Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:37][CH2:36][CH2:34][OH:35])=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.27 (1H, t, J=5 Hz), 8.51 (1H, s), 7.75 (1H, s), 7.31 (2H, dd, J=9, 6 Hz), 7.12 (2H, t, J=9 Hz), 5.03 (2H, s), 4.90 (1H, br), 4.12 (2H, s), 3.58 (2H, t, J=6 Hz), 3.54 (2H, m), 3.42 (2H, t, J=7 Hz), 3.40 (2H, t, J=7 Hz), 1.96 (2H, m, J=7 Hz), 1.80 (2H, m, J=7 Hz); HRMS calcd for C24H25FN4O5+H+: 469.1887. Found: 469.1896.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1.[ClH:33]>O1CCOCC1.CCOCC>[ClH:33].[F:1][C:2]1[CH:3]=[C:4]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)c(F)c2)cc1
Yield: 88 %

Procedure:
4-({[3-Fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride (0.23 g, 88%) was prepared as a white solid from 1,1-dimethylethyl 4-({[3-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarboxylate (Example 64, 0.30 g, 0.65 mmol), 1,4-dioxane (12 mL), ether (9 mL), 4.0M HCl in 1,4-dioxane (9 mL) and 2M HCl in ether (9 mL) in a manner similar to Example 66, Step 1. 1H NMR (400 MHz, CD3OD): δ 7.99 (d, 2H, J=8.5 Hz), 7.84 (d, 2H, J=8.5 Hz), 7.55-7.45 (m, 2H), 7.25-7.20 (m, 1H), 4.04 (d, 2H, J=5.9 Hz), 3.50-3.40 (m, 2H), 3.14 (s, 3H), 3.10-3.00 (m, 2H), 2.30-2.15 (m, 1H), 2.15-2.05 (m, 2H), 1.75-1.60 (m, 2H); LRMS (ESI), m/z 364 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:14][N:15](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:16].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:11]([N:15]([CH3:16])[CH3:14])=[O:13])=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1[nH]cc(C(=O)O)c1Cl
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]cc(C(=O)N(C)C)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-3-carboxylic acid (0.075 g, 0.368 mmol) in DMF (1 ml) was added HATU (0.168 g, 0.442 mmol), DIPEA (0.097 ml, 0.553 mmol) and dimethyl amine (2M in THF) (0.276 ml, 0.553 mmol) and the reaction stirred at RT for 1 h. Purification was accomplished by HPLC to afford methyl 3-chloro-4-[(dimethylamino)carbonyl]-1H-pyrrole-2-carboxylate (0.042 g, 49% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.40 (br. s., 1H) 7.23 (d, 1H) 3.80 (s, 3H) 2.93 (s, 6H). MS: m/z 231.0 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.[CH2:21]([Si:23]([CH2:27][CH3:28])([CH2:25][CH3:26])Cl)[CH3:22]>C1COCC1>[Br:13][C:14]1[CH:19]=[C:18]([Si:23]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:21][CH3:22])[C:17]([F:20])=[CH:16][N:15]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: Fc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC[Si](CC)(CC)c1cc(Br)ncc1F
Temperature: -75 °C
Reaction time: 1 h

Procedure:
A solution of diisopropylamine (25.3 g, 250 mmol) in 370 ml THF was cooled with a dry-ice acetone bath at −75° C. BuLi (100 ml, 250 mmol, 2.5 M in hexanes) was added dropwise while maintaining the temperature below −50° C. After the temperature of the mixture had reached −75° C. again, a solution of 2-bromo-5-fluoropyridine (36.7 g, 208 mmol) in 45 ml THF was added dropwise. The mixture was stirred for 1 h at −75° C. Triethylchlorosilane (39.2 g, 260 mmol) was added quickly. The temperature stayed below −50° C. The cooling bath was removed and the reaction mixture was allowed to warm to −15° C., poured onto aq. NH4Cl (10%). TBME was added and the layers were separated. The organic layer was washed with brine, dried with MgSO4.H2O, filtered and evaporated to give a brown liquid which was distilled at 0.5 mm Hg to yield the title compound as a slightly yellow liquid (b.p. 105-111° C.). HPLC: RtH11=2.284 min; ESIMS: 290, 292 [(M+H)+, 1Br]; 1H-NMR (400 MHz, CDCl3): 8.14 (s, 1H), 7.40 (d, 1H), 1.00-0.82 (m, 15H).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[CH3:6][O:7][C:8](OC)(OC)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[CH3:6][O:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: COC(OC)(OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: COC(=NS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methanesulfonamide (4.75 g, 50 mmol)) and trimethyl orthobenzoate (18.2 g, 100 mmol) was heated at 120° C. for 4 h in the presence of a catalytic amount of p-toluenesulfonic acid (50 mg). After being cooled to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with a saturated sodium bicarbonate aqueous solution and then water. The organic phase was dried over MgSO4, concentrated, and the resulting residue was treated with hexanes (100 mL) with stirring overnight. A white solid formed was filtered and washed with hexanes to yield a pure N-(methoxyphenylmethylene)methansulfonamide.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH2:36]([CH:41]1[CH2:46][CH2:45][CH:44]([CH:47]2[CH2:52][CH2:51][CH:50]([CH2:53][CH:54]=O)[CH2:49][CH2:48]2)[CH2:43][CH2:42]1)[CH2:37][CH2:38][CH2:39][CH3:40].CCOCC>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:7]=[CH:8]\[CH2:54][CH2:53][CH:50]2[CH2:51][CH2:52][CH:47]([CH:44]3[CH2:43][CH2:42][CH:41]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:46][CH2:45]3)[CH2:48][CH2:49]2)=[CH:28][CH:29]=1
Reactant: CCCCCC1CCC(C2CCC(CC=O)CC2)CC1
Reactant: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCC1CCC(C2CCC(CC/C=C\c3ccc(F)cc3)CC2)CC1
Yield: 57.8 %

Procedure:
4-fluorophenethyltriphenylphosphoniumbromide (4.2 g, 9 mmol) was dried and then dissolved in THF (10 ml), followed by stirring under ice cooling, adding potassium-t-butoxide (1.0 g, 9 mmol) slowly to the obtained reaction solution, stirring at room temperature for 2 hours after the completion of dropping, adding a THF (50 ml) solution of 4-(4-pentylcyclohexyl)-cyclohexylacetoaldehyde (2.7 g, 9.7 mmol) and further stirring for 5 hours, adding ether after the completion of reaction, filtering off the obtained white crystals deposited, concentrating the filtrate under reduced pressure, and purifying the obtained brown oil by means of silica gel column chromatography, to obtain a mixture (2.0 g, 5.2 mmol) of 1-(4-fluorophenyl)-4-(4-(4-pentylcyclohexyl)cyclohexyl)-2Z-butene with its E-isomer.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[C:14]([C:12]1[CH:13]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:35]3[CH:34]=[CH:33][C:32]([CH2:31][N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[CH:37][CH:36]=3)[CH:3]=2)[N:9]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:11]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(-c2cncc(Br)c2)nc(-c2ccccn2)n1
Reactant: CN1CCN(Cc2ccc(B(O)O)cc2)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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CN1CCN(Cc2ccc(-c3cncc(-c4cc(C(C)(C)C)nc(-c5ccccn5)n4)c3)cc2)CC1

Procedure:
To a solution of 4-(5-bromo-pyridin-3-yl)-6-tert-butyl-2-pyridin-2-yl-pyrimidine (1 eq, 200 mg, 0.542 mmol) in EtOH/DME (2 ml, 1:1) is added 4-(4-methyl-piperazin-1-ylmethyl)-phenyl-boronic acid (1.1 eq, 174 mg, 0.596 mmol), aqueous Na2CO3 solution (2 M, 3 eq, 0.812 ml, 1.63 mmol) and Pd(PPh3)4 (0.05 eq, 31 mg, 0.027 mmol). The resulting mixture is heated using microwave radiation for 20 min at 140° C. The mixture is filtered, washed with DCM and concentrated in vacuo. The residue is partitioned between sat. aqueous NaHCO3 solution and DCM and the organic layer is washed with brine, dried (MgSO4) concentrated under reduced pressure. The resulting residue is purified by reverse phase chromatography yielding the title compound; [M+H]+=479. 1H NMR (CDCl3, 400 MHz): 9.26 (d, 1H), 8.95 (d, 1H), 8.87 (m, 1H), 8.66 (t, 1H), 8.62 (m, 1H), 7.88 (td, 1H), 7.77 (s, 1H), 7.64 (d, 2H), 7.47 (d, 2H), 7.41 (ddd, 1H), 3.58 (s, 2H), 2.60-2.43 (m, 8H), 2.32 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]Cl.[C-]#N.[Na+].[CH3:18][N:19](C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:18]#[N:19])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: CN(C)C=O
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1cc(CC#N)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
3,4,5-trimethoxy benzyl chloride 7.0 g and sodium cyanide 6.3 g were dissolved into 50 ml of N,N-dimethylformamide and they were then stirred at 80° C. for 45 minutes. The temperature of the reactive liquid was then lowered down to the room temperature, 200 ml of water was added thereto and then extraction was made thrice by means of 100 ml of ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=2[C:9]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:35][CH2:36][C:37](Cl)=[O:38]>O1CCCC1>[Cl:35][CH2:36][C:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=2[C:9]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:38]
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3N)c(C3CCCCC3)c2s1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cc2[nH]c(-c3ccccc3NC(=O)CCl)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of methyl 5-(2-aminophenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate obtained in Step 9, sodium acetate (2.4 g, 29 mmol) and acetic acid (1.7 ml, 29 mmol) in tetrahydrofuran (70 ml) was added chloroacetyl chloride (2.3 ml, 29 mmol) under ice-cooling. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. Water (100 ml) was added to the obtained solid. The solid was collected by filtration, washed with diethyl ether (20 ml×2), and dried under reduced pressure to give methyl 5-[2-(2-chloroacetylamino)phenyl]-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (5 g, yield after 2 steps from Step 9: 58%).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH:25]([CH3:27])[CH3:26])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH:25]([C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)([CH3:27])[CH3:26]
Reactant: CC(C)c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 111.5 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 1.07 g, 26.8 mmol) in dry DMF (20 mL) at room temperature under nitrogen, Intermediate 5b (1.89 g, 11.6 mmol) was added portionwise over 2 min, and the resulting brown solution was stirred for 20 min. Intermediate 1f (1.60 g, 8.93 mmol) was added, and the solution stirred at 60° C. for 2 h. The dark brown solution was cooled to room temperature and concentrated under vacuum. The residue was purified by SCX-2, washing with MeOH (200 mL) and eluting with 2M NH3 in MeOH, to leave a dark brown foam (3.21 g). Further purification by FCC, using 2-10% [2M NH3 in MeOH] in DCM, gave a brown foam (2.11 g, 76%). 1H NMR (400 MHz, d6-DMSO): 1.37 (3H, d), 1.39 (3H, d), 1.59 (1H, m), 1.91 (1H, m), 2.11 (1H, m), 2.33 (1H, m), 3.58 (1H, sept), 3.96 (1H, dd), 5.55 (1H, dd), 7.18-7.37 (4H, m), 7.51 (1H, d), 7.68 (1H, d), 8.20 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]=[C:42]=[O:43]>ClCCl>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42]([N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13]1)=[O:43]
Reactant: COc1ccccc1N=C=O
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 2-methoxyphenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 mins. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (2-methoxy-phenyl)-amide as a white solid. (Yield 45 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:3]=1[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][N:6]=1.[Se](=O)=[O:31]>C(OCC)(=O)C>[CH2:22]([O:21][C:19]([C:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2)[C:5]([C:4](=[O:31])[C:3]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:2]=2[F:1])=[N:6][CH:7]=1)=[O:20])[CH3:23]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cnc(Cc2cc(OC)ccc2F)c2cc(OC)c(OC)cc12
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(C(=O)c2cc(OC)ccc2F)c2cc(OC)c(OC)cc12

Procedure:
The above 1-(2-fluoro-5-methoxybenzyl)-4-ethoxycarbonyl-6,7-dimethoxyisoquinoline was dissolved in ethyl acetate (25 ml) and selenium dioxide was added (723 mg). The mixture was refluxed for 1 hr until all starting material was consumed. The solution was filtered through a layer of Celite and the filtrate was concentrated. The residue was purified through a flash column chromatography using hexane and ethyl acetate (3/1 ratio) to give 1-(2-fluoro-5-methoxybenzoyl-6,7-dimethoxyisoquinoline-4-caboxylic acid ethyl ester (1.28 g). This ester (200 mg, 0.48 mmol) was suspended in 10 ml of methanol and 1N sodium hydroxide solution (2.0 ml) was added. The mixture was refluxed for 30 minutes and the solution was loaded to a preparative HPLC for purification to give 1-(2-Fluoro-5-methoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (138 mg). ES-MS calcd for C20H16FNO6 (m/e) 385.36, obsd 386.2 (M+H).
Reaction SMILES: C([BH3-])#N.[NH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(O)(=O)C.O=[CH:15][CH2:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[N:21]=[C:20]([C:34]#[N:35])[N:19]=1>C(#N)C>[N:4]1([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[N:21]=[C:20]([C:34]#[N:35])[N:19]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C1CCNCC1
Reactant: N#Cc1nc(CCC=O)cc(-c2cccc(C(F)(F)F)c2)n1
Agent: [BH3-]C#N
Solvent: CC#N
Solvent: CC(=O)O
Product: N#Cc1nc(CCCN2CCCCC2)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 150 °C

Procedure:
To a suspension of macroporous cyanoborohydride (102 mg, 2.35 mmol/g) in acetonitrile (0.5 mL), was added piperidine (19 μL), acetic acid (0.1 mL), and a solution of 4-(3-oxo-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (49 mg) in acetonitrile (0.5 mL). The mixture was heated in the microwave at 150° C. for 10 min, filtered in a fritted tube using a Vacmaster multi-filtration apparatus, and purified by preparative-HPLC. 4-(3-Piperidin-1-yl-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile was isolated as a clear gum (12 mg).
Reaction SMILES: [H][H].[ClH:3].[N+:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[OH:16])([O-])=O>[Pd].[Rh]>[ClH:3].[NH2:4][C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[OH:16]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: [Rh]
Agent: Cl
Product: Nc1ccc(O)c(N)c1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
Onto the bottom of a cylindrical reactor there is placed a chamber made of a foil with the thickness of 100 mcm and the working surface area of 50 cm2. The foil is made of an alloy consisting of 98% by mass of palladium and 2% by mass of rhodium. Commercial hydrogen comprising a mixture of hydrogen with nitrogen (at the volume ratio therebetween of 1:1). Under the pressure of 10 atm is continuously supplied at the rate of 60 ml/min into the chamber. Outside the chamber into the reactor there are charged 300 ml of a 30% aqueous solution of hydrochloric acid and 120 g of 2,4-dinitrophenol. The reactor is heated to the temperature of 110° C. and the pressure therein is increased to 10 atm. Under these conditions the process of hydrogenation is conducted under stirring for 5 hours. After cooling and precipitation with a 37% hydrochloric acid there are obtained 116.9 g of 2,4-diaminophenol hydrochloride which corresponds to 91% based on the starting 2,4-dinitrophenol.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]3[CH2:42][O:41][CH2:40]3)=[CH:34][CH:33]=2)=[CH:11][C:12](=[O:31])[N:13]([CH2:15][CH2:16][C@@:17]([S:27]([CH3:30])(=[O:29])=[O:28])([NH:19][O:20]C2CCCCO2)[CH3:18])[CH:14]=1>C(Cl)Cl>[F:8][C:9]1[C:10]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH:39]3[CH2:40][O:41][CH2:42]3)=[CH:34][CH:33]=2)=[CH:11][C:12](=[O:31])[N:13]([CH2:15][CH2:16][C@:17]([NH:19][OH:20])([S:27]([CH3:30])(=[O:29])=[O:28])[CH3:18])[CH:14]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(OC3COC3)cc2)cc1=O)(NOC1CCCCO1)S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@](CCn1cc(F)c(-c2ccc(OC3COC3)cc2)cc1=O)(NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of 5-fluoro-1-{(3R)-3-(methylsulfonyl)-3-[(tetrahydro-2H-pyran-2-yloxy)amino]butyl}-4-[4-(oxetan-3-yloxy)phenyl]pyridin-2(1H)-one (164 mg, 0.304 mmol) in DCM (10 mL). The reaction was allowed to stir at rt overnight and then concentrated under vacuum. The residue was re-dissolved in dichloromethane and n-heptane and concentrated again to afford the title compound as a solid. (113 mg, 82%). MS (LCMS) m/z 455.1 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69 (s, 3 H) 2.35 (ddd, J=13.66, 10.63, 5.17 Hz, 1 H) 2.53-2.67 (m, 1 H) 3.09 (s, 3 H) 3.91 (ddd, J=12.98, 10.63, 5.27 Hz, 1 H) 4.16-4.30 (m, 1 H) 4.69 (dd, J=7.51, 4.78 Hz, 2 H) 5.02 (t, J=6.73 Hz, 2 H) 5.33 (t, J=5.46 Hz, 1 H) 6.58 (d, J=7.42 Hz, 1 H) 6.85-6.91 (m, 2 H) 7.55 (dd, J=8.68, 1.85 Hz, 2 H) 7.80 (d, J=6.24 Hz, 1 H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2=[N:24][CH:25]=[CH:26][N:16]2[N:15]=1>CN(C)C=O>[CH3:11][C:5]([CH3:12])([CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])[CH2:4][O:3][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2=[N:24][CH:25]=[CH:26][N:16]2[N:15]=1
Reactant: CC(C)(CO)CS(N)(=O)=O
Reactant: Clc1nn2ccnc2c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(COc1nn2ccnc2c2ccccc12)CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
0.293 g of 60% oily sodium hydride was suspended in 10 ml of dimethylformamide. To this suspension, 0.577 g of 3-hydroxy-2,2-dimethyl -1-propanesulfonamide was added, followed by stirring at room temperature (15° to 20° C.) under reduced pressure for 30 minutes. To this mixture was added 0.703 g of 6-chloroimidazo[2,1-a]phthalazine, followed by stirring at room temperature for 3 hours. After dimethylformamide was distilled off under reduced pressure, ice water was added to the residue, which was subsequently adjusted to pH 5.0 by the addition of 5 N hydrochloric acid and then extracted with ethyl acetate-tetrahydrofuran (1:1). The extract was washed with 20 ml of saturated saline and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (20:20:1). The fraction containing the desired product was concentrated and ethyl ether was added to separate a crystal, which was collected by filtration, to yield 0.769 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH:6]=[CH:5][CH2:4][O:3]1.ClC1C=C(C=CC=1)C(OO)=[O:14]>ClCCl>[CH3:1][C:2]1([CH3:8])[CH2:7][CH:6]2[CH:5]([O:14]2)[CH2:4][O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC=CCO1
Solvent: ClCCl
Product: CC1(C)CC2OC2CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
To a solution of 2,2-dimethyl-3,6-dihydro-2H-pyran (4.0 g, 36 mmol) in dichloromethane (20 mL) was added 3-chloroperoxybenzoic acid (18.4 g, 107 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane, and washed with saturated aqueous sodium sulfite and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (5.0 g, crude) as a yellow oil, which was directly used in the next step without further purification.