Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH:3]1([O:6][C:7]2[N:8]=[CH:9][C:10]([C:13]([O:15]C)=[O:14])=[N:11][CH:12]=2)[CH2:5][CH2:4]1.Cl>O1CCCC1.O>[CH:3]1([O:6][C:7]2[N:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[N:11][CH:12]=2)[CH2:4][CH2:5]1
Reactant: COC(=O)c1cnc(OC2CC2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(OC2CC2)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Lithium hydroxide (264 mg, 6.28 mmol) is added to a solution of methyl 5-(cyclopropoxy)pyrazine-2-carboxylate (610 mg, 3.14 mmol) in tetrahydrofuran (10 mL) and water (0.5 mL). The reaction mixture is stirred for 1 hour at 50° C., cooled to ambient temperature, diluted with water, brought to pH=2 by slow addition of 1 M HCl, and extracted with dichloromethane (4 times). The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (550 mg, 97%). ES/MS (m/e): 181.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([CH:11]=[N:12][OH:13])=[CH:9][CH:8]=2)=[C:4](Cl)[CH:3]=1.BrC1C=CC(OC2C=CC(C=O)=CC=2)=C([C:35]([F:38])([F:37])[F:36])C=1>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([CH:11]=[N:12][OH:13])=[CH:9][CH:8]=2)=[C:4]([C:35]([F:38])([F:37])[F:36])[CH:3]=1
Reactant: ON=Cc1ccc(Oc2ccc(Br)cc2Cl)cc1
Reactant: O=Cc1ccc(Oc2ccc(Br)cc2C(F)(F)F)cc1
Product: ON=Cc1ccc(Oc2ccc(Br)cc2C(F)(F)F)cc1

Procedure:
Prepared analogously to 78b) starting from 4-(4-bromo-2-trifluoromethyl-phenoxy)-benzaldehyde, it was further reacted directly without chromatographic purification.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([N:27](C)[C:28](=O)OC(C)(C)C)[CH2:23]2)=[N:4][CH:5]=[C:6]([C:8](=[O:21])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:7]=1.[CH3:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[CH3:36][C:37]1[N:42]=[CH:41][C:40]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([NH:27][CH3:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:8]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)=[O:21])[CH:7]=2)=[CH:39][CH:38]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: Cc1ccc(B(O)O)cn1
Product: CN[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccc(C)nc2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 93 using (R)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (Stage 99.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.81 min, m/z=472.0 [M+H]+.
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][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=1)=[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][N:43]([C:48]([NH:47][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: COc1cccc(N=C=O)c1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(NC(=O)N2CCC(C(=O)Nc3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 66 %

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-4-carboxamide bis(trifluoroacetate) and 1-isocyanato-3-methoxybenzene as starting materials in 66% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.49 (s, 1H), 9.40 (s, 1H), 9.33 (s, 1H), 8.49 (s, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.72 (s, 1H), 7.10 (m, 5H), 6.87 (d, 1H), 6.79 (d, 1H), 6.48 (d, 1H), 4.20 (d, 2H), 3.68 (s, 3H), 2.87 (m, 6H), 2.66 (m, 1H), 1.89 (m, 2H), 1.61 (m, 2H). LCMS for C32H33ClN7O3 (M+H)+: m/z=598.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:28]=1.C[Si](C#C)(C)C>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:27]([C:2]1[CH:3]=[C:4]([CH2:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([OH:24])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)#[CH:28]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(CC(=O)O)Cc1ccc(OCCCNc2ccccn2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Product: C#Cc1cc(CC(C)(C)CC(=O)O)ccc1OCCCNc1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 161.9 %

Procedure:
The final product of EXAMPLE 13, STEP 4 (500 mg) was dissolved in Et3N (10 ml) was treated with Cul (40 mg), triphenylphosphine (80 mg), Pd(Ph3P)2Cl2 (40 mg) and (trimethylsilyl) acetylene (1 ml). The reaction mixture was heated to 120 C. in a sealed tube for 20 hours under nitrogen atmosphere. The mixture was cooled to room temperature and was filtered through celite under vacuum. The filtrate was concentrated. The residue was dissolved in ethyl acetate and was washed with a saturated solution of ammonium chloride and dried over Na2SO4. The solid was removed by filtration and the filtrate was concentrated. The cude product was purified by flash chromatography on silica gel (EtOAc/Hexane/NH4OH: 80/19.5/0.5) to give 181 mg of desired compound as oily gum. NMR spectrum was consistent for the proposed structure.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1ccc(OCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Methanesulfonylchloride (3.3 mL) was added dropwise over 5 min to a solution of 4-(2-hydroxyethoxy)benzaldehyde (example 108, step a) (6.4 g) and triethylamine (6.4 mL) in DCM (30 mL) at 0° C. under argon. The resulting mixture was stirred at 0° C. for 10 min and then at RT for 1 h. The reaction mixture was washed with brine (2×30 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 40-50% EtOAc in petroleum ether (40-60° C.) to give the subtitled compound as a viscous yellow oil. Yield 8.87 g.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[C:24](I)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[C:34]1[O:38][C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[C:24]([C:37]4[O:38][C:34]([CH:30]5[O:31][CH2:32][CH2:33][O:29]5)=[CH:35][CH:36]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1I
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Fc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(C2OCCO2)o1
Temperature: 100 °C
Reaction time: 4 h
Yield: 59.4 %

Procedure:
Synthesized according to Procedure B from a solution of (4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride (508 mg, 1 mmole), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole), diisopropylethyl amine (650 mg, 5 mmole), and dichlorobis(triphenylphosphine) palladium (140 mg, 0.2 mmole) in 6 ml of DMF under nitrogen was stirred at 100° C. (oil bath temperature) for 4 hours. The cooled reaction mixture was extracted with water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with brine (100 ml). The aqueous layers were combined and washed with additional ethyl acetate (100 ml). The organic layers were combined, dried with MgSO4, filtered and concentrated to a residue. The residue was chromatographed on silica gel with a methanol-chloroform mixture. Fractions were collected, combined, and concentrated. The resultant solid was suspended in dichloromethane (10 ml) and diethyl ether was added facilitate precipitation. The solid was filtered and dried under vacuum at room temperature to yield a yellowish solid 287 mg (59%). 1H NMR (400 MHz, DMSO-d6) δ: 10.1(s, 1H), 8.85(d, 1H), 8.45(s, 1H), 7.6(m, 3H), 7.44(d, 2H), 7.38(m, 2H), 7.31(m, 1H), 7.03(m, 2H), 6.94(m, 1H), 6.74(d, 1H), 6.01(s, 1H), 5.1(s, 2H), 4.10(m, 2H), 3.96(m, 2H). ESI-MS m/z 482(M−1).
Reaction SMILES: Cl.Cl.[C:3]([C:5]1([NH:12][C:13]([CH:15]([NH2:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:14])[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1)#[N:4].CN1CCOCC1.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C>[C:3]([C:5]1([NH:12][C:13]([CH:15]([NH:21][C:35]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:36])[CH2:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:14])[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]1)#[N:4]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC(C)(C)C)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN1CCC(C#N)(NC(=O)C(CC(C)(C)C)NC(=O)N2CCOCC2)CC1
Reaction time: 16 h
Yield: 21.7 %

Procedure:
[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butyl]-amine dihydrochloride (350 mg, 1.03 mmol) was mixed in 10 mL of DMF to which was added 1 mL of N-methyl morpholine followed by addition of 4-morpholine carbonyl chloride (180 mg, 1.20 mmol) as a solution in 5 mL of DMF. The reaction was stirred for 16 hours at which time the volatiles were removed in vacuo. The residue was redissolved in 150 mL of EtOAc and washed sequentially with 50 mL of saturated aqueous bicarbonate and 50 mL of brine. The organic layer was dried over sodium sulfate, decanted and concentrated. The product was purified by flash chromatography on silica gel using 100% methylene chloride to 12% methanol in methylene chloride as eluent to give the title compound as a thick oil (85 mg); MS, m/z 380=M+1.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(O)cc1
Product: Oc1ccc(OCc2ccccc2)cc1

Procedure:
In analogy to the procedure described in Example 1a), the alkylation of hydroquinone with benzylbromide yielded the 4-benzyloxy-phenol as a colourless solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])([CH3:3])[CH3:2].C([Li])CCC.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.C(OCC)(=O)C.Cl>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:32])=[O:31])[CH:9]=[C:8]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2[nH]cc(CCC(=O)O)c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of propionic acid (27) (96.3mg, 0.510 mmol) in tetrahydrofuran (10 ml), n-butyl lithium (1.40 ml, 2.24 mol) was added next and stirred for 30 minutes at −78° C. Benzene sulfonyl chloride (277 mg, 1.5 mmol) was added next, and the reaction was stirred for 16-24 hours, allowing temperature to rise from −78° C. to ambient conditions. The reaction was then diluted with ethyl acetate, and 1M HCl was added to adjust the pH to 1-2. The layers were then separated, and the organic layer was placed over magnesium sulfate and concentrated under reduced pressure. The crude material was then purified by flash chromatography with silica, eluting with 5% methanol in dichloromethane to yield the desire product (22) as a white solid. (M−1=386.4)
Reaction SMILES: Cl.Cl[C:3]1[NH:4][C:5](=[O:14])[C:6]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][C:7]=2[N:8]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC([O-])(C)C.[K+]>CS(C)=O>[CH3:13][C:10]1[CH:11]=[CH:12][C:6]2[C:5](=[O:14])[NH:4][C:3]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:8][C:7]=2[N:9]=1
Reactant: Cc1ccc2c(=O)[nH]c(Cl)nc2n1
Reactant: OCCCCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc2c(=O)[nH]c(OCCCCCc3ccccc3)nc2n1

Procedure:
In analogy to the procedure described in example 97.3, 2-chloro-7-methyl-3H-pyrido[2,3-d]pyrimidin-4-one hydrochloride was reacted with 5-phenyl-1-pentanol in DMSO in the presence of molecular sieves and potassium tert-butylate to give 7-methyl-2-(5-phenyl-pentyloxy)-3H-pyrido[2,3-d]pyrimidin-4-one as yellow crystals. MS: m/e=324.4 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[CH3:10]OC1C=CC(N)=CC=1>>[CH3:10][NH:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[O:2][CH3:1]
Reactant: COc1ccc(N)cc1
Reactant: COc1cccc(N)c1
Product: CNc1cccc(OC)c1
Yield: 77 %

Procedure:
m-Anisidine (Aldrich Chemical Corp.) was substituted for p-anisidine in the procedure described in Journal Chemical Society, London, 1969:2223, Perkin Transactions I., which gave N-methyl-m-anisidine, as an oil, 24.5 g, 77% yield. NMR was consistent with structure. MS: APCI: M+1: 138.2 (M: 137.2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.O[CH2:17][CH2:18][CH2:19][CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22].N(C(OCC)=O)=NC(OCC)=O.C1(O)C=CC=CC=1>O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:17][CH2:18][CH2:19][CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCOC(=O)C(CCCO)C(=O)OCC
Reactant: CCCCCCC#Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCCCCCC#Cc1cccc(OCCCC(C(=O)OCC)C(=O)OCC)c1
Temperature: 10 °C
Yield: 19 %

Procedure:
1-(3-Hydroxyphenyl)-oct-1-yne, (2.20 g, 0.01M) and diethyl 2-(3-hydroxypropyl)propane-1,3-dioate [2.40 g, 0.01M, (prepared by the method of A.G. Just et al, Tet. Letts., 3645-3647, (1979)] were dissolved in dry tetrahydrofuran, (50 ml) and triphenylphosphine, (4.20 g, 0.016M), added. The solution was stirred at 10° C. and diethyl azodicarboxylate, (2.80 g, 0.016M), added dropwise. The reaction was stirred for 0.5 h after which time TLC showed some unreacted phenol remaining. Further aliquots of the alcohol, (2.40 g, 0.01M), triphenylphosphine, (4.20 g, 0.016M) and dietyl azodicarboxylate (2.80 g, 0.016M) were added and the reaction stirred for 0.5 h. Evaporation of the solvent in vacuo gave a red oil which was purified by chromatography on silica gel eluting with dichloromethane→chloroform, to yield 0.770 g (19%) of the title compound as a colourless oil. νmax (film 1580, 1600, 1610, 1740, 1758, 2225 (weak) cm-1 ; δ(CDCl3) 0.87 (3H, distorted t, terminal CH3), 1.26 (6H, t, J 7 Hz, 2×ester CH3), 1.33 (8H, m, alkylene chain), 1.93 (4H, m, OCH2CH2CH2), 2.34 (2H, t, J 6 Hz, acetylenic CH2), 3.37 (1H, t, J 7 Hz, CH), 3.91 (2H, t, J 6 Hz, OCH2), 4.16 (4H, q, J 7 Hz, 2×ester CH2), 7.00 (4H, m, aromatics).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]3)[CH:16]=[N:17][C:4]=2[CH:3]=1.[Cl-].[Li+].CC1(C)CCCC(C)(C)N1[Mg]Cl.[F:40][C:41]1[C:42]([CH:47]=[O:48])=[N:43][CH:44]=[CH:45][CH:46]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]3)[C:16]([CH:47]([C:42]3[C:41]([F:40])=[CH:46][CH:45]=[CH:44][N:43]=3)[OH:48])=[N:17][C:4]=2[CH:3]=1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=Cc1ncccc1F
Agent: CC1(C)CCCC(C)(C)N1[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(C(O)c3ncccc3F)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (Preparative Example 3.1, Step 1) (1.2 g, 3.19 mmol) in THF (20 mL) was added 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (Aldrich, 1M in THF/toluene) (5.11 mL, 5.11 mmol) at −78° C., and the reaction was stirred at −78° C. for 2 hours under a nitrogen atmosphere. 3-fluoropicolinaldehyde (1.1 g, 9.59 mmol) dissolved in THF (4.0 mL) was added dropwise at −78° C., and the reaction was stirred for an additional 2 hours at −78° C. The reaction was quenched with aqueous saturated NH4Cl solution (50 mL) and extracted with ethyl acetate (2×40 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column (0 to 100% EtOAc/hexanes) afforded {6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl}(3-fluoropyridin-2-yl)methanol. MS APCI calcd. for C25H24Cl2FN5O [M+H]+ 500. found 500.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[CH3:10][CH:11]([C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=1)[C:12]#[CH:13]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:13]#[C:12][CH:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH3:10])=[CH:4][N:3]=1
Reactant: Nc1ncc(I)c(N)n1
Reactant: C#CC(C)c1cc(OC)c(OC)c(OC)c1
Product: COc1cc(C(C)C#Cc2cnc(N)nc2N)cc(OC)c1OC
Yield: 89.8 %

Procedure:
2,4-Diamino-5-iodopyrimidine (236 mg) was allowed to react with 5-(But-3-yn-2-yl)-1,2,3-trimethoxybenzene (440 mg) as per the general procedure to afford 2,4-Diamino-5-(3-(3,4,5-trimethoxyphenyl)but-1-ynyl)pyrimidine as a yellow powder (295 mg, 90%): Rf=0.29 (9:1, CHCl3:MeOH); mp=220-222° C.; 1H NMR (DMSO-d6) δ 7.85 (s, 1H), 6.75 (s, 2H), 6.28 (s, 2H), 3.99 (q, J) 6.8 Hz, 1H), 3.78 (s, 6H), 3.63 (s, 3H), 1.50 (d, J) 7.1 Hz, 3H); 13C NMR (DMSO-d6) δ 163.7, 152.8, 139.3, 136.0, 104.2, 104.1, 97.9, 76.2, 60.0, 60.0, 55.9, 55.8, 32.3, 24.3; Anal. (C17H20N4O3) C, H, N.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:4]=1[CH:5]=O.[C:17]([S:21]([NH2:23])=[O:22])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl.O.[O-]S([O-])(=O)=O.[Cu+2]>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:4]=1/[CH:5]=[N:23]/[S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22]
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)S(=O)/N=C/c1cc(C(F)(F)F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.3 %

Procedure:
A mixture of 2,5-bis trifluoromethyl benzaldehyde (21.5 g, 88.8 mmol), tert butyl sulfinamide (16.1 g, 133 mmol) and anhydrous CuSO4 (16.5 g, 103 mmol) in DCM (94 ml) was stirred at room temperature for 16 hours and at reflux for 3 days. The fine suspension was diluted with water and extracted with DCM. The extracts were washed with water, dried (MgSO4) and evaporated in vacuo to an off white solid which was purified by chromatography (silica, 4-10% EtOAc/isohexane) to give the desired N-{(1E)-[2,5-bis(trifluoromethyl)phenyl]methylene}-2-methylpropane-2-sulfinamide as a white crystalline solid (14.8 g, 91%); 1H NMR δ (ppm)(CDCl3): 8.98 (1 H, d, J=1.8 Hz), 8.46 (1 H, s), 7.92-7.85 (2 H, m), 1.29 (9 H, s); m/z (ES+) 346 (MH+).
Reaction SMILES: [CH2:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:17]N=O)(C)(C)C.ON1C(=O)C2=CC=CC=C2C1=O.C1(=NO)CCCCCCCCCCC1.[N+](C1CCCCCCCCCCC1)([O-])=O>C(N(CC)CC)C.C(O)(=O)C>[C:1]1(=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)ON=O
Reactant: C1CCCCCCCCCCC1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=[N+]([O-])C1CCCCCCCCCCC1
Agent: ON=C1CCCCCCCCCCC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=C1CCCCCCCCCCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Cyclododecane (1.66 g; 9.88 mmol), t-butylnitrite (2 mmol), N-hydroxyphthalimide (0.4 mmol), and acetic acid (2 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas for 1 hour. The resulting mixture was further treated with triethylamine (300 mg) with stirring at 80° C. for 30 minutes. The resulting reaction mixture was analyzed to find that cyclododecanone oxime, nitrocyclododecane, and cyclododecanone were formed in yields of 39%, 7%, and 5%, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(N)cn2)C1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 91.1 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with (R)-tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (439 mg, 1.5 mmol) to afford the desired product (516 mg, 91%) as a yellow solid:: ESI MS m/z 566 [C28H32BrN5O3+H]+.
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.CO[N:12]=[C:13]1[CH2:16][C@H:15]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:14]1[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>O1CCCC1>[CH3:34][C:31]([Si:28]([CH3:30])([CH3:29])[O:27][CH2:26][C@@H:14]1[C@@H:15]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16][C@H:13]1[NH2:12])([CH3:32])[CH3:33]
Reactant: CON=C1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](N)[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 186.3 g (4.9 mol) of sodium borohydride in 4 L of tetrahydrofuran (THF) was added (over a 30 minute period) 376 mL (4.9 mol) of trifluoroacetic acid (TFA), with ice water cooling to maintain temperature below 15° C. [2R,3S]-2,3-bis(((1,1-Dimethylethyl)dimethylsilyl)oxymethyl) cyclobutanone-O-methyl oxime (400 g, 1.03 mol), from Step 1E, in 3 L of THF was added with ice water cooling to maintain the temperature below 20° C. After stirring the reaction mixture at ambient temperature overnight, it was concentrated, diluted with methylene chloride (3 L) and washed portionwise (with cooling) with 400 mL of brine. After filtration, the layers of the filtrate were separated and the aqueous layer was washed with methylene chloride. The combined methylene chloride solution was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give crude title compound which was taken on to the next step without purification.