Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH:34]([OH:37])[CH2:35][OH:36].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:37][CH:34]([CH2:35][OH:36])[CH2:33][NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: NCC(O)CO
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCC(O)CO)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 31.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), (R/S)-3-aminopropane-1,2-diol (9.51 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were dissolved in DMF (1 mL). The mixture was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=28.9 min) to provide (R/S)-N-(2,3-dihydroxypropyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15 mg, 0.022 mmol, 32.1% yield): LCMS=505.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.35 Hz), 7.50-7.81 (7 H, m), 5.15 (1 H, s), 3.65-3.79 (1 H, m), 3.41-3.52 (2 H, m), 3.23-3.39 (2 H, m); HPLC peak RT=7.9 min (Method A).
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].O>CN(C)C=O>[CH3:27][O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]([CH3:17])=[C:8]1[N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:25]
Reactant: COC(=O)CCCCCBr
Reactant: Cc1c(-n2ccnc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCn1c(-n2ccnc2)c(C)c2ccccc21
Reaction time: 48 h

Procedure:
To a suspension of 60% sodium hydride (0.34 g) in dimethylformamide (10 ml), while stirring under nitrogen at 0°-5°, is added dropwise a solution of 2-(1-imidazolyl)-3-methyl-indole (1.50 g) in dimethylformamide (15 ml). Upon complete addition the mixture is stirred at 0°-5° for 1 hour. To the nearly complete solution is added methyl 6-bromohexanoate (1.67 g) dropwise. The mixture is stirred at 0°-5° for 0.5 hour, then for two days at room temperature. The solution is poured into water (100 ml) and extracted with ethyl acetate (3×50 ml), dried (MgSO4), filtered, and concentrated in vacuo to give an amber oil which is stirred with 100 ml of petroleum ether for 15 minutes. The mixture is placed in a separatory funnel and the insoluble amber oil separated and removed. The oil is dried in vacuo to give 1-(5-methoxycarbonylpentyl)-2-(1-imidazolyl)-3-methylindole as an oil; NMR (CDCl3): δ3.60 (3H), 3.90 (2H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[C:19]1([C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3ccccc3)nc2N1C(C)C
Temperature: 200 °C

Procedure:
A mixture of Intermediate C (100 mg, 0.37 mmol), 2-phenyl-1H-imidazole (533 mg, 3.7 mmol), Cut (35 mg, 0.18 mmol), trans-1,2-bis(methylamino)cyclo-hexane (52.5 mg, 0.07 mL, 0.37 mmol) and solid K2CO3 (511 mg, 3.7 mmol) in 2 mL of DMF was heated in a microwave reaction apparatus for 2 h at 200° C. After this time the reaction was transferred to a round bottom flask with the aid of EtOAc, then evaporated. The residue was purified by reverse-phase HPLC (PLRPS C-18 column, eluting with a gradient of 20-25% acetonitrile in water over 30 min) to give the title compound. LCMS: 377.2 m/z (M+H)+; ret. Time: 2.56 min (Analytical Method A); 1H NMR (400 MHz, CDCl3) δ: 7.9-7.8 (dd, 2H), 7.6-7.3 (m, 6H), 4.3 (dd, 1H), 3.8 (m, 1H), 3.4 (s, 3H), 1.9 (dd, 1H), 1.7 (dd, 1H), 1.05 (d, 3H), 0.9 (d, 3H) and 0.8 (d, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[C:37](=[O:39])=[O:38]>C1(C)C=CC=CC=1>[F:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:37]([OH:39])=[O:38])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(C(=O)O)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 2-bromo-5-[(2,5-difluorophenyl)[(4-fluorophenyl)thio]methyl ]-4-methylpyridine (1.39 g, 3.28 mmol) obtained in Example 10 in toluene (60 ml), a hexane solution of n-butyllithium (1.54 M, 2.55 ml, 3.93 mmol) was added in an argon atmosphere at −78° C. After stirring for 1 hour at the same temperature, carbon dioxide was bubbled thereinto the mixture. The reaction mixture was allowed to warm to room temperature over 2 hours, subsequently 0.1 N hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with methylene chloride:methanol=10:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol, diethyl ether and hexane, and was collected by filtration, to obtain the title compound (815 mg, 2.09 mmol, 64%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.P(Cl)(Cl)Cl.C([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)(C)C>ClC1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:31][C:30]1[CH:29]=[CH:28][C:27]([O:1][CH:2]([CH3:10])[CH3:3])=[CH:33][CH:32]=1)=[O:6]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCCCC2)ccc1O
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: CC(C)Oc1ccc(NC(=O)c2cc(S(=O)(=O)N3CCCCC3)ccc2O)cc1
Yield: 149.4 %

Procedure:
Chlorobenzene (2.0 mL) was added to 2-hydroxy-5-(piperidin-1-ylsulfonyl)benzoic acid (470 mg), and under stirring, phosphorus trichloride (0.072 mL) was added thereto and kept stirred at 130° C. for 1 hour. 4-Isopropylaniline (249 mg) was added to it, and stirred at 130° C. for 16 hours. The solvent was evaporated off under reduced pressure, then ethyl acetate was added thereto, washed with water and saturated brine in that order, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 50%, gradient) to give the intended product (515 mg, 75%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[O:8]([CH2:15][CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][C:19]=1[NH2:28])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:28][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:18]=1[NH:17][CH2:16][CH2:15][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:6]
Reactant: COCCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1NCCOc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: COCCC(=O)Nc1cnc2ccccc2c1NCCOc1ccccc1
Yield: 110.2 %

Procedure:
3-methoxypropanoyl chloride (0.86 ml, 7.9 mmol) was added dropwise over a 30 minute period to a chilled (ice bath) solution of N4-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol) in dichloromethane (100 ml). After a few hours, a precipitate formed. The solvent volume was reduced under vacuum to near dryness and hexane (100 ml) was added. Vacuum filtration provided 2.9 g of 3-methoxy—N-{4-[(2-phenoxyethyl)amino]quinolin-3-yl}propanamide as a hydrochloride salt.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([C:22]2[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1
Reactant: COc1cccc(OCCCCCl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: COc1cccc(OCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-(4-chlorobutoxy)-3-methoxybenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [N+:1]([CH:4]([CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)[C:5]([O:7]CC)=[O:6])([O-])=O.O.[ClH:26]>C(O)C.[Pd]>[ClH:26].[NH2:1][CH:4]([CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C1c2ccccc2C=Cc2ccccc21)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC(C(=O)O)C1c2ccccc2CCc2ccccc21

Procedure:
Ethyl α-nitro-5H-dibenzo[a,d]cycloheptene-5-acetate (13 g, 40 mmol) (Example 4, Step A) is dissolved in 150 mL of ethanol, 40 mL of water, and 3.5 mL of concentrated hydrochloric acid and hydrogenated with 2.0 g of 20% palladium on carbon (52 psi, 30 hours). The filtered solution is stripped and a white solid washed with diethyl ether, dried at 50° C./2 mm Hg. The crude product is used as is in the next step.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:31]=[N:30][C:12]3[N:13]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]4[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=4[C:11]=3[CH:10]=2)O1.Br[C:34]1[CH:49]=[CH:48][C:37]([CH2:38][N:39]2[CH:44]3[CH2:45][CH2:46][CH:40]2[CH2:41][CH:42]([OH:47])[CH2:43]3)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC.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>[OH:47][CH:42]1[CH2:41][CH:40]2[N:39]([CH2:38][C:37]3[CH:36]=[CH:35][C:34]([C:9]4[CH:31]=[N:30][C:12]5[N:13]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:14]6[CH:19]=[N:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=6[C:11]=5[CH:10]=4)=[CH:49][CH:48]=3)[CH:44]([CH2:45][CH2:46]2)[CH2:43]1
Reactant: CC1(C)OB(c2cnc3c(c2)c2cc(C#N)ncc2n3COCC[Si](C)(C)C)OC1(C)C
Reactant: OC1CC2CCC(C1)N2Cc1ccc(Br)cc1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(-c3ccc(CN4C5CCC4CC(O)C5)cc3)cnc21
Temperature: 100 °C
Yield: 59.8 %

Procedure:
A degassed mixture of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (217 mg, 0.48 mmol), 8-(4-bromobenzyl)-8-aza-bicyclo[3.2.1]octan-3-ol (157 mg, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (33 mg, 5 mol %) and cesium carbonate (157 mg, 0.48 mmol) in a mixture of DME (5 mL), IMS (2 mL) and water (1.3 mL) was heated under microwave irradiation at 100° C. for 30 minutes. The cooled reaction mixture was purified by flash chromatography (silica, 50 g column, Biotage, 0-5% (2N ammonia in MeOH) in DCM) to afford the title compound as an off-white solid (155 mg, 60%). 1H NMR (CDCl3, 300 MHz): 9.21-9.17 (m, 1H), 8.95 (d, J=2.1 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H), 8.43 (s, 1H), 7.67-7.53 (m, 4H), 6.04 (s, 2H), 3.70-3.58 (m, 4H), 3.35-3.15 (m, 2H), 2.20-1.60 (m, 10H), 0.95 (t, J=8.2 Hz, 2H), 0.00 (s, 9H). LCMS (Method B): RT=2.92 min, M+H+=540.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][O:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=1.CC1N(CCOC[Si](C)(C)C)N=CC=1.[Li]CCCC.[CH2:34]([Sn:38](Cl)([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH3:37]>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([Sn:38]([CH2:39][CH2:40][CH2:41][CH3:42])([CH2:43][CH2:44][CH2:45][CH3:46])[CH2:34][CH2:35][CH2:36][CH3:37])[N:4]([CH2:7][CH2:8][O:9][CH2:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[N:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccn(CCOC[Si](C)(C)C)n1
Agent: Cc1ccnn1CCOC[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)nn1CCOC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution containing a 1:1 mixture of 3-methyl-1-(2-trimethylsilanylmethoxy-ethyl)-1H-pyrazole and 5-methyl-1-(2-trimethylsilanylmethoxy-ethyl)-1H-pyrazole (1.5 g, 7.06 mmol) in THF (20 mL) at −78° C. was added dropwise n-BuLi (1.6M in hexanes, 4.4 mL, 1 equiv) while keeping the temperature below −70° C. The mixture was then stirred 30 min at −78° C. prior to the addition of tributyltin chloride (1.9 mL, 1 equiv) (the temperature was maintained below −70° C.). The mixture was stirred at −78° C. for 30 min and for 2 h at r.t. Hexanes was added to the mixture and the insoluble material was removed by filtration. Concentration of the solution in vacuo gave a colorless syrup. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (20/80)) to provide 3-methyl-5-tributylstannanyl-1-(2-trimethylsilanylmethoxy-ethyl)-1H-pyrazole (847 mg, 24%) as a colorless syrup. (TLC rf 0.33 in EtOAc/hexanes 5:95).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1CCCC1.[F:20][C:21]1[CH:22]=[CH:23][C:24](O)=[C:25]([C:27](=[O:29])[CH3:28])[CH:26]=1>CO>[F:20][C:21]1[CH:26]=[C:25]2[C:24](=[CH:23][CH:22]=1)[O:1][C:2]1([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH2:28][C:27]2=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1cc(F)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(F)ccc1O2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (12.1 g, 60.9 mmol) in pyrrolidine (7.3 mL, 87.2 mmol) and anhydrous methanol (16.5 mL) was added 1-(5-fluoro-2-hydroxy-phenyl)ethanone (9.3 g, 60.7 mmol). The reaction mixture was stirred at 80° C. for 2.5 hours. The methanol was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (150 mL), washed with 1N HCl (1×150 mL) and brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. The oil was diluted with hexanes (400 mL) and was heated at 60° C. until in solution. Once dissolved, the solution was allowed to cool to 25° C. The crystals were collected via vacuum filtration, rinsed with hexanes to obtain tert-butyl 6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (13.6 g, 67%) as a light yellow solid. ESI-MS m/z calc. 335.2. found 336.7 (M+1)+. Retention time 1.85 minutes (3 min run).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[C:42](=[O:45])([O-])[O-].[K+].[K+].O>C(COC)OC>[OH:45][C:42]1[CH:14]=[CH:15][C:7]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 131.9 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (300 mg, 0.505 mmol) was dissolved in dimethoxyethane (21 mL), and the solution was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (222 mg, 1.01 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (33.0 mg, 0.0404 mmol), potassium carbonate (349 mg, 2.53 mmol) and water (0.182 mL), followed by purification by flash column chromatography (chloroform/methanol=90/10 to 80/20) to obtain 4-(4-hydroxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (179 mg, yield 66%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f47) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([S:13][C:14]2[CH:19]=[CH:18][C:17](CC#N)=[CH:16][CH:15]=2)=[C:4]([CH3:23])[N:3]=1.[OH-:24].[K+].[CH3:26][CH2:27][OH:28]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:26][C:27]([OH:24])=[O:28])=[CH:16][CH:15]=2)=[C:4]([CH3:23])[N:3]=1
Reactant: CCCCNc1nc(N)nc(C)c1Sc1ccc(CC#N)cc1
Reactant: CCO
Reactant: [OH-]
Agent: [K+]
Product: CCCCNc1nc(N)nc(C)c1Sc1ccc(CC(=O)O)cc1

Procedure:
A mixture of the product from step (v) (610 mg) and aq. 5M KOH (2 ml) in EtOH (8 ml) was heated under reflux for 18 h. The mixture was purified by RPHPLC to give the subtitle compound as a solid, 392 mg.
Reaction SMILES: [CH:1]([PH:3](=[O:6])[CH:4]=[CH2:5])=[CH2:2].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]1[CH2:19]O[CH2:17][CH2:16]1>O>[CH2:7]([N:14]1[CH2:5][CH2:4][P:3](=[O:6])([CH2:17][CH:16]2[CH2:19][CH2:15]2)[CH2:1][CH2:2]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C[PH](=O)C=C
Reactant: NCc1ccccc1
Reactant: C1CCOC1
Solvent: O
Product: O=P1(CC2CC2)CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Yield: 81 %

Procedure:
Cyclopropylmethyl)-divinyl-phosphine oxide (3.56, 22.8 mmol) and benzylamine (3.0 mL, 27.4 mmol) were dissolved in a mixture of THF (100 mL) and deionized water (100 mL). The reaction mixture was heated at 90° C. for 24 hours. The reaction was not complete and so additional benzylamine (1.0 mL, 9.1 mmol) was added and the reaction mixture was heated for an additional six hours at 90° C. The reaction mixture was concentrated by rotary evaporation and the product was extracted into dichloromethane and washed with saturated brine. The organic phase was dried with sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was taken up in ethyl acetate and passed through a plug of silica. The product was then eluted from the silica with ethanol. The solvents were removed by rotary evaporation to yield 4.835 g of 1-benzyl-4-(cyclopropylmethyl)-[1,4]azaphosphinane 4-oxide (18.38 mmol, 81%) as an off-white crystalline solid. 1H NMR (400 MHz, DMSO) δ 7.38-7.30 (m, 4H); 7.30-7.24 (m, 1H); 3.59 (s, 2H); 2.81-2.63 (m, 4H); 1.94-1.83 (m, 2H); 1.82-1.71 (m, 2H); 1.74-1.68 (d of d, 2H); 0.96-0.83 (m, 1H); 0.56-0.49 (m, 2H); 0.22-0.14 (m, 2H); ESMS (m/z): (M+1)+ found, 264; (M+23)+ found, 286.
Reaction SMILES: [O:1]1[CH2:14][CH:2]1[CH2:3][O:4][C:5]1[C:13]2[C:9](=[N:10][S:11][N:12]=2)[CH:8]=[CH:7][CH:6]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>O1CCOCC1>[CH:15]([NH:18][CH2:14][CH:2]([OH:1])[CH2:3][O:4][C:5]1[C:13]2[C:9](=[N:10][S:11][N:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:17])[CH3:16]
Reactant: c1cc(OCC2CO2)c2nsnc2c1
Reactant: CC(C)N
Solvent: C1COCCO1
Product: CC(C)NCC(O)COc1cccc2nsnc12
Yield: 62 %

Procedure:
5.2 g (25 mM) 4-(2,3-epoxypropyloxy)-2,1,3-benzthiadiazole in 60 ml. dioxan were heated under reflux for 4 hours with 30 ml. isopropylamine. The reaction mixture was then evaporated and the residue was chromatographed on a silica gel column (silica gel particle size 0.063-0.200 mm., elution agent methanol with a small addition of glacial acetic acid). The residue obtained after evaporation of the eluted fractions was recrystallized from diisopropyl ether. There were obtained 4.1 g (62% of theory) 4-(3-isopropylamino-2-hydroxy-propyloxy)-2,1,3-benzthiadiazole, which had a melting point of 100°-102° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5](=O)[NH:4][CH2:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].O>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5](=[S:22])[NH:4][CH2:3]1
Reactant: CN1CNC(=O)C(c2ccccc2)(c2ccccn2)C1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccccc1
Solvent: O
Product: CN1CNC(=S)C(c2ccccc2)(c2ccccn2)C1

Procedure:
To a solution of 1,2,3,6-tetrahydro-1-methyl-5-phenyl-5-(2-pyridyl)-4(5H)-pyrimidinone in benzene is added 0.16 equivalent of phosphorus pentasulfide. The reaction mixture is heated gently for 30 minutes then water is added and the layers are separated. The aqueous layer is extracted again with benzene and the organic layers are combined, washed with water, dried (MgSO4) and concentrated in vacuo to give 1,2,3,6-tetrahydro-1-methyl-5-phenyl-5-(2-pyridyl)-4(5H)-pyrimidinethione.