Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:3]1.[Cl:12][C:13]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:15]2[C:16]([O:18][C:19](=O)[C:14]=12)=[O:17]>>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:1]2[C:16](=[O:17])[C:15]3=[C:21]([Cl:24])[CH:22]=[CH:23][C:13]([Cl:12])=[C:14]3[C:19]2=[O:18])[CH2:3][CH2:4]1)[CH2:9][CH2:10][CH3:11]
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Reactant: CCCCN1CCC(N)CC1
Product: CCCCN1CCC(N2C(=O)c3c(Cl)ccc(Cl)c3C2=O)CC1

Procedure:
4-Amino-1-n-butylpiperidine and 3,6-dichlorophthalic anhydride are reacted in a similar manner to that described in Example 3 to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:6]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:4]=1.C[Si]([N:32]=[N+:33]=[N-:34])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][NH:17][C:5]2[CH:6]=[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[C:11]([C:12]4[NH:34][N:33]=[N:32][N:13]=4)[CH:10]=3)[N:8]=[C:3]([O:2][CH3:1])[N:4]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(C#N)c3)nc(OC)n2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(CCNc2cc(-c3cccc(-c4nnn[nH]4)c3)nc(OC)n2)cc1
Yield: 45.1 %

Procedure:
A solution of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzonitrile [0.12 g, 0.33 mmol, Example 35(t)], trimethylsilylazide (0.22 mL, 1.65 mmol) and dibutyltinoxide (41 mg, 0.16 mmol) in toluene (5 mL) is heated to 95° C. for 6 hours. The reaction mixture is concentrated, and partitioned between water and ethyl acetate. The aqueous phase solution is acidified with dilute hydrochloric acid to pH, 3.0, and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 5% MeOH in DCM to afford [2-(4-methoxy-phenyl)-ethyl]-{2-methoxy-6-[3-(1H-tetrazol-5-yl)-phenyl]-pyrimidin-4-yl}-amine [60 mg, 45%, Example 24(a)]. LCMS: RT=2.65 minutes, MS: 404 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]5[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=5)[CH2:22][CH2:21]4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:3][CH:4]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: COc1ccc(I)cc1
Product: COc1ccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)cc1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-4-methoxybenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 482.0 (M+H)+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[NH:6]1)=O.[NH3:16]>CO>[CH3:15][O:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]([C:3]([NH2:16])=[O:2])[CH2:13]2
Reactant: N
Reactant: COC(=O)C1Cc2cc(OC)ccc2N1
Solvent: CO
Product: COc1ccc2c(c1)CC(C(N)=O)N2
Temperature: 25 °C

Procedure:
2,3-dihydro-5-methoxy-1H-indole-2-carboxylic acid methyl ester (0.084 mole) and 2M NH3 in methanol (500 ml) were combined and stirred at room temperature under argon over the weekend. The solution was concentrated to 100 ml, cooled in an ice bath, and filtered. The solid was rinsed with a small amount of cold methanol and dried. The residue was triturated in methanol/ACN and filtered, yielding 4.56 g of 2,3-dihydro-5-methoxy-1H-indole-2-carboxamide (intermediate 21, mp. 228-229° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][O:24][C:25](=[O:46])[C@H:26]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:45])=[O:37])=[CH:31][CH:30]=1)[NH2:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:23][O:24][C:25](=[O:46])[C@H:26]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36]([C:38]2[C:43]([Cl:44])=[CH:42][CH:41]=[CH:40][C:39]=2[Cl:45])=[O:37])=[CH:33][CH:34]=1)[NH:27][C:4]([C:3]1[CH:7]=[CH:8][C:9]([S:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:13])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)NCc2cccc(O)c2)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(S(=O)(=O)NCc2cccc(O)c2)cc1Cl
Yield: 54.5 %

Procedure:
A solution of 2-chloro-4-[(3-hydroxybenzylamino)sulfonyl]benzoic acid (50 mg; 0.146 mmol), 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (60 mg; 0.1486 mmol), HBTU (5 mg; 0.15 mmol) and DIPEA (0.102 mL; 0.585 mmol) in dimethylformamide (3 mL) was stirred for 17 hr under argon at room temperature, then was concentrated to dryness under reduced pressure. The residue was partitioned between dichloromethane (25 mL) and 0.5 N HCl (25 mL). The separated aqueous phase was re-extracted with dichloromethane (10 mL), then the organic extacts were washed in turn with water (2×25 mL). The combined dichloromethane layers were dried (Na2SO4) and evaporated to give 90 mg of the crude product as a dark oil. Chromatography of the oil over silica gel (9 g; 4:1 ethyl acetate-hexane) yielded 55 mg of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]sulfonyl]phenyl]carbonyl]-L-phenylalanine methyl ester, as a colorless solid. FAB HRMS: (C31H26Cl3N3O7S) Obs. Mass 690.0639 Calcd. Mass 690.0635 (M+H).
Reaction SMILES: N[C@@H]1C(=O)N2C(C(OC(C3C=CC=CC=3)C3C=CC=CC=3)=[O:12])=C(C=C)CS[C@H]12.[CH:29]1([N:35]=[C:36]=[N:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.CN(C)C=O>[C:36]([NH:35][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)([NH:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:12]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
A solution of diphenylmethyl 7βamino-3-vinylceph-3-em-4-carboxylate (1.57 g., 4 mmole) in methylene dichloride (25 ml.) with dicyclohexylcarbodiimide (907 mg., 4.4 mmole) was treated slowly (over 10 minutes) with a solution of D-2-t-butoxycarbonylamino-2-phenylacetic acid (1.1 g., 4.4 mmole) in N,N-dimethylformamide (10 ml.). The mixture was stirred at 23° for 30 minutes and dicyclohexylurea removed by filtration. The filtrate was washed with water and dried and evaporated in vacuo to give a pale yellow solid. This material was crystallised from methanol, and the isolated material washed with ether, to give the crude title cpompound (2.2 g.) (contaminated with dicyclohexylurea). The crude compound in benzene :ethyl acetate (2:5) was filtered through a short column of Kieselgel 0.02 - 0.5 mm., 10 cm. × 2.5 cm.). Evaporation of the solvent in vacuo and washing the crystalline residue with ether gave the pure title compound (1.6 g., 64%) as small needles m.p. 200°-202°, [α]D - 129° (CHCl3), λmax 294.5 nm. (ε 14,400), νmax. 3395 (NH), 1780 (β-lactam), 1712 (CO2R), 1690 and 1500 (CONH) and 912 cm.-1 (CH=CH2),τ(CDCl3) 3.05 (CHPh2),3.03 (CH=CH2, dd, J 17 and 11 Hz). 3.08 (NH, d, J 9 Hz) 4.23 (C(7) -H, dd, J 9 and 4.5 Hz), 4.28 (CH-NH, d, J 7 Hz), 4.65 and 4.79 (CH=CH2, two d, J 17 and 11 Hz resp.), 4.77 (CH-NH, d, J 7 Hz), 5.10 (C(6) -H, d, J 4.5 Hz), 6.46 and 6.70 (C(2) -CH, AB-q, J 18 Hz) 8.58 (C[CH3 ]3). (Found: C, 66.6; H, 5.6; N, 6.4; S, 5.1. C35H35N3O6S requires C, 67.2; H, 5.65; N, 6.7; S, 5.1%).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:37])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[N:15]=[N:14][C:13]=2[CH2:26][CH2:27][CH2:28][CH3:29])[CH:9]=[CH:8][C:7]=1[O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.Cl>C1COCC1.CO>[CH2:26]([C:13]1[N:14]=[N:15][C:16]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][C:7]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[C:6]([CH:11]=1)[C:5]([OH:37])=[O:4])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)O)c1
Reaction time: 8 h

Procedure:
2 N aq. lithium hydroxide solution (2.5 mmol, 1.25 mL) was added to a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid methyl ester (Example 71, 0.615 mmol, 296 mg) in THF (5 mL) and MeOH (1.25 mL). It was stirred overnight. Aq. HCl solution was added to adjust pH to neutral. The reaction mixture was partitioned between DCM (20 mL) and water (20 mL). The DCM layer was separated and dried over sodium sulfate. The organic solvents were removed in vacuo to give 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1([C:16]([CH3:18])=[CH2:17])[CH2:8][CH2:7][N:6]([CH2:9][C:10](OCC)=[O:11])[C:5]1=[O:15].[CH3:20][NH2:21]>CCO>[CH3:20][NH:21][C:10](=[O:11])[CH2:9][N:6]1[CH2:7][CH2:8][C:4]([CH2:3][CH:2]([CH3:19])[CH3:1])([C:16]([CH3:18])=[CH2:17])[C:5]1=[O:15]
Reactant: C=C(C)C1(CC(C)C)CCN(CC(=O)OCC)C1=O
Reactant: CN
Solvent: CCO
Product: C=C(C)C1(CC(C)C)CCN(CC(=O)NC)C1=O
Yield: 85 %

Procedure:
Ethyl 3-(2-methylpropyl)-2-oxo-3-(propen-2-yl)-1-pyrrolidineacetate (500 mg, 1.87 mmol) is stirred in a saturated solution of methylamine in EtOH (50 mL) at room temperature overnight. The solution is concentrated and purified by column chromatography (1:12:8 v/v CH2Cl2 :EtOAc:hexane) to give 401 mg (85%) of the title compound as an oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:39][CH3:40])=[CH:29][C:30]=2[O:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:39][CH3:40])=[CH:29][C:30]=4[O:32][CH:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COc1cc(OC2CCOCC2)c2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2c1
Yield: 28 %

Procedure:
Using the procedure described in Example 92A Step 3, using 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (0.193 g, 0.7 mmol) from Example 1A, 4-chloro-7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline from the previous step (0.212 g, 0.72 mmol), and Cs2CO3 (0.326 g, 1 mmol) in isopropanol (10 mL) at 60° C. for 4 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-yloxy]phenyl}urea as solid (0.104 g, 28%). 1H NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 8.58 (s, 1H), 7.94 (s, 1H), 7.56 (s, 1H), 7.37 (d and s, 2H), 6.95 (d and s, 2H), 6.59 (s, 1H), 5.89 (s, 1H), 4.76 (m 1H), 3.99 (m, 2H), 3.96 (s, 3H), 3.66 (m, 2H), 2.06 (m, 2H), 1.95 (m, 2H), 1.33 (s, 9H); LC-MS (ESI) m/z 534 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10](Br)=[CH:9]2)([O-:3])=[O:2].[CH2:15]([Sn](CCCC)(CCCC)C=C)[CH2:16]CC>C(COC)OC.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>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([CH:15]=[CH2:16])=[CH:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cc(Br)cnc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: C=Cc1cnc2c([N+](=O)[O-])cccc2c1
Yield: 53.5 %

Procedure:
A mixture of 8-nitro-3-bromoquinoline (300 mg), tri-n-butyl(vinyl)tin (491 mg) and tetrakis(triphenylphosphine)palladium(0) (28 mg) in dimethoxyethane (6 ml) was refluxed for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (n-hexane-toluene) to give 8-nitro-3-vinylquinoline (127 mg).
Reaction SMILES: [OH-].[Na+].[N:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[N+:4]=[N-:5].O.S([O-])(O)(=O)=O.[Na+]>CO>[N:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N+:4]=[N-:5]
Reactant: COC(=O)CCCCCCCCCCN=[N+]=[N-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=NCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
Crunched sodium hydroxide (709 mg, 17.7 mmol) was added to a solution of methyl 11-azidoundecanoate (4.03 g, 17.7 mmol) in methanol (75 ml). The reaction mixture was stirred for 16 h at room temperature. Water (50 ml) was added. The mixture was acidified to pH 2 by addition of a 10% aqueous solution of sodium hydrogensulphate and was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulphate. The solvent was removed in vacuo. The residue was dissolved in methanol (50 ml). Crunched sodium hydroxide (1.42 g, 35.4 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. Water (50 ml) was added. The mixture was acidified to pH 2 by addition of a 10% aqueous solution of sodium hydrogensulphate and was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulphate. The solvent was removed in vacuo to give 3.13 g of 11-azidoundecanoic acid.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.[C:15]1([CH:22]=[CH:21][CH:20]=[C:18]([OH:19])[CH:17]=1)[OH:16]>>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:20]1[CH:21]=[CH:22][C:15]([OH:16])=[CH:17][C:18]=1[OH:19])=[O:14]
Reactant: O=C(O)CCCCCBr
Reactant: Oc1cccc(O)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: O=C(CCCCCBr)c1ccc(O)cc1O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Tin chloride (8.18 g) and 6-bromohexanoic acid were stirred at 120° C. Thereto was added resorcinol (5.50 g), and the resulting mixture was stirred for 20 min. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate ester. The organic layer was washed with brine and dried, followed by evaporation of the solvent under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=30:1) to give 3.70 g of 6-bromo-1-(2,4-dihydroxyphenyl)-1-hexanone.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH:8]1[O:12][CH2:11][CH2:10][O:9]1)([CH3:7])[CH3:6].[C-]#[N:14].[Na+]>CS(C)=O.O>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]([CH3:7])([CH3:6])[CH2:4][CH2:3][C:2]#[N:14]
Reactant: CC(C)(CCCCl)C1OCCO1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(CCC#N)C1OCCO1
Temperature: 25 °C
Yield: 107.3 %

Procedure:
0.74 g (3.8 mmol) of 2-(4-chloro-1,1-dimethylbutyl)-1,3-dioxolane) and 0.50 g (7.7 mmol) of sodium cyanide in 5 mL of DMSO was heated to 100° C. with stirring. After 18 hours the solution was cooled to RT, diluted with water, and the mixture extracted with ether (3×). The combined ether extracts were washed with water (3×), dried over MgSO4, and concentrated in vacuo to afford 0.69 g (90%) of the desired compound as a light yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]4[CH:25]=CC=[CH:22][CH:21]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1OC[O:37]C1CO>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][CH:20]4[CH2:21][CH2:22][O:37][CH2:25]4)=[C:13]([O:27][CH3:28])[CH:12]=3)=[CH:9][N:8]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCC1COCO1
Reactant: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)Oc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCOCC3)c3ncnc(N)c23)ccc1NC(=O)OC1CCOC1
Temperature: 100 °C

Procedure:
Phenyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (30 mg, 0.065 mmol) was mixed glycerol formal (0.05 mL) in pyridine (0.5 mL). The reaction mixture was heated at 100° C. overnight. The solvent was removed and the residue was purified by preparative reverse phase PHLC to give tetrahydro-3-furanyl N-[4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate (2 mg, 0.004 mmol). 1H NMR (CDCl-d) δ 2.06(m, 4H), 3.66(m, 2H), 3.92(m, 3H), 4.07(m, 6H), 4.79(m, 1H), 4.83(d, J=6.3 Hz, 1H), 4.96(m, 1H), 5.04(d, J=6.3 Hz, 1H), 6.15(vbs, 2H), 6.96 (s, 1H), 7.05(m, 2H), 7.53(s, 1H), 8.15(d, J=8.2 Hz, 1H), 8.22(s, 1H). LC/MS MH30 =471 and 1,3-dioxolan-4-ylmethyl N-(4-(4-amino-7-tetrahydro-2H-4-pyranyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)carbamate(6.0 mg, 0.013 mmol). 1H NMR (CDCl-d) δ 2.06(m, 4H), 3.66(m, 2H), 3.75(m, 1H), 3.92(m, 3H), 4.03(m, 1H), 4.13(m, 1H), 4.34(m, 2H), 4.94(s, 1H), 4.97(m, 1H), 5.10(s, 1H), 5.32(bs, 2H), 6.97(s, 1H), 7.03 (m, 2H), 7.06(d, J=8.2 Hz, 1H), 7.38(s, 1H), 8.15(d, J=7.9 Hz, 1H), 8.31(s, 1H). LC/MS MH30 =471.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[BrH:21].N([O-])=O.[Na+].[Br-]>O>[Br:21][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Br
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Agent: O=N[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)c1ccc(C2CCCCC2)c(Br)c1

Procedure:
To 11.1 g. (0.044 moles) of ethyl 3-amino-4-cyclohexylphenylglyoxylate suspension in 225 ml. of 40% hydrobromic acid and cooled to 0° C is added dropwise a solution of 2.34 g. of sodium nitrite in 30 ml. of water. To this mixture is added a solution of 20 g. of curpous bromide in 350 ml. of 40% hydrobromic acid added portion wise and stirred for 15 hours. The reaction mixture is then poured onto ice water, extracted with chloroform, dried over sodium sulfate and concentrated in vacuo. The residue is then crystallized to obtain 3-bromo-4-cyclohexylphenylglyoxylic acid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.C([O-])(O)=[O:24].[Na+]>C(O)(=O)C.OS(O)(=O)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:24])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2
Reactant: O=C([O-])O
Reactant: Cc1nc(C#N)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(C(N)=O)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Yield: 34 %

Procedure:
6-Methyl-5-(6-(trifluoromethyl)-1H-indazol-4-yl)picolinonitrile (0.02 g, 0.066 mmol) in acetic acid (2 mL) and H2SO4 (2 mL) was stirred at room temperature for 18 hours. The reaction mixture was subsequently poured into a conical flask containing ice and was carefully neutralized with NaHCO3 and extracted into DCM. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (Waters SunFire C18, 5 μm, 30 mm ID×75 mm column) eluting with a gradient of 45-55% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) to give the title compound as white solid (0.32 g, 34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H), 7.42 (d, J=1.26 Hz, 1H), 7.73 (br s, 1H), 7.90-8.08 (m, 3H), 8.14 (br s, 1H); ESI-MS m/z [M+H]+ calc'd for C15H11F3N4O, 321.1. found 321.2.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:19]#[N:20])=[CH:9]2)=[CH:5][CH:4]=1)=[O:2].[OH-:21].[Na+]>O1CCCC1.[Ag]=O>[C:19]([C:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:12][N:8]([C:6]2[O:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][CH:5]=2)[CH:9]=1)#[N:20]
Reactant: N#Cc1cn(-c2ccc(C=O)o2)cc1-c1ccccc1
Reactant: [OH-]
Agent: O=[Ag]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cn(-c2ccc(C(=O)O)o2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(5-formylfuran-2-yl)-4-phenyl-1H-pyrrole-3-carbonitrile (0.14 g) in tetrahydrofuran (4 mL) were added silver oxide (0.15 g) and sodium hydroxide aqueous solution (2 mol/L, 0.4 mL), and this mixture was stirred at room temperature for 6 hours. The insoluble material was removed by filtration, and this filtrate was concentrated. To this residue were added water (15 mL) and hydrochloric acid (2 mol/L, 2 mL), this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This residue was purified by column chromatography on silica gel (eluent: methanol/dichloromethane=1/10−1/5) to give the title compound (0.040 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:24]4[CH2:25][CH2:26][N:27]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[CH2:28][CH:29]=4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(Cl)(=O)OC(Cl)C>ClC(Cl)C.C(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([C:24]4[CH2:25][CH2:26][N:27]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[CH2:28][CH:29]=4)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:12][CH2:13]1
Reactant: CCCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(Cc5ccccc5)CC4)sc3c2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
To a solution of 2-(I-benzylpiperidin-4-yloxy)-6-(1-(propylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (1.812 g, 3.54 mmol) in dichloroethane (30 mL) at 0° C. was added 1-chloroethyl carbonochloridate (0.497 mL, 4.60 mmol). Upon completion of addition, the reaction mixture was stirred at 0° C. for 15 min and then heated to reflux, where it stirred for 1 h. At the conclusion of this period, the volatiles were removed under vacuum and the resulting sample was dissolved in MeOH (30 mL) and then heated to reflux, where it stirred for 1 h. After this time, the reaction mixture was cooled to rt and then concentrated under reduced pressure to yield a residue. The residue was diluted with CH2Cl2 and washed with aq K2CO3 (saturated, 10 mL) and brine (10 mL). The organic layer was dried (Na2SO4), filtered, and then concentrated to afford Compound 15A (1.405 g, 3.33 mmol, 94% yield). LC/MS (m/z)=422 (M+H)+.