Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1

Procedure:
To a suspension of 6-chloronicotinoyl chloride (10.5 g, 59.7 mmole) in dry dichloromethane (100 mL) was added 4-fluoroaniline (5.6 mL, 59.7 mmole), followed by the dropwise addition of N,N-diisopropylethylamine (21 mL, 19 mmol).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4][CH2:5][CH3:6])=[O:3].O.[NH2:12][NH2:13]>>[NH:12]([C:1](=[O:8])[C:2]([O:4][CH2:5][CH3:6])=[O:3])[NH2:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: NN
Solvent: O
Product: CCOC(=O)C(=O)NN
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of diethyl oxalate (9-1) (6.0 g, 41.04 mmol) in alcohol (30 mL) was added hydrazine hydrate (2.4 mL, 49.26 mmol) dropwise at −20° C. After the addition was over, the solution was stirred for 30 min. The solution was filtered and the filtrate was evaporated to give the product as a white solid (3.0 g, 55%). The compound was used for the next step directly without further purification. LRMS (ESI) calculated M+H for C4H9N2O3: 133.1. Found: 133.3.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(C)C.[CH3:25][S:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:28]=1[CH:29]=O.Cl>C1COCC1>[CH3:25][S:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:28]=1[CH:29]=[CH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)C[Si](C)(C)C
Reactant: CCCCCCc1cccc(SC)c1C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCc1cccc(SC)c1C=CC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of lithium diisopropylamide, afforded by combining 3.4 g of diisopropylamine with 26 ml of n-butyllithium, at -40° C. in THF is added tert-butyl trimethylsilylacetate (8 g, 0.042 mmol) and the mixture stirred for 1 hour. To the reaction mixture is added 2-methylthio-6-n-hexylbenzaldehyde (7.08 g, 0.03 mmol) dropwise and stirred for 2 hours at -40° C. The reaction mixture is allowed to warm to -10° C. and cold lN HCl poured in. The mixture is extracted with diethyl ether. The extracts are washed with water and then brine, dried over MgSO4 and concentrated to afford tert-butyl 2-methylthio-6-n-hexylcinnamate which is hydrolyzed in methylene chloride with trifluoroacetic acid by refluxing overnight to afford the subtitle compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[C:21](N=C(N(C)C)N(C)C)([CH3:24])([CH3:23])[CH3:22].BrCC(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([N:8]([CH2:22][CH:21]([CH3:24])[CH3:23])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH2:19])=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:7]=1
Reactant: C=Cc1ccc(S(=O)(=O)Nc2cc(Cl)ccc2F)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC(C)CBr
Solvent: CC#N
Product: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2cc(Cl)ccc2F)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of N-(5-chloro-2-fluorophenyl)-4-vinylbenzenesulfonamide (822 mg, 2.64 mmol) in acetonitrile (10 mL) stirred in air at 20° C., was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (903 mg, 5.27 mmol). The reaction mixture was stirred at 20° C. for 2 hours. 1-bromo-2-methylpropane (0.573 mL, 5.27 mmol) was then added and the reaction vessel sealed and heated by microwaves (Emrys Optimiser) to 150° C. for 30 minutes. After cooling, the reaction mixture was concentrated in vacuo and redissolved in ethyl acetate. The organic phase was washed with water (10 mL), dried using a hydrophobic frit and evaporated in vacuo to give the crude product as a yellow oil which solidified. The crude was purified by silica (Si) chromatography using a 0-50% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product, 824 mg as a colourless oil. LCMS [LCMS2] Rt 1.46 min, m/z (ES+) 368 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=O)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:17]([NH:16][C:12]2[C:8]3[CH:9]=[CH:10][N:11]=[C:3]([C:2]([NH2:7])=[O:1])[C:4]=3[N:5]=[CH:6][N:14]=2)[CH2:18][NH:19][CH3:32])=[CH:34][C:35]=1[C:40]([F:41])([F:42])[F:43]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1ccc(Cl)c(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)nccc12)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Compound 42 was prepared following general synthesis scheme 8 wherein a mixture of 4-Hydroxy-pyrido[3,2-d]pyrimidine-8-carboxylamide (G) and 4-Hydroxy-pyrido[3,4-d]pyrimidine-8-carboxylamide (H) was reacted with N—[(S)-2-Amino-2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride. LC/MS [425 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.28 (s, 1H), 9.00 (d, J=4.5 Hz, 1H), 8.55 (s, 1H), 8.38 (d, J=4.5 Hz, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.77 (d, J=7.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 5.64-5.44 (m, 1H), 3.20-3.09 (m, 1H), 3.04-2.88 (m, 1H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH2:10][CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[CH:4][N:3]=1.Cl.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH:18]1[C:23](O)=[O:24].CCN(C(C)C)C(C)C>CS(C)=O.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:9]([CH2:10][CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)[C:23](=[O:24])[CH:18]3[CH2:19][O:20][CH2:21][CH2:22][N:17]3[C:6]=2[N:7]=1
Reactant: Clc1ncc(NCC2CCOC2)c(Cl)n1
Reactant: O=C(O)C1COCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1CC1CCOC1
Temperature: 100 °C
Yield: 408.9 %

Procedure:
2,4-Dichloro-N-((tetrahydrofuran-3-yl)methyl)pyrimidin-5-amine (7 g, 28.2 mmol), morpholine-3-carboxylic acid hydrochloride (832 mg, 4.97 mmol), and DIPEA (2.67 ml, 15.28 mmol) were combined in DMSO (8 ml). The reaction mixture was heated overnight at 100° C. Upon cooling the solution was diluted with water then extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 6.6 g of 2-chloro-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a brown oil which was used without further purification. [M+H] found 325.
Reaction SMILES: CO[C:3](=O)[NH:4][C@H:5]1[C@@H:10]([CH3:11])[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:12]([N:7]1[CH2:8][CH2:9][CH:10]([CH3:11])[CH:5]([NH:4][CH3:3])[CH2:6]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)N[C@@H]1CN(Cc2ccccc2)CC[C@@H]1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNC1CN(Cc2ccccc2)CCC1C
Temperature: 20 °C
Yield: 90 %

Procedure:
The reduction of cis-(1-benzyl-4-methyl-piperidin-3-yl)-carbamic acid methyl ester was performed by charging 2 grams substrate (1 equiv., 7.62 mmol) to a solution of 20 ml THF (10 volumes) and 15.2 ml 1 M LAH in THF (2 equiv., 15.2 mmol). The addition was performed at a rate so that the temperature reached 30°-40° C. and then the reaction was allowed to cool to 20° C. The reaction was worked up by quenching with 40 ml Rochelle Salt (20 volumes) to a temperature of 35° C. and then extracting the product 2 times into 20 ml methylene chloride (10 volumes). The filtrate was then concentrated to a clear and colorless oil. (90% yield). Note that the starting material needs to be clean in order for this reaction to proceed in high yield.
Reaction SMILES: [OH-].[Li+].[CH2:3]([S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[C:22]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:21]=2)=[CH:13][C:12]=1[O:37][CH3:38])(=[O:9])=[O:8])[CH2:4][CH2:5][CH3:6]>O1CCCC1>[CH2:3]([S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([O:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:21]=2)=[CH:13][C:12]=1[O:37][CH3:38])(=[O:8])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1cc(CCCc2ccc(OS(=O)(=O)CCCC)c(OC)c2)ccc1CCC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCOc1cc(CCCc2ccc(OS(=O)(=O)CCCC)c(OC)c2)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
0.66 ml (0.66 mmol) of aqueous 1M lithium hydroxide solution is added to a solution of 171 mg (0.33 mmol) of methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-butoxyphenyl)propanoate in 3 ml of tetrahydrofuran, and the reaction mixture is then stirred for 18 hours at room temperature. After evaporating to dryness, the reaction medium is taken up in 10 ml of water and acidified with acetic acid to pH 4, and then extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate and filtered. The solvents are evaporated off and the residue is then purified by chromatography on a column of silica eluted with a 99/1 dichloromethane/methanol mixture. 99 mg (60%) of 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-butoxyphenyl)propanoic acid are obtained in the form of a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](OCC)=[O:11])=[CH:7][C:6]=2[CH:15]=1.[BH4-].[Na+].O.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2o1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2cc(Br)ccc2o1
Reaction time: 18 h
Yield: 64 %

Procedure:
A solution of ethyl 5-bromo-2-benzofurancarboxylate (2.20 g, 8.19 mmol) in tetrahydrofuran (75 ml) was added with sodium borohydride (1.24 g) and some drops of water. The mixture was refluxed under stirring for 18 h and, after that, was added with some drops of concentrated HCl. The volatiles were evaporated off and the resulting residue was diluted with water and extracted with ethyl ether (3×75 ml). After drying and evaporating off the solvent under reduced pressure, a crude was obtained which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform, 60:40. 1.19 g of the title product were recovered as a white solid with melting point 101-103° C. (64% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:29][C:30]1[C:31]2[N:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:32]=2[N:33]=[CH:34][N:35]=1.[ClH:41].C([O-])(O)=O.[Na+]>CC(O)(C)C.O1CCOCC1>[ClH:29].[ClH:41].[NH2:7][C:8]1[C@:9]([CH3:27])([C:23]([F:24])([F:25])[F:26])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30]3[C:31]4[N:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:32]=4[N:33]=[CH:34][N:35]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CO[C@@]1(C)C(F)(F)F
Reactant: Clc1cnc2c(Cl)ncnc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: C[C@@]1(c2cc(Nc3ncnc4cc(Cl)cnc34)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Temperature: 100 °C

Procedure:
To a solution of [(2R,5R)-5-(5-amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (CAS registry 1262859-70-0) (138 mg, 0.34 mmol) and 4,7-dichloro-pyrido[3,2-d]pyrimidine (CAS registry 917757-12-1) (75 mg, 0.374 mmol) in tBuOH (2 ml) was added 0.1 ml 4N HCl in dioxane and the reaction mixture was heated in a microwave oven for 1 h at 100° C. The reaction mixture was basified with saturated NaHCO3 solution and the product was extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was dissolved in THF, acidified with 1N HCl in Et2O, and concentrated. The remaining yellow solid was two times triturated with Et2O and subsequently dried to afford the title compound as light yellow amorphous solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:2].N1C=CC=C(C=[CH:30][C:31](N)=[O:32])C=1.ClC(OCC)=S>>[C:31]([N:8]1[CH2:9][CH2:10][C:11]2[C:3]([C:1]#[N:2])=[C:4]([NH:12][C:13](=[O:22])/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:5][C:6]=2[CH2:7]1)(=[O:32])[CH3:30]
Reactant: NC(=O)C=Cc1cccnc1
Reactant: N#Cc1c(NC(=O)C=Cc2ccccc2)sc2c1CCNC2
Agent: CCOC(=S)Cl
Product: CC(=O)N1CCc2c(sc(NC(=O)/C=C/c3ccccc3)c2C#N)C1

Procedure:
The following compounds 35 and 36 can be prepared according to the general procedure F described below starting from N-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-acrylamide (compound B1) or N-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(pyridin-3-yl)-acrylamide (compound B2) and ethyl chlorothioformate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:11]1[CH:12]=[C:13]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH:14]=[CH:15][C:16]=1[F:17].C([O-])(=O)C([O-])=O.[OH:39][C:40]1[CH:53]=[CH:52][CH:51]=[CH:50][C:41]=1[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=O>C(O)C.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:25][CH:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)[C:11]1[CH:12]=[C:13]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:41]2[CH:50]=[CH:51][CH:52]=[CH:53][C:40]=2[OH:39])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: CN1CCC(OC(c2nc3ccccc3[nH]2)c2cc(C#CCCCCN)ccc2F)CC1
Reactant: O=C(c1ccccc1)c1ccccc1O
Agent: O=C([O-])C(=O)[O-]
Solvent: CCO
Solvent: O
Product: CN1CCC(OC(c2nc3ccccc3[nH]2)c2cc(C#CCCCCN=C(c3ccccc3)c3ccccc3O)ccc2F)CC1

Procedure:
A mixture of 6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate (example 557, 70 mg), 2-hydroxybenzophenone (30 mg) in ethanol (4 mL) is refluxed for 4 h. The mixture is then cooled, diluted with water and extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0 to 90/10/0.5) to afford 2-[(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl]hex-5-ynylimino)phenylmethyl}phenol. TLC (Eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5) Rf=0.15.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1.[C:17]([OH:21])(C)(C)[CH3:18].C(OC(C)C)(C)C>[Zn]>[C:17]([O:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:14][CH:13]=1)(=[O:21])[CH3:18]
Reactant: OCc1ccc(COC2CCCCO2)cc1
Reactant: CC(C)(C)O
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CC(=O)OCc1ccc(COC2CCCCO2)cc1
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of (4-((tetrahydro-2H-pyran-2-yloxy)methyl)phenyl)methanol (3.0 mmol), t-butanol (3.6 mmol), the zinc cluster obtained in the above-described Example 5 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, 4-((tetrahydro-2H-pyran-2-yloxy)methyl)benzyl acetate was obtained in a yield of 92.9%.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[CH:16]=[O:17])[CH:10]=[C:9]([NH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C>C1COCC1>[N:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH2:16][OH:17])[CH:18]=[CH:19][CH:20]=3)[CH:10]=[C:9]([NH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=Cc1cccc(-c2cc(Nc3cccnc3)nc(N3CCOCC3)c2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1cccc(-c2cc(Nc3cccnc3)nc(N3CCOCC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aldehyde 39 is suspended in THF and DIBALH (1.6 N solution in THF, 3 eq) is added dropwise via a syringe. The reaction mixture is stirred at room temperature overnight, then quenched with water. The aqueous phase is extracted repeatedly with EtOAc. The organic extracts are collected and dried (Na2SO4). Evaporation of the solvent under reduced pressure and purification by reverse phase preparatory HPLC, affords compound 40.
Reaction SMILES: C1COCC1.CCOC(/N=N/C(OCC)=O)=O.[OH:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]([C:26]2[C:34]3[C:29](=[CH:30][C:31]([N+:35]([O-:37])=[O:36])=[CH:32][CH:33]=3)[N:28]([CH3:38])[CH:27]=2)=[C:22]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]([CH3:48])[CH:40]=2)[C:21]1=[O:49].[CH2:50]([O:57][P:58]([O-])([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:48][N:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]([C:22]2[C:21](=[O:49])[N:20]([CH2:19][O:18][P:58](=[O:59])([O:60][CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[O:57][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:24](=[O:25])[C:23]=2[C:26]2[C:34]3[C:29](=[CH:30][C:31]([N+:35]([O-:37])=[O:36])=[CH:32][CH:33]=3)[N:28]([CH3:38])[CH:27]=2)=[CH:40]1
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(CO)C2=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)N(COP(=O)(OCc3ccccc3)OCc3ccccc3)C2=O)c2ccccc21
Temperature: 20 °C
Reaction time: 14 h

Procedure:
To a cool solution (10° C.) of THF containing 0.12 g (0.68 mmole) of diethylazodicarboxylate, 0.20 g (0.46 mmole) of 1-hydroxymethyl-3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (from Step a above), and 0.40 g (1.43 mmole) of dibenzylphosphate was added dropwise 5 ml of a solution containing 0.128 g (0.49 mmole) of triphenylphosphine. The resulting mixture was stirred for 14 hours at 20° C. All solvent was evaporated and the residue was purified by chromatography using silica gel and eluting with a mixture of EtOAc/Hexanes to afford phosphoric acid dibenzyl ester 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl ester as a brick red solid (mp=105-109° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([OH:33])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].CBr>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]([CH2:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]3)[C:11]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:17]4)[C:10]=3[N:9]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(O)cccc32)C1
Agent: CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CCCn2c(COc3ccc(Cl)cc3)nc3c(OCC4CCCN(C(=O)OC(C)(C)C)C4)cccc32)C1
Temperature: 25 °C

Procedure:
A solution of (RS) 2-(4-chlorophenoxymethyl)-4-hydroxy-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]benzimidazole (75 mg, 0.15 mmol, 1.0 eq) in dry N,N-dimethylformamide (1.0 ml) was treated with sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting mixture was stirred at room temperature for thirty minutes, after which time 1-(t-butoxycarbonyl)piperidin-3-yl)methyl bromide (0.18 mmol, 1.2 eq) was added. The resulting mixture was stirred for three hours at 70° C. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with diethyl ether (3×10 ml). The organic fractions were combined, washed with water (2×10 ml), then brine (1×10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to give a crude product. The title product was further purified by flash chromatography to provide a crystalline product.
Reaction SMILES: C([SiH](CC)CC)C.O[CH:9]([C:16]1[S:30][C:19]2[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])=[N:21][N:22]([CH3:25])[C:23](=[O:24])[C:18]=2[CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH3:25][N:22]1[C:23](=[O:24])[C:18]2[CH:17]=[C:16]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:30][C:19]=2[C:20]([CH2:26][CH:27]([CH3:29])[CH3:28])=[N:21]1
Reactant: CC(C)Cc1nn(C)c(=O)c2cc(C(O)c3ccccc3)sc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Cc1nn(C)c(=O)c2cc(Cc3ccccc3)sc12
Reaction time: 24 h
Yield: 81 %

Procedure:
Triethylsilane (1.0 ml) was added to a stirred solution of 2-[1-hydroxy-1-phenylmethyl]-5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one (example 14, 1.44 g) in trifluoroacetic acid (2 ml) and dichloromethane (10 ml) at room temperature. After 24 hours, saturated sodium hydrogen carbonate solution (100 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The organic extracts were washed twice with saturated sodium hydrogen carbonate solution, then with brine, and then dried, filtered and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate:isohexane (1:4 then 1:3), to give the title compound (1.11 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:7]([OH:14])[C:6]([CH3:15])=[CH:5][C:3]=1O.[CH:16]([C:18]1([OH:22])[CH2:21][CH2:20][CH2:19]1)=[CH2:17]>O1CCOCC1.C(OCC)(=O)C>[CH3:15][C:6]1[C:7]([OH:14])=[C:8]([CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])[C:2]([CH3:1])=[C:3]2[C:5]=1[CH2:17][CH2:16][C:18]1([O:22]2)[CH2:21][CH2:20][CH2:19]1
Reactant: C=CC1(O)CCC1
Reactant: Cc1cc(O)c(C)c(CCC(C)C)c1O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(O)c(CCC(C)C)c(C)c2c1CCC1(CCC1)O2
Yield: 45.1 %

Procedure:
To a solution of 2,5-dimethyl-3-(3-methylbutyl)hydroquinone (208 mg) and BF3-ether (0.25 mL) in dioxane (3 mL) was added 1-vinyl-cyclobutanol (98 mg) in dioxane (3 mL) over 50 min at 110° C. degree under nitrogen. The reaction was refluxed for one additional hour. The solution was diluted with ethyl acetate and washed with water and brine, and dried. After evaporation the residue waschromatographed (silica gel, hexane-ethyl acetate 0% to 3%) gave 5,8-dimethyl-7-(3-methylbutyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (130 mg).