Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[Cl:12][C:13]1[CH:14]=[C:15]([N:24]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[N:25]2)[CH:16]=[CH:17][C:18]=1[CH:19]=[CH:20][N+:21]([O-])=O.Cl>O1CCCC1.O>[ClH:12].[Cl:12][C:13]1[CH:14]=[C:15]([N:24]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[N:25]2)[CH:16]=[CH:17][C:18]=1[CH2:19][CH2:20][NH2:21]
Reactant: O=[N+]([O-])C=Cc1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: NCCc1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl
Temperature: 25 °C

Procedure:
To a cooled (0° C.) solution of sodium borohydride (238.6 mg, 6.28 mmol) in anhydrous tetrahydrofuran (8 mL) at 0° C. was added boron trifluoride diethyl etherate (1.13 g, 7.93 mmol) dropwise. The resultant solution was then stirred for 10 min at 0° C. and for 15 min at room temperature. A solution of 1-[3-chloro-4-(2-nitroethenyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole (i.e. the product of Step B; 420 mg, 1.32 mmol) in anhydrous tetrahydrofuran (5.2 mL) was added dropwise via cannula, and the resulting mixture was refluxed for 7.5 h and then allowed to cool to room temperature. Water (17 mL) was added dropwise, followed by 1 N hydrochloric acid (17 mL). The reaction mixture was concentrated under reduced pressure, and the residue was triturated with petroleum ether to afford the title compound (320 mg).
Reaction SMILES: [CH2:1](Br)[CH3:2].[C:4]([O:8][C:9](=[O:41])[N:10]([CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C:27]1[C:28]2[C:33]([CH:34]=[C:35]3[C:40]=1[CH:39]=[CH:38][CH:37]=[CH:36]3)=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:7])([CH3:6])[CH3:5].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:4]([O:8][C:9](=[O:41])[N:10]([CH2:22][CH2:23][CH2:24][N:25]([CH2:26][C:27]1[C:40]2[C:35]([CH:34]=[C:33]3[C:28]=1[CH:29]=[CH:30][CH:31]=[CH:32]3)=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:1][CH3:2])[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCBr
Reactant: CC(C)(C)OC(=O)NCCCN(CCCNCc1c2ccccc2cc2ccccc12)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc1c2ccccc2cc2ccccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Ethylbromide (EtBr, 508 mg, 4.66 mmol) was dissolved in anhydrous acetonitrile and added to a stirring mixture of compound 10 (805 mg, 1.55 mmol) and anhydrous K2CO3 (644 mg, 4.66 mmol). The mixture was then stirred overnight at 75° C. under a N2 atmosphere. After the confirmation of the disappearance of the 10 by TLC, the solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL) and washed three times with aqueous sodium carbonate. The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under vacuum. Flash column chromatography of the residue gave 11 as a light yellow oil. Yield 80%; Rf=0.35 (3% MeOH/CHCl3); 1H NMR (CDCl3) δ 8.43 (d, 2H), 8.25 (s, 1H), 7.86 (d, 2H), 7.43 (m, 2H), 7.37 (m, 2H), 4.34 (s, 2H), 2.78-2.92 (m, 4H), 2.64 (m, 4H), 2.36 (m, 2H), 1.21-1.48 (m, 23H), 1.16 (m, 2H); 13C NMR (CDCl3) δ 155.7, 131.1 (3C), 131.0, 128.7 (2C), 127.0 (2C), 125.2 (2C), 124.8 (2C), 124.5 (2C), 78.9, 78.4, 53.4, 50.6, 50.0, 47.9, 45.3, 43.5, 37.1, 28.3 (6C), 26.5, 11.7. HRMS (FAB) m/z calcd. for C33H47N3O4 (M+H)+ 550.3639, found 550.3619.
Reaction SMILES: Br[C:2]1([C:7]([NH:9][C:10]([NH2:12])=[O:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Na+].[C:14]([O:17][CH2:18][C:19]1[CH2:20][S:21][C@@H:22]2[C@H:29]([NH:30][C:31](=[O:40])/[C:32](/[C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)=[N:33]\[OH:34])[C:28](=[O:41])[N:23]2[C:24]=1[C:25]([O-:27])=[O:26])(=[O:16])[CH3:15].C([O-])(=O)C>CS(C)=O.CCO>[C:14]([O:17][CH2:18][C:19]1[CH2:20][S:21][C@@H:22]2[C@H:29]([NH:30][C:31](=[O:40])/[C:32](/[C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)=[N:33]\[O:34][C:2]3([C:7]([NH:9][C:10]([NH2:12])=[O:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]3)[C:28](=[O:41])[N:23]2[C:24]=1[C:25]([OH:27])=[O:26])(=[O:16])[CH3:15]
Reactant: NC(=O)NC(=O)C1(Br)CCCC1
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O)c3ccco3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC3(C(=O)NC(N)=O)CCCC3)c3ccco3)[C@H]2SC1
Yield: 85 %

Procedure:
This was prepared from 1-bromo-1-ureidocarbonylcyclopentane and (6R,7R)-3-acetoxymethyl-7-[Z-2-(fur-2-yl)-2-hydroxyiminoacetamido]-ceph-3-em-4-carboxylic acid sodium salt, in a similar manner to Example 2. [α]D22 +95° (c 0.55, DMSO), λmax (EtOH) 275 nm (ε16,500), νmax (Nujol) 3420, 3300 (NH, NH2), 3700-2100 (bonded OH), 1788 (β-lactam), 1735 (acetate), 1710, 1690, 1565, 1550 cm-1 (CONH, CONHCONH2), τ (DMSO d6) 7.92 (OAc), 4.95, 5.28 (dd J 13) (3 --CH2), 6.23, 6.49 (dd, J 18) (2 --CH2), 4.71 (d, J=5) (6 H), 4.09 (dd J=5, 8) (7 H), 0.02 (d, J=8) (CONH), 2.11, 3.19, 3.32 (furyl), 7.9-8.3 (cyclopentyl), 0.65 (CONHCO), 2.17, 2.64 (CONH2). Yield: 85%.
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([C:8](=O)[CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH2:6]2
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3cccs3)CC21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCc3cccs3)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a solution of N-(3-{6-methyl-3-[3-(2-thienyl)propanoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide (Preparation 125, 200 mg, 0.49 mmol) in anhydrous tetrahydrofuran (7.5 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.99 ml, 0.99 mmol) and the mixture was stirred at room temperature for 2 h. The rapidly stirred reaction mixture was treated sequentially with water (1.0 ml), sodium hydrogen carbonate (1.0 g) and ethyl acetate (25 ml). After 15 min the reaction mixture was filtered and concentrated in vacuo to afford a light yellow oil. This was purified by chromatography using a Biotage Flash 12™ cartridge packed with silica gel (8 g) eluting with hexane: ethyl acetate (100:0 to 0:100) to afford the title compound as a colourless oil (135 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[O:5][C:6]1[C:7]([N+:20]([O-])=O)=[C:8]([CH:10]=[C:11]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=1)[NH2:9].[H][H]>[OH-].[Pd+2].[OH-].[C].CO>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[O:5][C:6]1[CH:12]=[C:11]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=[C:8]([NH2:9])[C:7]=1[NH2:20]
Reactant: COc1ccccc1Oc1cc(Oc2cccnc2)cc(N)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1Oc1cc(Oc2cccnc2)cc(N)c1N

Procedure:
1 g of 20% palladium hydroxide-carbon catalyst was added to a methanol (20 ml) solution of 1.33 g of 3-(2-methoxyphenoxy)-2-nitro-5-(pyridin-3-yloxy)-aniline, and the reaction liquid was stirred for 4 hours in a hydrogen atmosphere. The catalyst was removed through filtration, the solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/2 to ethyl acetate) to obtain the entitled compound as a pale orange oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:22][C:23]([OH:25])=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][CH2:27][N:28]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(N)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:22][C:23](=[O:25])[NH:28][CH2:27][CH3:26])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N(CC(=O)O)Cc2ccc(Cl)cc2)C1
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCNC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
To a solution of 3-[carboxymethyl-(4-chloro-benzyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.48 g, 1.30 mmol) in tetrahydrofuran (10 mL) was added EDCI (0.39 g, 1.95 mmol), HOBT (0.26 g, 1.95 mmol), and stirred for 30 min., followed by the addition of N-methyl morpholine (0.43 mL, 3.90 mmol) and N-ethyl amine (0.1 mL, 1.95 mmol). The reaction mixture was stirred at room temperature for 18 h. Upon concentration, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (50%) to ethyl acetate (100%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>C(O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[C:3]([CH:6]=1)[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)c1ccc([N+](=O)[O-])cc1C#N
Reaction time: 1 h
Yield: 86.6 %

Procedure:
2-Chloro-5-nitrobenzonitrile (15 g) and diethylamine (15 g) were added to ethanol (100 ml) and the mixture was stirred at a refluxing temperature for 1 h. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous ethanol to give 5-nitro-2-diethylaminobenzonitrile (15.6 g), melting point: 98° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([I:9])=[CH:7][C:6]([C:10](=[O:16])[CH2:11][NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:5][C:4]=1[F:17].[BH4-].[Na+]>>[NH2:2][C:3]1[C:8]([I:9])=[CH:7][C:6]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]2[CH2:15][CH2:14]2)=[CH:5][C:4]=1[F:17]
Reactant: Nc1c(F)cc(C(=O)CNC2CC2)cc1I
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Nc1c(F)cc(C(O)CNC2CC2)cc1I

Procedure:
m.p. of the hydrochloride: 199°-201° C. (decomp.), was prepared from 4'-amino-2-cyclopropylamino-3'-fluoro-5'-iodo-acetophenone and sodium borohydride analogous to Example 49.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].O.[NH2:18][C:19]1[N:28]=[C:27]([C:29]([N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32]2)=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[N:20]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:18][C:19]1[N:28]=[C:27]([C:29]([N:31]2[CH2:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:39]2)=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:2]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=3[CH:4]=[O:5])[CH:25]=2)[N:20]=1
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Reactant: O=Cc1cc(O)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccc(O)cc3C=O)ccc2n1
Temperature: 120 °C

Procedure:
72 mg of 2-bromo-5-hydroxybenzaldehyde, 100 mg of potassium carbonate, 1 ml of water and 15 mg of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added to a solution of 150 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 3 ml of ethanol under argon. The mixture is heated at 120° C. for min; the hot mixture is filtered through kieselguhr, and the filtrate is evaporated. The residue obtained was triturated with 2 ml of acetonitrile, and the precipitate formed was filtered off with suction. Yield: 56 mg (38%) of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-5-hydroxybenzaldehyde; HPLC retention time: 1.67 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N)(=O)C>C(O)(=O)C>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)cc1OC
Agent: CC(N)=O
Solvent: CC(=O)O
Product: COc1ccc(NC(C)=O)cc1OC
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
In general, the reaction schemes 1 and 2 shown above, may be applied to this specific synthetic sequence. Beginning with Scheme 2, 10 grams (65.28 mmoles) of 4-amino veratrole (Scheme 2, structure VII, a.k.a. 3,4-dimethoxyaniline, Aldrich Chemical Co.) was dissolved in 20 grams of glacial acetic acid in a 100 mL round bottomed flask. To the flask was added 22 grams of ice followed by the dropwise addition of 1.1 equivalents of acetic anhydride (7.3 grams, Aldrich Chemical Co.) with stirring via an addition funnel over a 30 minute time interval. The reaction to make the acetamide intermediate of 4-aminoveratrole occurred with the evolution of heat after which the reaction flask was placed into a water bath and heated for an hour at 55° C. The stirring was continued overnight. The 4-acetamidoveratrole product was not isolated, but the next reaction step was continued by the addition of 5.9 grams of nitric acid in 8 mL of water and the reaction was cooled to 15° C. in an ice-water bath. As the nitration reaction preceded the purple colored reaction solution turned to a red-orange color. The reaction flask was cooled in a refrigerator overnight and a red-orange powder precipitated from the solution.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].[CH3:9][S:10][CH2:11]Cl.C(N(CC)CC)C>>[C:1]([O:8][CH2:9][S:10][CH3:11])(=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6]
Reactant: CSCCl
Reactant: CCCC=CC(=O)O
Solvent: CCN(CC)CC
Product: CCCC=CC(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting 2-hexenoic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 75°-76° C./2 mm Hg, nD20 1.4836.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]([CH3:28])[C:14]3[C:18]4[N:19]=[C:20]([CH2:24][CH2:25][CH3:26])[NH:21][C:22](=O)[C:17]=4[S:16][C:15]=3[N:27]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O=P(Cl)(Cl)[Cl:31]>>[Cl:31][C:22]1[C:17]2[S:16][C:15]3[N:27]=[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:12]=[C:13]([CH3:28])[C:14]=3[C:18]=2[N:19]=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1nc2c(sc3nc(-c4ccc(OC)c(OC)c4)cc(C)c32)c(=O)[nH]1
Product: CCCc1nc(Cl)c2sc3nc(-c4ccc(OC)c(OC)c4)cc(C)c3c2n1
Temperature: 0 °C
Yield: 100.1 %

Procedure:
0.57 g (1.4 mmol) 7-(3,4-dimethoxyphenyl)-9-methyl-2-propyl-pyrido[3′,2′:4,5]thieno-[3,2-d]pyrimidin-4-one is refluxed in 8 ml (86.4 mmol) phosphoroxychloride for 9 h. Then, the product is poured onto about 50 g ice water. The precipitate is sucked off, washed with about 250 ml water, suck dried and dried in vacuo at 50° C. 0.58 g (96%) 4-chloro-7-(3,4-dimethoxyphenyl)-9-methyl-2-propyl-pyrido[3′,2′:4,5]-thieno[3,2-d]pyrimidine is obtained.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C:16]2[C:24]3[C:19](=[C:20]([O:25][CH3:26])[N:21]=[CH:22][CH:23]=3)[N:18]([CH3:27])[CH:17]=2)=[CH:4][CH:3]=1>O1CCCC1.[Pd]>[F:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[C:16]2[C:24]3[C:19](=[C:20]([O:25][CH3:26])[N:21]=[CH:22][CH:23]=3)[N:18]([CH3:27])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: COc1nccc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3)cn(C)c12
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1nccc2c(-c3cc(N)ccc3Oc3ccc(F)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of Example 15A (167 mg, 0.425 mmol) in tetrahydrofuran (20 mL) was added to 10% palladium on carbon (34 mg, 0.319 mmol) in a 50 mL pressure bottle and stirred at ambient temperature under hydrogen at 30 psi for 1 hour. The solution was filtered through a syringe filter and concentrated to give the title compound (152 mg, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][O:26][CH2:27][CH3:28].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][CH2:25][O:26][CH2:27][CH3:28])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOCCBr
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1cc(C2CCN(C(=O)OCC)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
Under inert atmosphere, a solution of 12.5 g (0.045 mol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester in 50 ml of anhydrous DMF was added dropwise to a suspension containing 2.75 g (0.068 mol) of sodium hydride (60% in mineral oil) in 200 ml of anhydrous DMF. After stirring at room temperature for 1 hour, 6.6 ml (0.06 mol) of 1-bromo-2-ethoxyethane were added. The reaction mixture was heated at 60° C. for 3 hours. The crude mixture was poured into water and extracted with ethyl acetate. After drying, the solvent was removed under reduced pressure and 16 g of a crude oil were obtained and used in the next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18](O)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:19])[CH2:13][CH2:12]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NCC(=O)OCc2ccccc2)CC1
Yield: 83.2 %

Procedure:
A solution of [4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetic acid (Example 44, 0.300 g, 1.03 mmol), benzyl glycinate hydrochloride (0.250 g, 1.24 mmol), EDCI (0.238 g, 1.24 mmol), HOBt (0.168 g, 1.24 mmol) and triethylamine (201 μL, 1.44 mmol) in acetonitrile (10 mL) was stirred at room temperature for 2 days. The reaction mixture was poured into saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:10 to 50:50) to provide benzyl N-{[4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetyl}glycinate (0.375 g, 83%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][C@@H:20]1[CH2:25][NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>>[CH3:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])[C@@H:20]1[CH2:25][NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][N:28]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-c2cnccc2C)c(C(=O)O)c1
Product: Cc1ccc(-c2cnccc2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using 5-methyl-2-(4-methylpyridin-3-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 483 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:34]([NH2:36])=[O:35])=[N:4][C:5]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2S(C1C=CC=CC=1)(=O)=O.NC1C(C(OC)=O)=NC(C2C=CC=[C:65]([OH:69])C=2)=NC=1NC1C=CC=C2C=1C=CN2S(C1C=CC=CC=1)(=O)=O>N.CO>[OH:33][C:29]1[CH:28]=[C:27]([C:5]2[N:6]=[C:7]3[C:2]([NH:1][C:65](=[O:69])[N:8]3[C:9]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:10]=3[CH:11]=[CH:12][NH:13]4)=[C:3]([C:34]([NH2:36])=[O:35])[N:4]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: NC(=O)c1nc(-c2cccc(O)c2)nc(Nc2cccc3c2ccn3S(=O)(=O)c2ccccc2)c1N
Reactant: COC(=O)c1nc(-c2cccc(O)c2)nc(Nc2cccc3c2ccn3S(=O)(=O)c2ccccc2)c1N
Agent: N
Solvent: CO
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2-c1cccc2[nH]ccc12

Procedure:
5-Amino-2-(3-hydroxyphenyl)-6-(1-(phenylsulfonyl)-1H-indol-4-ylamino)pyrimidine-4-carboxamide. Methyl 5-amino-2-(3-hydroxyphenyl)-6-(1-(phenylsulfonyl)-1H-indol-4-ylamino)pyrimidine-4-carboxylate (0.1 g, 0.19 mmol) was stirred in 7N NH3/MeOH (20 mL) at 55° C. for 24 h. LCMS shows only the desired product. The mixture was concentrated to afford the title compound, 50 mg, 0.1 mmol, 50%. MS (ESI) m/z 501.5[M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[CH:37]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)([CH3:39])[CH3:38].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH:43]3[CH2:44][CH2:45][N:40]([CH:37]([CH3:39])[CH3:38])[CH2:41][CH2:42]3)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCN(C(C)C)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.1 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (310 mg, 0.63 mmol) was dissolved (using gentle heating) in dry tetrahydrofuran (20 ml). The resulting solution was cooled to room temperature and, with stirring, treated with a solution of 1-isopropyl-4-piperidinone (90 mg, 0.63 mmol) and acetic acid (45 mg) in dry tetrahydrofuran (5 ml). The mixture was stirred for 1 hr, sodium triacetoxyborohydride (200 mg, 0.94 mmol) added and stirring continued for a further 18 hr. The solvent was then removed under reduced pressure and the residue partitioned between a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate. The organic phase was separated and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol:ammonia (90:10:0.5) changing to dichloromethane:methanol:ammonia (85:15:0.75) to afford the title compound as a foam (140 mg). MS: 616 (MH+).