hydrochloride, The reaction mixture was refluxed under nitrogen for 18 h, cooled to room temperature and then evaporated to dryness. The resultant residue was partitioned between water and ethyl acetate. The organic layer was washed with 1N HCl (2X), water (2X) and brine and dried over MgSO4. Filtration and concentration gave oil which was purified by flash chromatography on silica gel. Elution of the column with a mixture of hexane-ethyl acetate (7:3) gave the title compound substituted at the 10-position, mp 138°-139° C. IR (KBr) 1703 cm-1. 'H NMR (CDCl3, 250 MHz) w 1.32-1.54 (m, 1H),2.60-2.87 (m, 2H), 2.65 (d, J=7.5 Hz, 2H), 3.72-3.83 (m, 1H), 5.25 (s, 2H), 6.78-6.88 (m, 1H), 6.81 (d, J=8.0 Hz, 2H), 7.04 (d,d, J=4.5, 9.0 Hz, 1H), 7.20-7.30 (buried m, 1H), 7.23 (d, J=8.0 Hz, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[CH:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:9])([CH3:6])([CH3:5])[CH3:4].[F:32][CH2:33][CH2:34]I>CN(C=O)C>[C:3]([O:7][C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[C:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:34][CH2:33][F:32])[C:21]([O:23][CH3:24])=[O:22])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: FCCI
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCF)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (60% dispersion in mineral oil) (22 mg, 0.55 mmol) in anhydrous DMF (3 mL) under nitrogen atmosphere was added methyl 2-(4-(tert-butoxycarbonylamino)-1H-indol-1-yl)-2-(4-chlorophenyl)acetate (207 mg, 0.5 mmol), as described in Example 2 step B, in anhydrous DMF (2 mL) and the mixture was then stirred at 0° C. for 1 h. To this mixture was added 1-fluoro-2-iodoethane (17.4 mg, 1 mmol), and the mixture was then stirred at room temperature for 4 h. The volatile was evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (10/1 to 3/1, v/v) to afford the title compound as a white solid. LC/MS m/z=405.1[M+H]+.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:28]3[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Reactant: OC1CCNCC1
Solvent: CCCCO
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCC(O)CC2)nc1

Procedure:
Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 74 mg of 4-hydroxypiperidine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-hydroxypiperidin-1-yl)nicotinamide. MS (Q1) 409.3 (M)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[S:24]([O:15][CH2:14][CH2:13][CH2:12][O:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)(=[O:26])(=[O:25])[CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCOc1ccnc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCOc1ccnc2ccccc12
Yield: 53 %

Procedure:
A solution of the 3-(quinolin-4-yloxy)propan-1-ol obtained in step a) (0.5298 g, 2.6 mmol) was treated with triethylamine (0.60 mL) and methanesulfonyl chloride (0.55 g, 4.8 mmol) in dichloromethane (5 mL). After the starting material was consumed, the reaction was diluted with dichloromethane, washed with water, aq NaHCO3 and evaporated. The residue was purified by column chromatography on SiO2 and eluted with ethyl acetate. The product was obtained as a light yellow solid (0.3868 g, 53%). 1H NMR (400 MHz, CDCl3): 2.43 (2H, m), 3.00 (3H, s), 4.38 (2H, t, J=5.8 Hz), 4.55 (2H, t, J=5.8 Hz), 6.80 (1H, d, J=5.5 Hz), 7.55 (1H, t, J=8.0 Hz), 7.75 (1H, ddd, J=1.2, 7.0, 8.2 Hz), 8.20 (1H, d, J=8.4 Hz), 8.13 (1H, d, J=8.4 Hz), 8.77 (1H, d, J=5.3 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:23]2[CH2:28][CH2:27][N:26]([C:29](OCC3C=CC=CC=3)=O)[CH2:25][CH2:24]2)[N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[H][H]>CO.C(O)(=O)C.[Pd]>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][N:11]2[C:10]([CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[C:12]2[CH3:13])=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: Cc1c(C(=O)OC(C)(C)C)cc(C2CCN(C(=O)OCc3ccccc3)CC2)n1CCc1ccc(F)cc1
Agent: [Pd]
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(C(=O)OC(C)(C)C)cc(C2CCN(C)CC2)n1CCc1ccc(F)cc1

Procedure:
A 340 mg portion of benzyl 4-{4-(tert-butoxycarbonyl)-1-[2-(4-fluorophenyl)ethyl]-5-methyl-1H-pyrrol-2-yl}piperidine-1-carboxylate was dissolved in 7 ml of methanol, and 159 μl of 37% formalin, 3 drops of acetic acid and 45 mg of 10% palladium-activated carbon were added, followed by stirring at room temperature for 2 hours in an atmosphere of hydrogen. The reaction liquid was filtered through celite, the filtrate was concentrated under a reduced pressure, 50 ml of a saturated sodium bicarbonate aqueous solution was added to the residue, and the resulting solid was collected by filtration to obtain 232 mg of tert-butyl 1-[2-(4-fluorophenyl)ethyl]-2-methyl-5-(1-methylpiperidin-4-yl)-1H-pyrrole-3-carboxylate as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.Br.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(OC(F)(F)F)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Yield: 90.8 %

Procedure:
In a similar manner to that described in Reference example 37(b), a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)-2-(4-trifluoromethoxyphenoxy)propionate (4.08 g), which is the product of Reference example 40(a), a solution of hydrogen bromide in acetic acid (25%, 40 ml) and potassium carbonate (1.68 g) and the reaction mixture was treated to afford the desired compound (2.98 g) as a colorless oil.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C@@H:39]([OH:41])[CH3:40]>>[OH:41][C@@H:39]([CH3:40])[CH2:38][NH:37][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:29]=1
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 93.6 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 52 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][C@@H:24]([CH2:27][CH2:28][CH2:29][C:30]([CH3:32])=[CH2:31])[CH2:25][OH:26]>C(Cl)Cl>[CH3:23][C@@H:24]([CH2:27][CH2:28][CH2:29][C:30]([CH3:32])=[CH2:31])[CH:25]=[O:26]
Reactant: C=C(C)CCC[C@H](C)CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C=C(C)CCC[C@H](C)C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
As reported by Schinzer et al.104 Dess-Martin periodinane (3.23 g, 7.61 mmol, 1.2 equiv) was added to a solution of alcohol 75 (0.9 g, 6.34 mmol) in methylene chloride (12 ml). The mixture was stirred at room temperature for 15 min before it was subjected to flash column chromatography (10% EtOAc/hexanes) to furnish aldehyde 67 (0.745 g, 84%) as highly volatile colorless liquid: [α]22D=+11.8 (c=0.5, CHCl3); TLC Rf=0.64 (silica gel, 25% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 9.57-9.56 (d, 3J=1.8 Hz, 1H), 4.661 (s, 1H), 4.62 (s, 1H), 2.34-2.28 (m, 1H), 2.01-1.95 (t, 3J=7.8 Hz, 2H), 1.69-1.62 (m, 4H), 1.48-1.27 (m, 3H), 1.06-1.04 (d, 3J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 205.282, 145.420, 110.441, 46.390, 37.845, 30.20, 24.969, 22.444, 13.523.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.ClC(Cl)(Cl)C(=N)O[CH2:76][CH:77]=[CH:78][C:79]1[CH:84]=[CH:83][C:82]([O:85][Si:86]([C:89]([CH3:92])([CH3:91])[CH3:90])([CH3:88])[CH3:87])=[CH:81][CH:80]=1>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:76][CH:77]=[CH:78][C:79]3[CH:84]=[CH:83][C:82]([O:85][Si:86]([C:89]([CH3:90])([CH3:92])[CH3:91])([CH3:88])[CH3:87])=[CH:81][CH:80]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=CCOC(=N)C(Cl)(Cl)Cl)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(O[Si](C)(C)C(C)(C)C)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,-10,16-tetraone (700 mg in 12 ml methylene chloride)-4-t-butyldimethylsiloxycinnamyl trichloroacetimidate (550 μl neat) was added and the reagents allowed to mix for 5 minutes. Camphorsulfonic acid (35 mg) was added and the mixture stirred at room temperature. After 5 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×15 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (190 mg). 1H NMR spectrum was consistent with the desired structure.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=O>>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)[CH:33]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccnc3)cs2)C1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 54 mg (0.269 mmol) of 2-bromo-1-pyridin-3-ylethanone were reacted according to the General Method 3. Yield: 24 mg (21% of theory)
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A169) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]3[O:19][C:13]4=[C:14]([NH2:18])[N:15]=[CH:16][CH:17]=[C:12]4[CH:11]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.[I:20]C1C=NC(N)=C2OC(C3C=CC=C4C=3C=CN=C4)=CC=12>>[S:1]1[C:5]2[C:6]([C:10]3[O:19][C:13]4=[C:14]([NH2:18])[N:15]=[CH:16][C:17]([I:20])=[C:12]4[CH:11]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1
Reactant: Nc1ncc(I)c2cc(-c3cccc4cnccc34)oc12
Reactant: Nc1nccc2cc(-c3cccc4cnsc34)oc12
Product: Nc1ncc(I)c2cc(-c3cccc4cnsc34)oc12
Yield: 92 %

Procedure:
The title compound was prepared in 92% yield from 2-(1,2-benzothiazol-7-yl)furo[2,3-c]pyridin-7-amine by a procedure analogous to Intermediate 10, Step B. 1H NMR (300 MHz, CDCl3): δ 4.62 (br. s, 2H), 7.13 (s, 1H), 7.73 (t, J=5.7 Hz, 1H), 7.98 (s, 1H), 8.35-8.45 (m, 2H), 9.28 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:16][C:17](=[O:25])[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:27][CH3:28]>CCO.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([O:25][CH2:27][CH3:28])[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Reactant: CCI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOc1nc(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1-(3-benzyloxy-phenyl)-8-chloro-2H-imidazo[1,5-a]pyrazin-3-one (50.0 mg, 0.14 mmol) and silver carbonate (85 mg, 0.31 mmol) in anhydrous EtOH (1 mL) was charged with iodoethane (0.012 mL, 0.15 mmol) and stirred at rt for 48 h. The reaction mixture was partitioned between DCM and H2O and separated. The aqueous layer was washed with DCM (3×) and the combined organic layers were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo and the crude material was purified by chromatography on silica gel [eluting with 2% EtOAc in DCM], to yield the desired product as a yellow oil/gum; 1H NMR (CDCl3, 400 MHz) δ 1.51 (t, J=7.2 Hz, 3H), 4.68 (q, J=7.2 Hz, 2H), 5.13 (s, 2H), 7.00-7.05 (m, 1H), 7.13 (d, J=5.2 Hz, 1H), 7.27-7.48 (m, 9H); MS (ES+) m/z=380.07 (100) [MH+], HPLC: tR=4.04 min (MicromassZQ, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][C:12](=[CH2:17])[C:13]([O:15]C)=[O:14])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[C:18]([OH:21])(=[S:20])[CH3:19]>>[C:18]([S:20][CH2:17][CH:12]([CH2:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)[C:13]([OH:15])=[O:14])(=[O:21])[CH3:19]
Reactant: CC(O)=S
Reactant: C=C(Cc1cc2c(cc1Cl)OCO2)C(=O)OC
Product: CC(=O)SCC(Cc1cc2c(cc1Cl)OCO2)C(=O)O

Procedure:
The operation is carried out as in Stage 4 of Example 1 starting with 223 mg of product obtained in Stage 4 above and 0.16 ml thioacetic acid. In this way 172 mg of expected product is obtained.