Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[C:19]([OH:26])[C:18]=2[CH2:27][CH2:28][CH3:29])=[CH:10][CH:9]=[CH:8][N:7]=1.[C:31](=O)([O-])[O-].[Cs+].[Cs+].IC>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[C:19]([O:26][CH3:31])[C:18]=2[CH2:27][CH2:28][CH3:29])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(OCCCOc2cccnc2CCC(=O)OC)ccc(C(C)=O)c1O
Agent: [Cs+]
Solvent: CI
Product: CCCc1c(OCCCOc2cccnc2CCC(=O)OC)ccc(C(C)=O)c1OC
Yield: 91.9 %

Procedure:
Under the conditions of example 2 A, 600 mg of 3-{3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propoxy]-2-pyridyl}-propionic acid methyl ester in the presence of 940 mg of cesium carbonate instead of potassium carbonate is reacted with 205 mg of iodomethane, worked up, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 570 mg of 3-{3-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](O)=[O:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](=[O:18])[NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 81.3 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxy-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.92 mmol) and benzylamine (107 mg, 1.0 mmol) to give 310 mg of the title compound (81%): mp>250° C.; 1H NMR (270 MHz, DMSO-d6) δ12.12 (s, 1H), 8.68 (t, 1H, J=6.1 Hz), 7.12~7.31 (m, 7H), 5.13~5.19 (m, 1H), 4.26 (d, 2H, J=6.1 Hz), 2.78 (dm, 1H, J=16.8 Hz), 2.39~2.61 (m, 2H), 1.85~2.00 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.O.[CH3:13][N:14]1CCCC1=O>>[NH:9]1[CH2:8][CH2:7][O:6][C:5]2[N:10]=[CH:11][C:2]([C:13]#[N:14])=[CH:3][C:4]1=2
Reactant: CN1CCCC1=O
Reactant: Brc1cnc2c(c1)NCCO2
Solvent: O
Product: N#Cc1cnc2c(c1)NCCO2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a 5 ml flask, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (24 mg, 0.111 mmol) was dissolved in N-methylpyrrolidone (NMP) (20.3 ml), and cuprous cyanide (CuCN) (16 mg, 0.178 mmol) was added thereto and then stirred in microwave at 180□ for 10 minutes using microwave (100 W) apparatus. The reaction mixture was cooled to room temperature and water (10 ml) was added thereto, and extracted with ethyl acetate (10 ml*2). The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=20:1. The fractions containing the product were collected and evaporated to obtain pale-yellow solid (17 mg, quantitative yield).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1>C1COCC1>[OH:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCC(O)CC1
Temperature: 25 °C

Procedure:
To a heated (40° C.) solution of tert-butyl 2-bromoacetate (7.38 mL, 49.9 mmol) in THF (10 mL) was added dropwise a solution of piperidin-4-ol (5.050 g, 49.9 mmol) and TEA (6.96 mL, 49.9 mmol) in THF (50 mL). The mixture was refluxed for 2 hours and then cooled to RT and filtered through a pad of Celite® brand filter aid. The filtrate was evaporated and the residue diluted with EtOAc (50 mL), washed with water (50 mL), brine (10 mL), and the organic layer dried over Na2SO4, filtered and evaporated. The material was purified via flash chromatography using a linear gradient of 0% to 10% of 1% NH4OH in MeOH in DCM. The title compound was isolated as an off-white solid (4.865 g, 45% yield).
Reaction SMILES: [C:1]1([CH2:7][N:8](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([C:44](=[O:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)S(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+].[Na].[Cl-].[NH4+].N>>[C:1]1([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:52](=[O:59])[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([C:44](=[O:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCCN(CCCCCCCN(CCCCN(Cc2ccccc2)S(=O)(=O)c2ccc(C)cc2)C(=O)c2ccccc2)C(=O)c2ccccc2)Cc2ccccc2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: O=C(c1ccccc1)N(CCCCCCCN(CCCCNCc1ccccc1)C(=O)c1ccccc1)CCCCNCc1ccccc1

Procedure:
Mix 1,19-bis[(phenyl)methyl]-1,19-bis[(4-methylphenyl)sulfonyl]-6,14-bis(benzoyl)-1,6,14,19-tetraazanonadecane (4g, 4 mmol) in dry liquid ammonium (25 mL) at -40° C. Add small pieces of sodium until a permanent blue color remains. Discharge the excess sodium with saturated ammonium chloride. Allow the ammonia to evaporate spontaneously and partition the residue between ethyl acetate and water. Separate the organic phase, dry (MgSO4) and evaporate the solvent on vacuo. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][C:20]=1[OH:29])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N:31]1[C:40]2[C:35](=[C:36]([CH2:41][CH2:42]O)[CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][C:20]=1[O:29][CH2:42][CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:35]=1[CH:34]=[CH:33][CH:32]=[N:31]2)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCc1cccc2ncccc12
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCCc1cccc2ncccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
3-(4-Acetylamino-2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (0.40 g, 0.9 mmol) was combined with 2-Quinolin-5-yl-ethanol (0.155 g, 0.9 mmol) and triphenyl phosphine (355 mg, 1.3 mmol) in 15 mL THF. The solution was cooled to 0° C. DEAD (0.21 mL, 1.3 mmol) was added. The reaction was slowly warmed to room temperature, and stirred overnight. The reaction mixture was concentrated in vacuo. The crude product was chromatorgraphed using 1:1 ethyl acetate/hexanes followed by ethyl acetate, and then 10% methanol in ethyl acetate to yield 3-[4-acetylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester 450 mg (83%) of an off-white solid. MS (APCI) m/z 601.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[OH:14].[H-].[Na+].[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][CH:29](OC2C=CC(Cl)=CC=2C=O)C1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CCOC(C)=O>CN(C=O)C.O>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH:30]([O:14][C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=2)[CH2:29]1)=[O:26])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2C=O)C1
Reactant: Oc1cc(F)ccc1OCc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2OCc2cccc(Cl)c2)C1
Temperature: 50 °C
Yield: 124.1 %

Procedure:
To the title compound of Step B (200 mg, 0.79 mmol) in DMF (5.0 mL) was added 60 wt % NaH (34.3 mg, 0.86 mmol). The mixture was heated to 50° C. for 1 h then cooled to rt and 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester (Example 90 Step A, 229 mg, 0.91 mmol) in DMF was added. This mixture was heated to 80° C. for 18 h, cooled to rt and treated with EtOAc (50 mL) and H2O (100 mL). The organic layer was separated, washed with H2O (2×50 mL) and dried to give a solid (400 mg). This solid was purified on RP HPLC to yield the title compound (90 mg, 28%). 1H NMR (CDCl3) 7.44 (s, 1H), 7.36-7.23 (m, 3H), 6.86 (dd, J=8.9, 5.4 Hz, 1H), 6.60 (dd, J=8.0, 2.9 Hz, 1H), 6.33 (dd, J=9.6, 2.9 Hz, 1H), 5.03 (s, 2H), 4.90-4.80 (m, 1H), 4.33-4.22 (m, 2H), 4.07-4.02 (m, 2H), 1.54-1.28 (m, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[C:37]([Cl:44])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[Cl:44][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH3:43]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOc1ccc(OB([O-])[O-])cc1Cl
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.1 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3-chloro-4-ethoxyphenyl borate (127 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 30 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:4) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-(3-chloro-4-ethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 49) (38 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:15][C:14]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:30][O:31]C5CCCCO5)=[O:29])[CH:21]=4)[O:16]3)[CH2:13]2)=[CH:3]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:13][C:14]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:30][OH:31])=[O:29])[CH:21]=4)[O:16]3)[CH2:15]2)=[CH:3]1
Reactant: Cn1cc(CN2CC3(CC(=O)c4cc(/C=C/C(=O)NOC5CCCCO5)ccc4O3)C2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cc(CN2CC3(CC(=O)c4cc(/C=C/C(=O)NO)ccc4O3)C2)c2ccccc21
Yield: 100.3 %

Procedure:
(E)-3-[1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)acrylamide (102 mg, 0.203 mmol) in DCM (5 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hyroxy-acrylamide (85 mg, hydrochloride salt) as a light brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21](OC(=O)N)(C)(C)C>>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:12]1[CH2:11][CH2:10][N:13]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:21]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc(N)cn2)C1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N)cn2)C1

Procedure:
With a method similar to that used for the preparation of (S)-3-(5-amino-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester above, (S)-1-(5-amino-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester was prepared by the hydrogenation of (S)-1-(5-nitro-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester. This material was directly used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[CH:11]1([C:14](O)=O)[CH2:13][CH2:12]1>>[CH:11]1([C:14]2[NH:1][C:2]3[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=3[N:8]=2)[CH2:13][CH2:12]1
Reactant: Cc1cc(O)cc(N)c1N
Reactant: O=C(O)C1CC1
Product: Cc1cc(O)cc2[nH]c(C3CC3)nc12

Procedure:
0.55 g (4.00 mmol) 3,4-diamino-5-methyl-phenol and 1.67 mL (20.00 mmol) cyclopropanecarboxylic acid were stirred for 1 h at 120° C. Then the reaction mixture w evaporated down i.vac. and further reacted as crude product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6](Cl)=[O:7].C(N(CC)C(C)C)(C)C.Cl.[N+:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29])([O-:24])=[O:23]>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=2)=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(F)cc1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccc([N+](=O)[O-])c1)c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.1 %

Procedure:
A solution of 4-fluoro salicylic acid chloride (12.3 g, 70.3 mmol) in dichloromethane (140 mL) was cooled to 0° C., and treated with N,N-diisopropylethylamine (31.0 mL, 175 mmol) and 3-nitrobenzylamine hydrochloride (16 g, 84.6 mmol). After stirring at room temperature for 24 h, the solution was concentrated in vacuo and diluted with ethyl acetate. The organic layer was washed successively with aq 2 N HCl and saturated aq NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) provided 4-fluoro-2-hydroxy-N-(3-nitro-benzyl)-benzamide as a yellow solid (13.7 g, 67%): 1H NMR (DMSO-d6 300 MHz) δ 12.75 (s, 1 H), 9.43 (t, J=6.0 Hz, 1 H), 8.11 (ddd, J, =8.3, J2=2.1 Hz, J3=1.2 Hz, 1 H), 8.18 (t, J=1.5 Hz, 1 H), 7.94 (dd, J1=8.9 Hz, J2=6.5 Hz, 1 H), 7.78 (td, J1=7.8 Hz, J2=1.4 Hz, 1 H), 7.63 (t, J=8.0 Hz, 1 H), 6.81–6.72 (m, 2 H), 4.61 (d, J=5.7 Hz, 2 H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:18][NH:19][CH3:20].[ClH:21].[CH3:22]NC.C([BH3-])#N.[Na+].Cl>CO>[ClH:21].[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:22])[N:19]([CH3:20])[CH3:18]
Reactant: CNC
Reactant: CCCCCC(=O)Cc1cc(OC)ccc1I
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCC(CCc1cc(OC)ccc1I)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 13.0 g (0.036 mole) of 1-(2-iodo-5-methoxyphenyl)heptan-2-one, 46.6 ml (0.18 mole) of a solution of 3.86 M dimethylamine in methanol, 8.24 g (0.101 mole) of dimethylamine hydrochloride, 100 ml of methanol and 1.82 g (0.029 mole) of sodium cyanoborohydride was stirred overnight under an atmosphere of nitrogen. Stirring was continued an additional two hours and the reaction mixture acidified to pH 1 by addition of concentrated hyirochloric acid. The solvent was evaporated in vacuo, the residue partitioned between methylene chloride and water, and the methylene chloride layer separated, washed with Na2S2O5 solution followed by a washing with 3 M sodium hydroxide solution. The organic phase was dried over anhydrous potassium carbonate and evaporated in vacuo to yield a yellow oil. The oil was dissolved in methanol and the solution treated with ethereal hydrogen chloride to pH 5. The solvent was removed in vacuo and the residue dissolved in 45 ml of refluxing ethyl acetate. Some slight turbidity was removed by filtration through filter aid. The filtrate was cooled to room temperature and diluted with 20 ml of diethyl ether. The solution was cooled overnight in a refrigerator and the resulting solid, 3.34 g, removed by filtration. The filtrate was evaporated in vacuo, the residue triturated with ether and seeded to yield a second crop of off-white solid, 1.66 g. One recrystallization from ethyl acetate yielded pure 2-iodo-5-methoxy-N,N-dimethylalphapentylbenzenepropanamine hydrochloride, mp 100°-103° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:19]2[NH:20][C:21](=O)[C:22]([OH:30])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:19]2[NH:20][CH2:21][C:22]([OH:30])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(C2(NC(=O)OCc3ccccc3)CCC(=O)CC2)[nH]c(=O)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C1=C(O)CNC(C2(NC(=O)OCc3ccccc3)CCC(O)CC2)=N1
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of ethyl 2-(1-(benzyloxycarbonylamino)-4-oxocyclohexyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (1.5 g, 3.5 mmol) in methanol (35 mL) at room temperature was added NaBH4 (138 mg, 3.66 mol) and the resulting mixture was stirred for 1 h. Methanol was then removed under reduced pressure and the mixture was diluted with CH2Cl2 (200 mL), washed with 1N HCl (100 mL) followed by brine (100 mL). The organic fraction was dried (Na2SO4), filtered and concentrated to afford the title compound as a light yellow solid (1.3 g, 86% yield). 1H NMR (500 MHz, DMSO-D6) δ: 12.46 (s, 1H), 10.24 (s, 1H), 7.31-7.35 (m, 5H), 7.11 (brs, 1H), 4.28-4.32 (m, 2H), 4.29 (q, 2H, J=7.22 Hz), 3.43-3.46 (m, 1H), 2.31-2.33 (m, 1H), 2.15-2.22 (m, 2H), 1.77-1.83 (m, 2H), 1.65-1.67 (m, 2H), 1.44-1.49 (m, 2H), 1.28 (t, 3H, J=7.22 Hz). LCMS (M+H)=432.37.
Reaction SMILES: [H-].[Na+].CS(O[CH:8]([CH2:18][CH:19]([C:40]1[S:41][CH:42]=[C:43]([Cl:45])[N:44]=1)[C:20]1[NH:21][C:22]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[C:23]2[C:28](=[O:29])[N:27]([CH3:30])[C:26](=[O:31])[N:25]([CH3:32])[C:24]=12)[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=O)=O>C1COCC1>[Si:11]([O:10][CH2:9][CH:8]1[CH2:18][CH:19]([C:40]2[S:41][CH:42]=[C:43]([Cl:45])[N:44]=2)[C:20]2[N:21]1[C:22]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)=[C:23]1[C:28](=[O:29])[N:27]([CH3:30])[C:26](=[O:31])[N:25]([CH3:32])[C:24]1=2)([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13]
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(CC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)c3nc(Cl)cs3)c2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)CC3CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Sodium hydride (127 mg, 3.18 mmol) was added to a solution of 1-((tert-butyldimethylsilyl)oxy)-4-(4-chlorothiazol-2-yl)-4-(5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-7-yl)butan-2-yl methanesulfonate (712 mg, 1.061 mmol) in THF (30 mL). The mixture was stirred at room temperature for 35 mins. The reaction was quenched with water and extracted with DCM (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane afforded the title compound as a mixture of diastereomers.
Reaction SMILES: CO.C(N(CC)CC)C.Cl.Cl.C([O:15][C@@H:16]1[C@@H:53]([O:54]C(=O)C)[C@H:52]([O:58]C(=O)C)[C@@H:51]([CH2:62][O:63]C(=O)C)[O:50][C@H:17]1[O:18][C:19]1[C:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][C:37]4([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[CH2:36]3)=[CH:27][C:26]=2[CH3:46])=[C:22]([CH:47]([CH3:49])[CH3:48])[NH:21][N:20]=1)(=O)C>O>[O:18]([C:19]1[C:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][C:37]4([CH2:41][CH2:42][NH:43][CH2:44][CH2:45]4)[CH2:36]3)=[CH:27][C:26]=2[CH3:46])=[C:22]([CH:47]([CH3:49])[CH3:48])[NH:21][N:20]=1)[C@@H:17]1[O:50][C@H:51]([CH2:62][OH:63])[C@@H:52]([OH:58])[C@H:53]([OH:54])[C@H:16]1[OH:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCNCC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc(/C=C/CCN2CCCC3(CCNCC3)C2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
Add methanol (5 mL), triethylamine (3 mL), and water (3 mL) to 4-{4-[(1E)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (480 mg, 0.24 mmol). After 18 hours (overnight) at room temperature, concentrate to dryness under reduced pressure. Purify the resulting residue by preparative HPLC method: high pH, 25% B for 4 min, 25-40 B % for 4 min @85 mL/min using a 30×75 mm, 5 um C18XBridge ODB column, solvent A—H2O w NH4HCO3@pH 10, solvent B—MeCN to yield the title compound as a solid (50 mg, 0.08 mmol).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][C@@H:10]([C:24](O)=[O:25])[C@@H:11]([O:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[C:12]([OH:14])=[O:13])=[O:8])=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C>>[O:25]=[C:24]1[C@H:10]([O:9][C:7](=[O:8])[C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C@@H:11]([O:15][C:16](=[O:17])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12](=[O:13])[O:14]1
Reactant: O=C(O[C@@H](C(=O)O)[C@@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O[C@H]1C(=O)OC(=O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
To a 3-necked 5 L round bottom flask fitted with a mechanical stirrer and a teflon coated thermocouple was added (−)-2,3-dibenzoyl-L-tartaric acid (1000 g, 2.79 mol) followed by acetic anhydride (2 L). The suspension was stirred and heated to 85° C. for 2 h during which time the starting material gradually dissolved. A short time thereafter, the product began to crystallize in the reaction mixture and the suspension was then cooled to 25° C. The product was collected by filtration, washed with 10% acetone in hexane (2×1 L), and dried in a vacuum oven at 50° C. overnight to afford the title compound (102) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.0 (s, 2H), 7.45 (app. t, 4H), 7.65 (app. t, 2H), 8.05 (d, 4H).