Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:39])[C@@H:5]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:19]([NH2:27])[N:18]=2)=[CH:11][CH:10]=1)C.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].O.CC#N>O1CCOCC1.Cl>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[NH2:27][C:19]1[N:18]=[C:17]([C:16]#[C:15][C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][CH2:6][C@H:5]([NH:29][S:30]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)(=[O:32])=[O:31])[C:4]([OH:39])=[O:3])=[O:28])=[CH:10][CH:11]=2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2
Reactant: CCOC(=O)[C@H](CNC(=O)c1ccc(C#Cc2nc(N)cc3ccccc23)cc1)NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc2ccccc2c(C#Cc2ccc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2)n1

Procedure:
A solution of ester 35-4 (0.46 g, 0.85 mmol) in dioxane (4 mL) and 6N HCl (8.5 mL) was heated to 60° C. overnight. Concentration yielded an orange solid. Prep. HPLC (C18, 0.1% TFA H2O/CH3CN) followed by lyophilization gave trifluoroacetate 35-5 as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[N:5]([CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)[C:6](=[O:10])[C:7]=1[N:8]=O.[C:20](OC(=O)C)(=O)[CH3:21]>>[CH3:18][CH:17]([CH3:19])[CH2:16][N:3]1[C:2]2[NH:1][C:20]([CH3:21])=[N:8][C:7]=2[C:6](=[O:10])[N:5]2[CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=[C:4]12
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)CN1C2=NC(C)(C)CN2C(=O)C(N=O)=C1N
Product: Cc1nc2c([nH]1)N(CC(C)C)C1=NC(C)(C)CN1C2=O

Procedure:
The nitroso compound produced in Procedure 130 was catalytically hydrogenated and cyclized by the treatment with acetic anhydride according to the method of Procedure 63.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:25]([Cl:26])=[CH:24][C:8]([C:9]([NH:11][CH:12]([CH3:23])[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2C(O)=O)=[O:14])=[O:10])=[C:7]([O:27][CH3:28])[CH:6]=1)(=[O:3])[CH3:2].[O:29]=[C:30]1[O:34][CH:33]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40]C=2)[CH:32]([NH:44][C:45](C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=[O:46])[CH2:31]1>>[CH2:36]([O:35][CH:33]1[CH:32]([NH:44][C:45]([CH:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:13](=[O:14])[CH:12]([NH:11][C:9](=[O:10])[C:8]2[CH:24]=[C:25]([Cl:26])[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=2[O:27][CH3:28])[CH3:23])=[O:46])[CH2:31][C:30](=[O:29])[O:34]1)[C:37]1[CH:38]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC(C)C(=O)N1CCCC1C(=O)O
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC(C)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 82 %

Procedure:
Prepared from syn-{2-[2-(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-pyrrolidin-1-yl]-1-methyl-2-oxo-ethyl}-carbamic acid tert-butyl ester and 97c following the procedure used for 98a to afford the title compound (222 mg, 82% yield). 1H-NMR (500 MHz, CD3OD) δ 1.23 (d, 0.6H), 1.42 (d, 2.4H), 1.72-2.27 (m, 4H), 2.23 (s, 3H), 2.63 (dd, 1H), 2.77-2.88 (m, 1H), 3.43-3.52 (m, 0.5H), 3.56-3.71 (m, 1.5H), 3.74-3.85 (m, 1H), 3.98 (s, 3H), 4.38-4.50 (m, 1.5H), 4.51-4.92 (m, 4.5H), 5.63-5.76 (m, 1H), 7.23-7.40 (m, 5H), 7.97 (s, 1H), 8.45 (d, 1H), 8.69-8.80 (m, 1H) Analytical HPLC 11.63 min LC-MS (ES+) m/e=601.2 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].[CH3:14][O:15][C:16](=[O:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1>N1C=CC=CC=1.C(N(CC)CC)C.ClCCl>[CH3:14][O:15][C:16]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)=[O:5])=[O:22])=[CH:19][CH:18]=1)=[O:26]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(C(=O)CN)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCC(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
To a solution of 2-amino-4′-methoxyacetophenone hydrochloride (5.33 g) in pyridine (4.28 ml), triethylamine (3.68 ml) and dichloromethane (50 ml) was added dropwise a solution of terephthalic acid monomethyl ester (5.25 g) in dichloromethane (10 ml) at 0° C. The reaction mixture was allowed to warm to room temperature, and stirred for 3 hours. To the reaction mixture was added dichloromethane (200 ml), washed with 1N-sodium hydroxide (100 ml×2), saturated hydrogen carbonate aqueous solution (100 ml×2) and brine, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in n-hexane, and collected by filtration to give 2-(4-methoxycarbonyl-benzamido)-4′-methoxyacetophenone (7.97 g).
Reaction SMILES: FC1C=C(F)C=C(F)C=1C(NC1C=CC=C([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])N=1)=O.C[N:29]1[CH2:34][CH2:33]C(C(O)=O)[CH2:31][CH2:30]1.S(Cl)(Cl)=O.C(NCC)C>>[CH2:30]([N:29]([CH2:34][CH3:33])[C:13]([CH:15]1[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]1)=[O:14])[CH3:31]
Reactant: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Reactant: CN1CCC(C(=O)O)CC1
Solvent: CCNCC
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)C1CCN(C)CC1

Procedure:
The present invention relates to a process for preparing 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or salt thereof, further comprising the step of: reacting 1-methylpiperidine-4-carboxylic acid with thionyl chloride and diethyl amine to yield N,N-diethyl-1-methylpiperidine-4-carboxamide.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2.CN(C)[CH:19]=[O:20]>O1CCCC1>[N:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[CH:19]=[O:20])[CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc2cccnc12
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=Cc1cccc2cccnc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
sec-Butyllithium (1.4 M in cyclohexane, 5.0 ml, 7.0 mmol) is added dropwise to a stirred solution of 8-bromoquinoline (1.29 g, 6.22 mmol) and anhydrous tetrahydrofuran (22 ml) at −78° C. under nitrogen. The reaction is then stirred at −78° C. for 10 min and then dimethylformamide (2.5 ml, 32.3 mmol) is added. The reaction is then stirred for 10 min at −78° C. and then quenched with water. The reaction is poured into saturated sodium bicarbonate (100 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate is dried over sodium sulfate and then the sodium sulfate is filtered. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexanes to yield (0.57 g, 58%) of quinoline-8-carboxaldehyde: mass spectrum (ion spray): m/z=158.0 (+1): 1H NMR (CDCl3): δ=11.46 (1H, s), 9.06-9.04 (1H, m), 8.34-8.32 (1H, m), 8.26-8.23 (1H, m), 8.11-8.08 (1H, m), 7.70-7.66 (1H, m), 7.53-7.50 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:13]2[C:14]3[C:19]([N:20]=[C:21]([CH3:22])[C:12]2=[C:11]([CH3:24])[N:10]=1)=[CH:18][CH:17]=[C:16](F)[CH:15]=3.FC1C=C(Cl)C=CC=1[N+]([O-])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:13]2[C:14]3[C:19]([N:20]=[C:21]([CH3:22])[C:12]2=[C:11]([CH3:24])[N:10]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Cc1nc(-c2cc(Cl)ccc2Cl)n2c1c(C)nc1ccc(F)cc12
Agent: O=[N+]([O-])c1ccc(Cl)cc1F
Product: Cc1nc(-c2cc(Cl)ccc2Cl)n2c1c(C)nc1ccccc12
Yield: 30 %

Procedure:
1-(2,5-Dichlorophenyl)-3,4-dimethylimidazo[1,5-a]quinoxaline was synthesized in a manner similar to 1-(2,5-dichlorophenyl)-8-fluoro-3,4-dimethylimidazo[1,5-a]quinoxaline starting with 2-fluoro-4-chloronitrobenzene. A white solid was recovered (0.04 g) 30% yield. MS (ES) m/z 342.0 [M+1]+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2].[C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)#[N:23]>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:8]=[C:9]([O:11][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Reactant: N#Cc1ccc(CBr)cc1
Product: CCOC(=O)c1cc(OCc2ccc(C#N)cc2)cc(Oc2ccc(C#N)cc2)c1
Yield: 78.6 %

Procedure:
Using 0.66 g (2.3 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester and 4-cyanobenzylbromide (0.45 g, 2.3 mmol) and following the procedure of Example 42(b) afforded 0.72 g of the required product. 1H NMR (DMSO-d6): δ 1.3 (3H, t), 4.3 (2H, q), 5.35 (2H, s), 7.16 (4H, m), 7.44 (1H, s), 7.66 (2H, s), 7.88 (4H, d).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].[N:47]([CH2:50][CH3:51])=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:48]([NH:47][CH2:50][CH3:51])=[O:49])[CH2:41]1)=[O:39]
Reactant: CCN=C=O
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N1CCCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 36 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and isocyanato-ethane as starting materials in 36% yield. LCMS for C27H31ClN7O2 (M+H)+: m/z=520.2.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2[N:11]=[CH:10][NH:9][N:8]=2)=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:15].[K+]>O>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([C:7]2[N:11]=[CH:10][NH:9][N:8]=2)=[O:15])=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Fc1ccc(Cc2nc[nH]n2)cc1
Agent: [K+]
Solvent: O
Product: O=C(c1ccc(F)cc1)c1nc[nH]n1

Procedure:
3-(4-Fluorobenzyl)-1,2,4-triazole (9 g.) and potassium permanganate (13.5 g.) were heated in water at 80° for 1 hour. The reaction mixture was filtered, and the residue was washed twice each with water and chloroform. The combined filtrate and washings were adjusted to pH 3 and filtered. The solid residue was dissolved, as far as possible, in hot methanol, the solution was filtered and evaporated to dryness to give 3-(4-fluorobenzoyl)-1,2,4-triazole as a cream-colored solid, m.p. 225°-230°.
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH2:22]([CH:24]1[CH:32]([NH2:33])[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[CH2:25]1)[CH3:23]>>[CH2:1]([C:3]1[C:4]([NH:33][CH:32]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH2:25][CH:24]2[CH2:22][CH3:23])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: CCC1Cc2cccnc2C1N
Product: CCc1cnc(CC)c(NC2c3ncccc3CC2CC)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 6-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.41, 7.66, 7.58, 7.15, 5.53, 4.89, 3.15, 2.71–2.57, 2.31, 2.01, 1.99, 1.65, 1.34, 1.22, 1.04; HRMS (FAB) calcd for C18H24N4+H 297.2079, found 297.2080.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[CH:21]1([CH2:24][O:25][C:26]2[N:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=2)[CH2:23][CH2:22]1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:32]([C:29]3[CH:28]=[N:27][C:26]([O:25][CH2:24][CH:21]4[CH2:23][CH2:22]4)=[CH:31][N:30]=3)=[O:33])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1cnc(OCC2CC2)cn1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3cnc(OCC4CC4)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=464.3 [M+H]+.
Reaction SMILES: C[S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]#[N:10].[Br:11]Br>ClC1C=CC=CC=1>[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[S:2][Br:11])#[N:10]
Reactant: BrBr
Reactant: CSc1ccccc1C#N
Solvent: Clc1ccccc1
Product: N#Cc1ccccc1SBr
Temperature: 100 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
74.5 g (0.500 mol) of 2-cyanophenyl methyl sulfide and 250 g of chlorobenzene were placed in a 500 ml four-neck flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser and 96.0 g (0.600 mol) of bromine was added dropwise thereto at about 100° C. over five hours while stirring. The excess bromine was removed with an aqueous sodium carbonate solution, followed by distillation under reduced pressure to obtain 90.4 g of 2-cyanobenzenesulfenyl bromide. The yield starting from 2-cyanophenyl methyl sulfide was 84.5%.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].N1C=CC=CC=1.[CH2:15]([O:18][CH2:19][C@H:20]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:21]O)[CH:16]=[CH2:17]>ClCCl>[CH2:15]([O:18][CH2:19][CH:20]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][O:4][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:6])=[O:5])[CH:16]=[CH2:17]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: C=CCOC[C@@H](CO)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOCC(COS(=O)(=O)C(F)(F)F)OCc1ccccc1
Yield: 101.1 %

Procedure:
Trifluoromethanesulfonic acid (5.95 ml, 36.3 mmol) is added dropwise at -30° C. to a mixture of dichloromethane (130 ml) and pyridine (3.19 g, 40.3 mmol). Compound 12 (8.95 g, 40.3 mmol) in dichloromethane (60 ml) is then added dropwise at -25° C. The mixture is allowed to come to room temperature and is concentrated in vacuo, and the residue is chromatographed (hexane/ethyl acetate 6:1). Compound 13a (13 g, 91%) is obtained.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Sb](Cl)(Cl)(Cl)(Cl)Cl>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:4][C@@H:3]([C@H:5]2[O:6][C@@H:11]3[O:12][C:9]([CH3:11])([CH3:7])[O:10][C@@H:9]3[C@H:7]2[OH:8])[CH2:2][O:1]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Temperature: 60 °C
Reaction time: 8 h
Yield: 144.8 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-glucose and 149.5 mg of antimony pentachloride, and the mixture was refluxed with stirring in a water bath of 60° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. After completion of the reaction, 1.60 g of the starting sugar was recovered by filtration. A small amount of pyridine was then added to the filtrate, and the acetone was distilled off under reduced pressure. The residue was dissolved in benzene, and the solution was washed with aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The benzene was distilled off under reduced pressure to give 10.46 g (72.4%) of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose. The compound, when recrystallized from a mixed solvent of chloroform-n-hexane (1:2), showed a melting point of 107°-109° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[CH:5][CH:4]=1)#N.O.[PH2]([O-])=[O:28].[Na+].C(O)(=O)C.N1C=CC=CC=1>[Ni].O>[CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[O:24][CH3:25])=[CH:5][CH:4]=1)=[O:28]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(C#N)cc23)c(OC)c1
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Cc2cccc3ccc(C=O)cc23)c(OC)c1
Temperature: 50 °C
Yield: 47.3 %

Procedure:
To a mixture of methyl 4-(7-cyanonaphth-1-ylmethyl)-3-methoxybenzoate (1.06 g), sodium hypophosphite hydrate (2.25 g), glacial acetic acid (4 ml), pyridine (8 ml) and water (4 ml) was added Raney nickel (330 mg of material resulting from decanting water from a 50% (w/w) slurry in water). The reaction mixture was heated to 50° C. for 1 h and cooled, ethyl acetate was added and the mixture filtered through diatomaceous earth with ethyl acetate wash. The organic layer was washed (1N HCl twice, brine), dried (MgSO4) and evaporated. Purification by flash chromatography, eluting with methylene chloride, and trituration with ether afforded methyl 4-(7-formylnaphth-1-ylmeth-yl)-3-methoxybenzoate (506 mg, 47%) as a colorless solid; mp 103°-4° C., MS(CI), m/e=336(M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C(C)(C)C)=[O:8])[N:3]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.O>ClCCl>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[NH:3]1
Reactant: CN1CCC(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(C(=O)O)N1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of bis(1,1-dimethylethyl) 2-methyl-1,5-pyrazolidinedicarboxylate dissolved in dichloromethane (DCM) (25 mL) was added TFA (30.7 mL, 398 mmol) and water (3.59 mL, 199 mmol). The reaction was stirred at rt and monitored by LCMS. When the reaction was deemed complete, the solvent was evaporated under reduced pressure to give a residue which was azeotroped from toluene (50 mL×3) in order to remove the TFA and water. The crude product was obtained as a colorless oil (97% yield based on TFA Salt), which was used directly for the next step. LC-MS (ES) m/e 130.9 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH3:2][CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)[CH3:3]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: CC(C)N1CCNCC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: COC(=O)c1ccc(N2CCN(C(C)C)CC2)cc1
Temperature: 130 °C
Yield: 64.8 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.014 g, 0.02 mmol) was added to a deoxygenated suspension of 1-isopropylpiperazine (0.151 g, 1.18 mmol), methyl 4-bromobenzoate (0.215 g, 1 mmol), potassium carbonate (0.193 g, 1.4 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.012 g, 0.03 mmol) in DME (4 mL), and sealed into a microwave tube. The reaction was heated to 130° C. for 10 mins in the microwave reactor and cooled to room temperature. The reaction mixture was evaporated to dryness, redissolved in EtOAc (25 mL) and washed sequentially with water (15 mL) and saturated brine (15 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by silica column chromatography, eluting with 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl 4-(4-propan-2-yl-piperizin-1-yl)benzoate (0.170 g, 64.8%) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:4][C:3]=1[F:9]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(Br)c(F)c1)OCC
Temperature: 135 °C
Yield: 101.3 %

Procedure:
4-Bromo-3-fluorophenol (7 g, 0.03665 mol) and potassium carbonate (7.6 g, 0.055 mol) were dissolved in N,N-dimethylformamide (9 mL). 2-Bromo-1,1-diethoxyethane (8.5 mL, 0.055 mol) was added and the reaction mixture was stirred and heated to 135° C. for 7 h. The solvent was removed after the reaction was completed. The residue was dissolved in ethyl acetate and washed with 2M NaOH solution. The organic phase was dried over Na2SO4. The solvent was evaporated to yield 1-bromo-4-(2,2-diethoxyethoxy)-2-fluorobenzene as an oil (11.4 g, 100%).
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:52]=[CH:51][CH:50]=[CH:49][C:10]=1[CH2:11][N:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH3:32])[CH:25]=3)=[N:16][C:15]=2[C:14]([C:33]#[N:34])=[C:13]1[N:35]1[CH2:40][CH2:39][CH2:38][C@@H:37]([NH:41]C(=O)OC(C)(C)C)[CH2:36]1>O1CCOCC1>[ClH:8].[NH2:41][C@@H:37]1[CH2:38][CH2:39][CH2:40][N:35]([C:13]2[N:12]([CH2:11][C:10]3[CH:49]=[CH:50][CH:51]=[CH:52][C:9]=3[Cl:8])[C:20]3[C:19](=[O:21])[N:18]([CH3:22])[C:17]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH3:32])[CH:25]=4)=[N:16][C:15]=3[C:14]=2[C:33]#[N:34])[CH2:36]1
Reactant: CCOc1cccc(Oc2nc3c(C#N)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n(Cc4ccccc4Cl)c3c(=O)n2C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1cccc(Oc2nc3c(C#N)c(N4CCC[C@@H](N)C4)n(Cc4ccccc4Cl)c3c(=O)n2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 204.3 %

Procedure:
A 4N hydrochloric acid/1,4-dioxane solution (5 ml) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-2-(3-ethoxyphenoxy)-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidine-3-yl}carbamate (185 mg) in 1,4-dioxane (3 ml), and the resulting mixture was stirred at 25° C. for 2 hours and then concentrated under reduced pressure to obtain the title compound (170 mg).