Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[NH2:16][C@H:17]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C@@H:18]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=1)[CH2:19][CH2:20][C:21]([OH:23])=O.[CH3:39][C:40]([CH3:42])=O.ClC(Cl)C>CN(C=O)C>[Cl:31][C:26]1[CH:25]=[C:24]([C@@H:18]2[C@@H:17]([C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[N:16]([CH:40]([CH3:42])[CH3:39])[C:21](=[O:23])[CH2:20][CH2:19]2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CC(C)=O
Reactant: N[C@H](c1ccc(Cl)cc1)[C@H](CCC(=O)O)c1ccc(F)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: CC(C)N1C(=O)CC[C@H](c2ccc(F)c(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (1.796 g, 8.48 mmol) was added to a solution of (4R,5S)-5-amino-4-(3-chloro-4-fluorophenyl)-5-(4-chlorophenyl)pentanoic acid hydrochloride (2.56 g, 6.52 mmol; Example 390, Step B) and acetone (0.491 mL, 6.68 mmol) in anhydrous DMF (6.52 mL) at rt. The reaction mixture was stirred at rt for 16 hours. Dichloroethane (25 mL) was added followed by 3 Å molecular sieves. The reaction mixture was heated to 70° C. for 22 hours, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using a 220 g column and eluting with 30 to 100% EtOAc/hexanes provided the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([N:15]([CH2:24][CH3:25])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[CH3:14]>[N+](C1C=CC=CC=1)([O-])=O>[CH2:13]([N:15]([C:16]1[CH:17]=[CH:18][C:19]([C:20]2[NH:12][C:11]3[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=3[N:1]=2)=[CH:22][CH:23]=1)[CH2:24][CH3:25])[CH3:14]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCN(CC)c1ccc(-c2nc3cc(C(=O)OC)ccc3[nH]2)cc1
Temperature: 145 °C
Yield: 81.9 %

Procedure:
Methyl 3,4-diaminobenzoate (0.73 g, 4.42 mmol), 4-(diethylamino)benzaldehyde (3.0 g, 16.9 mmol) were dissolved in nitrobenzene (30 mL) and refluxed on a 145° C. oil bath overnight. The nitrobenzene was then removed in vacuo using a Kugelrohr apparatus (60° C., 0.1 mm Hg). The remaining oily residue was dissolved in CHCl3 and washed with water (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude oil was then purified through colurnn chromatography using a solvent system of 1% MeOH/CHCl3 to give methyl 2-(4-(N,N-diethyl)aminophenyl)benzimidazole-6-carboxylate as a yellowish solid (1.17 g, 82% yield). TLC (2.5% MeOH/CHCl3) Rf=0.26; 1H-NMR (500 MHz, CDCl3) 9.87 (s br, 1H), 8.30 (s br, 1H), 7.94 (dd, 1.5, 8.5, 1H), 7.91 (d, 8.5, 2H), 7.60 (s br, 1H), 6.72 (d, 8.5, 2H), 3.42 (q, 7.0, 4H), 1.21 (t, 7.0, 6H); IR (neat) 3508, 2063, 2920, 1712, 1611, 1504, 1434, 1360, 1307, 1269, 1205, 1157, 1082, 1008, 821, 751.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:7]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[C:8]2[C:17]3[CH:16]=[CH:15][C:14]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:26])[C:9]=2[N:27]=1)(=O)C.[OH-].[Na+]>CO>[NH2:26][C:10]1[C:9]2[N:27]=[C:6]([CH2:5][OH:4])[N:7]([CH2:28][C:29]([CH3:31])([OH:32])[CH3:30])[C:8]=2[C:17]2[CH:16]=[CH:15][C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][C:12]=2[N:11]=1
Reactant: CC(=O)OCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(OCc4ccccc4)ccc3c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of [4-amino-7-benzyloxy-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate (34.0 g, 0.0782 mol) in methanol (150 mL) was heated at reflux, and a solution of aqueous sodium hydroxide (50 mL of 1.7 M) was added, over a period of five minutes. A white precipitate formed, and the reaction was heated at reflux for one hour. The reaction mixture was allowed to cool to room temperature and stirred for about three hours. The precipitate was isolated by filtration, washed with deionized water and methanol, and then dried under vacuum at 50° C. to provide 24.9 g of the crude product. The crude product (6.0 g) was recrystallized from a mixture of 2-propanol:acetic acid 9:1 (470 mL); the hot solution was treated with activated charcoal and filtered through a layer of CELITE filter aid. The crystals were isolated by filtration, washed with a small volume of 2-propanol:acetic acid, and dried under vacuum at 50° C. The product was stirred with aqueous sodium hydroxide (200 mL of 0.15 M) for three hours, isolated by filtration, washed with deionized water, stirred with methanol (100 mL) for one hour, isolated by filtration, washed with methanol, and dried under vacuum at 60° C. Finally, the product (4.5 g) was recrystallized from DMF, isolated by filtration, and dried under vacuum to provide 1-[4-amino-7-benzyloxy-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 284.5-285.5° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:28][CH3:29])[CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:39][C:40]1[C:59]([F:60])=[CH:58][CH:57]=[CH:56][C:41]=1[CH2:42][NH:43][C:44](=[O:55])OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:28]([CH3:29])[C:44]([NH:43][CH2:42][C:41]1[CH:56]=[CH:57][CH:58]=[C:59]([F:60])[C:40]=1[Cl:39])=[O:55])[CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of (S)-tert-butyl 4-(5-(tert-butyldimethylsilyloxy)-4-(methylamino)pentanoyl)piperazine-1-carboxylate (16 g, 37.3 mmol) and DIEA (1.3 mL, 7.46 mmol) in THF (180 mL) was added 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (12 g, 37.3 mmol). The reaction mixture was stirred at RT for 2 h and concentrated. The residue was purified on silica gel using a mixture of EtOAc and hexanes to give (S)-tert-butyl 4-(5-(tert-butyldimethylsilyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoyl)piperazine-1-carboxylate (14.3 g, 62.4% for three steps). LRMS (M+H) m/z 615.3.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(=O)OC)c1ccc(O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1ccc(O)c(Cl)c1
Yield: 97.9 %

Procedure:
Methyl 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetate (syn isomer) (2.6 g.) and a 2N aqueous solution of sodium hydroxide (10.6 ml.) were treated according to a similar manner to that of Preparation (5-3) (c) to give 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.4 g.), mp 147° to 150° C. (dec.).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][N:30]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH:31]1[CH2:35][CH2:34][O:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:29][N:30]([CH:31]1[CH2:35][CH2:34][O:33][CH2:32]1)[CH:36]1[CH2:37][CH2:38][N:39]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:6]=[C:5]([N:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]2[CH3:28])[N:4]=3)[CH2:40][CH2:41]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CN(C1CCNCC1)C1CCOC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N(C)C4CCOC4)CC3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (72 mg, 0.19 mmol), methylpiperidin-4-yl(tetrahydrofuran-3-yl)amine (42 mg, 0.23 mmol) and 4 Å powdered molecular sieves (200 mg) in DCE (5 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (81 mg, 0.38 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 389 as a white solid (55 mg, 53%). LCMS (Method G): RT 4.96 min [M+H]+ 546.3. 1H NMR (CDCl3, 400 MHz): δ 8.11-8.07 (m, 1 H); 7.73-7.69 (m, 1 H); 7.29-7.24 (m, 2 H); 4.35 (m, 4 H); 3.96 (m, 1 H); 3.92-3.80 (m, 8 H); 3.83-3.71 (m, 4 H); 3.43 (m, 1 H); 3.02-2.90 (m, 4 H); 2.52 (m, 1 H); 2.26 (s, 3 H); 2.16 (m, 2 H); 2.03 (m, 1 H); 1.90 (m, 1 H); 1.77 (s, 3 H) and 1.59 (m, 2 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][N:6]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[N:9]2[CH:22]=[C:23]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[N:27]([S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)(=[O:36])=[O:35])[CH:26]=3)[CH:24]=[C:8]2[C:7]1=[O:43]>C(Cl)Cl.CO.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:10]2[N:9]3[CH:22]=[C:23]([C:25]4[C:33]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[N:27]([S:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)(=[O:35])=[O:36])[CH:26]=4)[CH:24]=[C:8]3[C:7](=[O:43])[N:6]([CH2:5][C:4]3[CH:44]=[CH:45][C:46]([O:48][CH3:49])=[CH:47][C:3]=3[O:2][CH3:1])[CH:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(Cn2cc(Cc3ccc([N+](=O)[O-])cc3)n3cc(-c4cn(S(=O)(=O)c5ccccc5)c5ncccc45)cc3c2=O)c(OC)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Cn2cc(Cc3ccc(N)cc3)n3cc(-c4cn(S(=O)(=O)c5ccccc5)c5ncccc45)cc3c2=O)c(OC)c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 23H (6 g, 8.89 mmol) in a mixture of CH2Cl2 (400 mL) and CH3OH (50 mL) was added 10% Pd/C (0.8 g) under nitrogen. The reaction mixture was purged with H2, and stirred under hydrogen (40 psi) overnight. The solid material was filtered off, and the filtrate was concentrated to afford the title compound. LC-MS (ESI): m/z 646 (M+H), RT: 1.87 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](C=O)=[CH:7][CH:8]=1.CO[CH:13]([O:16][CH3:17])[O:14][CH3:15].Cl.[OH-].[K+]>CO>[CH3:17][O:16][CH:13]([O:14][CH3:15])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COC(OC)OC
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(OC)OC)cc1
Temperature: 12.5 °C
Reaction time: 17 h
Yield: 95.2 %

Procedure:
Anisaldehyde (40 g) and trimethylorthoformate (48.25 ml) were added to MeOH (60 ml) at 20-25° C. and the mixture was cooled to 10-15° C. Conc. HCl (0.26 ml) was then added to the mixture at 10-15° C. and was warmed to 20-25° C. followed by stirring at the same temperature for 16-18 hours. 5% aqueous KOH (40 ml) was added to the reaction mixture at 20-25° C. in 10 min and further stirred for 10 minutes. The reaction mixture was extracted with hexane (2×200 ml) and the combined organic layer was washed with DM water (200 ml). The organic layer was concentrated below 40° C. to obtain title compound (51.0 g, 95.2%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=O)=O)=CC=1.[Br-:29].[Li+]>CC(C)=O.CCOCC>[Br:29][CH2:12][CH2:13][CH:14]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC(c2ccc(F)cc2)c2ccc(F)cc2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: Fc1ccc(C(CCBr)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3,3-bis(4-fluorophenyl)propyl 4-methylbenzenesulfonate, prepared in the previous step, in acetone (100 mL) was added lithium bromide (17.83 g, 205 mmol). The reaction mixture was stirred at room temperature for 17 h, and concentrated. The crude reaction mixture was diluted with Et2O, washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 0% to 20% EtOAc in hexanes) gave 3-bromo-1,1-bis(4-fluorophenyl)propane.
Reaction SMILES: C([C:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][N:6]2[CH2:15][CH2:16][CH2:17][C:5]=12)(O)=O.[Br:18]N1C(=O)CCC1=O>CC(N(C)C)=O.CCOC(C)=O>[Br:18][C:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][N:6]2[CH2:15][CH2:16][CH2:17][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1c(-c2ccccc2)nn2c1CCC2
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Brc1c(-c2ccccc2)nn2c1CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-carboxy-2-phenyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (820 mg, 3.59 mmol) in dry DMA (15 mL) previously degassed add N-bromosuccinimide (NBS) (702.8 mg, 3.95 mmol) and stir at room temperature for 18 hours. Then, dilute with EtOAc (80 mL) and wash with cooled water (5×10 mL). Dry the organic phase (MgSO4), and concentrate in vacuo to obtain a yellow solid, 1.0 g. MS(ES+): m/z=263.0 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:9][O:8][C:5]1[C:4]([O:10][CH3:11])=[CH:3][C:2]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(Br)cnc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1cc(C#C[Si](C)(C)C)cnc1OC
Reaction time: 16 h
Yield: 70.6 %

Procedure:
Copper (I) iodide (0.56 g, 2.9 mmol), bis(triphenylphosphine)palladium(II) dichloride (2.1 g, 2.9 mmol), and 5-bromo-2,3-dimethoxypyridine (12.8 g, 59 mmol) were added to triethylamine (80 ml) which produced a yellow suspension. The reaction was thoroughly degassed and ethynyltrimethylsilane (5.8 g, 59 mmol) was added to the stirred suspension which was then stirred for 16 hours and concentrated. The crude material was purified by column chromatography (SiO2; 0-10% ethyl acetate in petrol) to afford 2,3-dimethoxy-5-[(trimethylsilyl)ethynyl]pyridine (9.8 g, 71%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([NH2:21])=[O:20])[CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([NH2:21])=[O:20])[CH2:14]1
Reactant: NC(=O)C1CCCNC1
Reactant: BrCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)C1CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (0.2 g, 0.87 mmol) and piperidine-3-carboxylic acid amide (0.13 g, 1.05 mmol) in acetonitrile (20 ml) was added K2CO3 (0.60 g, 4.36 mmol) and KI (0.72 g, 4.36 mmol). The reaction mixture was refluxed for 2 h. Water (100 ml) was then added. The reaction mixture was extracted with EtOAc (3×5 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (EtOAc/heptane, 50:50).
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[N:6](CC3C=CC(OC)=CC=3)[C:7](=[O:32])[CH:8]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[N:9]=[C:10]([N:11]3[CH2:20][CH2:19][C:14]4(OCC[O:15]4)[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.Cl>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[NH:6][C:7](=[O:32])[CH:8]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[N:9]=[C:10]([N:11]3[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccc4ccccc4c3)N=C(N3CCC4(CC3)OCCO4)c3cc(Cl)ccc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1CCN(C2=NC(Cc3ccc4ccccc4c3)C(=O)Nc3ccc(Cl)cc32)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 21.2 %

Procedure:
7-Chloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.14 g, 0.24 mmol) was dissolved in 1,4-dioxane (4 mL), and concentrated aqueous hydrochloric acid (4 mL) was added. The reaction mixture was stirred at 60° C. for 5 hours, then the temperature increased to 80° C. for 2 hours. The solution was cooled, diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, brine, dried with sodium sulfate, decanted and concentrated in the presence of silica. Chromatography provided 7-chloro-3-(naphthalen-2-ylmethyl)-5-(4-oxopiperidin-1-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (22 mg, 22% yield). ESI m/z measured 432.1487 [M+H]+. calculated 432.1479.
Reaction SMILES: [CH3:1][C:2]([OH:9])([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]#[CH:4].Br[C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:14]=[CH:15][CH:16]=1.CN(C=O)C>C(N(CC)CC)C>[F:23][C:22]([F:24])([F:25])[C:21]([NH:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:4]#[C:3][C:2]([OH:9])([CH3:1])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:12]=1)=[O:26]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(C)(O)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(C)(O)C#Cc1cccc(CCCNC(=O)C(F)(F)F)c1

Procedure:
Coupling of 3,4,4-trimethylpent-1-yn-3-ol with bromide 3 in a 1:1 mixture of DMF and triethylamine gave 2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3,4,4-trimethylpent-1-ynyl)phenyl)propyl)acetamide as an orange oil. Yield (0.84 g, 73%): 1H NMR (400 MHz, CD3OD) δ 7.15-7.25 (m, 4H), 3.29 (t, J=7.2 Hz, 2H), 2.61 (t, J=8.0 Hz, 2H), 1.86 (quint, J=7.6 Hz, 2H), 1.49 (s, 3H), 1.09 (br s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:21][C:22]([OH:24])=[O:23].N1CCCCC1.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:21][C:22]([OH:24])=[O:23]
Reactant: COc1ccccc1Sc1ccc(C=O)c(Cl)c1Cl
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccccc1Sc1ccc(C=CC(=O)O)c(Cl)c1Cl
Yield: 75.3 %

Procedure:
A mixture of 2,3-dichloro-4-(2-methoxyphenylthio)-benzaldehyde (2.03 g), 1.44 g malonic acid, 5 mL pyridine, and 0.100 g piperidine was heated to 115 degrees for 1.5 hours. The mixture was cooled, and ice and HCl were added. The resulting solid was: filtered, washed with water and dissolved in tetrahydrofuran. This solution was dried over sodium sulfate, the solvent removed and ether added to give 1.733 g of product, m.p. 187-188 C.
Reaction SMILES: [CH3:1][O:2][C:3]1N=[C:7]2[C:9]([C:13]3[N:24]([S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=[N:22]O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:35][CH3:36].[CH:37](O)=O>C(O)C.O.[Zn]>[O:2]([C:3]1[CH:37]=[C:7]2[C:6](=[CH:5][C:4]=1[O:35][CH3:36])[N:11]([CH3:12])[CH:10]=[C:9]2[C:13]1[N:24]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:26])=[O:27])[C:16]2=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH2:22])=[C:15]2[CH:14]=1)[CH3:1]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=NO)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: O=CO
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: COc1cc2c(-c3cc4c(CN)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Reaction time: 24 h

Procedure:
To a solution of 0.56 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde oxime in 30 cm3 of ethanol and 25 cm3 of water, at a temperature in the region of 20° C., is added 0.216 g of zinc and 12 cm3 of concentrated formic acid. A further 0.216 g of zinc is added and the mixture is stirred for a further 24 hours. The reaction medium is stirred at this same temperature for 24 hours. The reaction medium is filtered through Celite and the filtrate is concentrated under reduced pressure. The residue obtained is purified by flash-pack chromatography (SiO2, dichloromethane/methanol 95/05, then dichloromethane/methanol/triethylamine 100/10/1, then dichloromethane/methanol/28% aqueous ammonia 100/10/2 by volume as eluents, Ar). The residue obtained is again purified by flash-pack chromatography (SiO2, dichloromethane/methanol/28% aqueous ammonia 460/40/1.5 by volume as eluents, Ar). 0.03 g of [2-(5,6-dimethoxy1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]methylamine is obtained with the following characteristics:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[Na+].[Na+].[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>COCCOC.O>[N:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])=[CH:17][CH:16]=1
Reactant: OB(O)c1ccncc1
Reactant: Nc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1cccc(-c2ccncc2)c1
Yield: 93.5 %

Procedure:
3-Bromoaniline (0.24 ml, 2.2 mmol) and sodium carbonate (0.70 g, 6.6 mmol) were suspended in a mixture of 1,2-dimethoxyethane (16 ml) and water (4 ml). The reaction mixture was then treated with 4-pyridyl boronic acid (0.27 g, 2.2 mmol), and flushed with Argon. Tetrakis (triphenylphosphine)-palladium (0) (0.35 g) was then added, and the mixture was heated to reflux under Argon for 24 hours. The reaction mixture was allowed to cool after which it was partitioned between dichloromethane and water. The aqueous layer was again extracted with dichloromethane. The combined extracts were then dried (Na2SO4) and concentrated in vacuo to afford a pale yellow solid (0.35 g). This was chromatographed on silica gel eluting with ethyl acetate to afford the title compound as a white solid (0.15 g, 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([CH2:14][OH:15])[CH:10]=1.C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([CH:14]=[O:15])[CH:10]=1
Reactant: OCc1c[nH]c(-c2c(F)cccc2F)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1c[nH]c(-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution (26 mL) of [5-(2,6-difluorophenyl)-1H-pyrrol-3-yl]methanol (2.56 g) in acetonitrile were added tetra-n-propylammonium perruthenate (430 mg), N-methylmorpholine N-oxide (2.15 g) and molecular sieves 4 A powder (5 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (60 mL) and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as pale-red crystals (yield 1.94 g, 77%).