Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30].[ClH:33]>CN1CCCC1=O.O1CCOCC1>[ClH:33].[C:1]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(C)(O)CN
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NCC(C)(C)O)cc3)cc2s1
Temperature: 150 °C
Yield: 25 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester (intermediate 78) (135 mg, 0.34 mmol) and 1-amino-2-methylpropan-2-ol (153 mg, 1.718 mmol) in 3 ml of N-methylpyrrolidone in a 5 ml microwave vial, equipped with a magnetic bar, is heated for 20 minutes at 150° C. by microwave. The reaction medium is extracted with ethyl acetate (3×20 ml) and washed with water (4×25 ml). The organic phase is dried over magnesium sulfate, filtered and then evaporated to dryness. The residue obtained is purified by chromatography on silica, on an 8 g 15-35 μm AIT column, eluting with a 9/1 ethyl acetate/cyclohexane mixture. After evaporating off the solvent, 55 mg of a colorless solid are obtained. The product is dissolved in a minimum amount of dioxane, and 4 N hydrochloric acid dissolved in dioxane is added. The precipitate obtained is filtered off by suction, washed with dioxane and then dried under vacuum at 40° C. to give 42 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic acid 2-butyrylaminobenzothiazol-6-yl ester hydrochloride, i.e. a yield of 25%.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC>CCOCC>[C:1]1([Li:18])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: CCOCC
Product: [Li]c1cccc2c1Cc1ccccc1-2

Procedure:
Here 5 g (30 mmol) fluorene, dissolved in ether, was reacted for three hours with 18.8 ml of butyllithium (1.6M in hexane). The solvent was evaporated to yield yellow fluorenyl lithium. Then 11.4 g (45 mmol) of Ph2SiCl2, i.e. diphenyl dichloro silane, was dissolved in 200 ml of pentane and the solid fluorenyl lithium was added in one portion to the pentane solution. After stirring for one hour, the mixture was filtered, the precipitated LiCl was eluated with 50 ml of ether, and the solvent evaporated from the combined organic layers to yield a yellow powder characterized by GC/MS as FlSiPh2Cl, i.e. fluorenyl-diphenyl chlorosilane. Crystallization in pentane yields colorless crystals of the product, from which a H-NMR-spectra could be obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:30][CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:44](=O)[CH2:45][CH3:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:44][CH2:45][CH3:46])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C@H:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[CH:32][CH:33]=4)=[O:26])=[CH:20][C:19]=3[CH:43]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3CCC)cc1
Reaction time: 20 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (120 mg) and propionaldehyde (0.15 ml) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.13 g) at room temperature, and the mixture was stirred for 20 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:2), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 83) (105.4 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([Br:31])[CH:18]=1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]1[CH:75]=[CH:74][CH:73]=[C:72]([OH:76])[C:67]=1[C:68]([O:70][CH3:71])=[O:69].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:28])(=[O:29])[NH:26][C:25](=[O:30])[CH2:24]2)=[C:19]([Br:31])[CH:18]=1)[C:13]([NH:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]1[CH:75]=[CH:74][CH:73]=[C:72]([OH:76])[C:67]=1[C:68]([O:70][CH3:71])=[O:69])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Reactant: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
(2S)-2-[(Benzyloxy)carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid (10.2 mg, 0.020 mmol) in DMF (2.00 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10.6 mg, 0.0240 mmol). After five minutes methyl 2-(4-aminobutoxy)-6-hydroxybenzoate hydrochloride (8.27 mg, 0.030 mmol) and N,N-diisopropylethylamine (17.4 μL, 0.100 mmol) were added and the solution stirred at rt for 2 h. Purification by preparative LCMS afforded product as a white solid (8.9 mg, 61%). 1H NMR (400 MHz, CD3OD): δ 8.07 (brs, 1H), 7.63 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.31–7.23 (m, 7H), 6.49–6.46 (m, 2H), 5.43 (t, J=6.1 Hz, 1H), 5.02 (s, 2H), 4.33–4.29 (m, 1H), 3.97–3.92 (m, 2H), 3.85 (s, 3H), 3.47–3.36 (m, 2H), 3.29–2.82 (m, 4H), 1.68–1.60 (m, 4H); LCMS found for C32H35BrN3O10S (M+H)+: m/z=734.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=O)[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].P(Cl)(Cl)([Cl:19])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[N:14][C:13]([Cl:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2ccc(=O)[nH]n2)cc1Br
Product: COc1ccc(-c2ccc(Cl)nn2)cc1Br

Procedure:
A suspension of 100 g. of 6-(3-bromo-4-methoxyphenyl)-3(2H)-pyridazinone [J. Heterocyclic Chem. 11, 775 (1974) ]in 150 ml. of phosphorus oxychloride is refluxed until a clear solution is obtained (approximately 5 hours). The solution is cooled and excess phosphorus oxychloride is removed under vacuum to give a brown solid which is triturated with ice water. The solid is collected by filtration and is recrystallized to afford 3-(3-bromo-4-methoxyphenyl)-6-chloropyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([NH:8][C:9]([NH:11][C:12](=[O:22])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=2[Cl:21])=[O:10])[CH:7]=1.[CH3:25][N:26]=[C:27]=[O:28]>C(#N)C>[Cl:21][C:14]1[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=1[C:12]([NH:11][C:9](=[O:10])[NH:8][C:6]1[CH:7]=[C:2]([NH:1][C:27]([NH:26][CH3:25])=[O:28])[CH:3]=[CH:4][C:5]=1[O:23][CH3:24])=[O:22]
Reactant: CN=C=O
Reactant: COc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Solvent: CC#N
Product: CNC(=O)Nc1ccc(OC)c(NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
600 mg (1.7 mmol) of 1-(5-amino-2-methoxyphenyl)-3-(2-chloro-4,5-difluoro-benzoyl)urea were dissolved in 5 ml of acetonitrile, and 69 mg (1.7 mmol) of methyl isocyanate were added. After stirring at room temperature for one hour, the resulting precipitate was filtered off with suction. 638 mg (91%) of the desired product were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH:11](O)[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:9])=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1>C(Cl)(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH:11]([NH:36][C:35]2[CH:37]=[CH:38][C:32]([Cl:31])=[CH:33][CH:34]=2)[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)=[O:13])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(NC(O)C(=O)c1cccc2ccccc12)c1ccc(Br)cn1
Reactant: Nc1ccc(Cl)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(NC(Nc1ccc(Cl)cc1)C(=O)c1cccc2ccccc12)c1ccc(Br)cn1
Temperature: 50 °C
Yield: 36.9 %

Procedure:
5-bromo-N-(1-hydroxy-2-(naphthalen-1-yl)-2-oxoethyl)picolinamide 113 (0.74 g, 1.93 mmol) in chloroform (20 mL) was reacted with PCl5 (0.43 g, 1.96 mmol). The mixture was heated to 50° C. for 30 minutes and cooled to 0° C. 4-Chloroaniline 114 (0.512 g, 4.01 mmol) in THF (10 mL) was added and allowed to react for 1 hour. The reaction was quenched with water and the product was extracted with ethyl acetate. The organic solution was dried over MgSO4, filtered and concentrated onto silica gel. The product was purified by auto flash column chromatography (30 to 50% CH2Cl2: hexane) followed by titration with diethyl ether to give 5-bromo-N-(1-(4-chlorophenylamino)-2-(naphthalen-1-yl)-2-oxoethyl)picolinamide (Compound-1, 352 mg, 37%). 1H NMR (300 MHz, CDCl3): δ=8.83 (d, J=8.7 Hz, 1H), 8.50 (d, J=1.5 Hz, 1H), 8.46 (d, J=9.6 Hz, 1H), 8.39 (dd, J=1.2, 7.2 Hz, 1H), 8.07-8.03 (m, 2H), 7.93 (dd, J=2.4, 8.7 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.68-7.63 (m, 1H), 7.56 (t, J=7.8 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.09-7.03 (m, 1H), 6.82 (d, J=9.0 Hz, 2H) 5.41 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][N:28]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[N:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: COc1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Product: COc1cnc(N2CCC([C@H]3Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-methoxy-pyrimidine following a procedure analogous to that described for Example 79. LC (method 10): tR=1.48 min; Mass spectrum (ESI+): m/z=472 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]O)[CH:2]=1.S(Cl)(Cl)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[N+:20]=[N-:21]
Reactant: OCc1ccccc1-c1cccnc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=NCc1ccccc1-c1cccnc1

Procedure:
The product of Example 119A, thionyl chloride and sodium azide were processed according to the method of Example 115A to provide the product. MS (ESI+) m/z 211 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[CH:16]=1)(=[NH:4])[NH2:3].[OH-].[Na+].[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27]([NH:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[CH:16]=1)=[NH:3])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(N)c1ccc2oc(C(=O)O)cc2c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Tetrahydrofuran (200 ml) was added to hydrochloride (7.55 g, 31.4 mmol) of 5-amidino-2-benzofurancarboxylic acid, and the mixture was ice-cooled. The mixture was maintained at pH 10 with a 1N aqueous sodium hydroxide solution while dropwise addition of benzyloxycarbonyl chloride (6.74 ml, 47.0 mmol) over about 15 minutes. The mixture was stirred for 30 minutes and then at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting precipitate was collected by filtration, and washed with water and an equivalent mixture of n-hexane and ethyl acetate to give 7.94 g of 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid as a pale-yellow solid (75%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C@H:6]([OH:8])[C@@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[O:12]=[C:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[CH:14]=[CH:15]/[C:16](O)=[O:17].C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([O:8][C:16](=[O:17])/[CH:15]=[CH:14]/[C:13](=[O:12])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1
Reactant: O=C(O)/C=C/C(=O)c1ccccc1
Reactant: CC1CC[C@H](C(C)C)[C@@H](O)C1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1CCC(C(C)C)C(OC(=O)/C=C/C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.43 g (0.028 mole) of (+)-menthol and 0.34 g (0.003 mole) of 4-dimethylaminopyridine are added to a solution of 5.0 g (0.028 mole) of (E)-4-oxo-4-phenyl-2-butenoic acid in 60 ml of anhydrous dichloromethane. After cooling the solution to 0° C., a solution of 5.86 g (0.028 mole) of N,N-dicyclohexylcarbodiimide in 20 ml of anhydrous dichloromethane is added. The mixture is stirred at 0° C. for 30 minutes, then at room temperature for one hour. The reaction mixture is worked up as described in Example 1 to give the crude product as a dark-brown oil in a yield of 8.1 g (91%) which is purified by using column chromatography as described in Example 1. The named compound is obtained in a yield of 6.7 g, Rf =0.78 (dichloromethane); [α]D25 =+65° (c=2.0, chloroform).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)#[N:27]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C(=O)c1ccc(C#N)cc1)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
The synthesis of the starting material, 3-tert-butoxycarbonyl-3,9-diaza-spiro[5.5]undecane, was accomplished as described in U.S. Pat. No. 5,451,578. This mateial (1.45 g) was dissolved in CH2Cl2 (25 mL) and cooled to 0° C. under an argon atmosphere. To this solution was added triethylamine (1.67 mL) and 4-dimethylaminopyridine (70 mg) followed by 4-cyanobenzoyl chloride (1.04 g). The mixture was stirred overnight as it warmed to rt. It was cooled to 0° C., and ice cold 1 M HCl (30 mL) was carefully added. The resulting mixture was washed with EtOAc (3×30 mL). Then washing the EtOAc with saturated NaHCO3 and brine followed by drying with MgSO4 and evaporation of the solvent under reduced pressure afforded the title compound (1.62 g, 74%) as a yellow foam. Chromatography on silica gel with hexanes/ethyl acetate (2:1) as eluant gave pure compound.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[C:34]([NH:35]C(=O)OCC3C=CC=CC=3)=[CH:33][C:32]3[C:27](=[CH:28][C:29]([N:46]4[CH2:51][CH2:50][N:49]([CH3:52])[C:48](=[O:53])[CH2:47]4)=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:10]1)=O)(C)(C)C>CO.Br.CC(O)=O>[NH2:35][C:34]1[C:25]([C:23]([NH:22][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[N:11]2[CH2:12][C@H:13]([CH3:15])[CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:24])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([N:46]1[CH2:51][CH2:50][N:49]([CH3:52])[C:48](=[O:53])[CH2:47]1)[CH:28]=2
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl [2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(4-methyl-3-oxopiperazin-1-yl)quinolin-3-yl]carbamate (0.005 g, 0.007 mmol) in 1 mL of MeOH and 2 mL of 33% HBr in AcOH was stirred at room temperature for 2 h. The mixture was evaporated to dryness under reduced pressure. The resulting residue was dissolved in 4 mL of MeOH and treated with 0.5 mL of NH4OH solution. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C26H33N8O2 [M+H]+: m/z=489.3. found: 489.3.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)=O.[C:23]1([SH:33])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:23]1([S:33][CH2:6][CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Sc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1[nH]c2ccccc2c1CCCSc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 10A (42 mg), naphthalene thiol (45 mg), and potassium carbonate (36 mg) in acetonitrile (2 mL) was heated at 80° C. for 3 days. The reaction mixture was poured into water, extracted with dichloromethane and purified by flash chromatography on silica gel with 0-20% ethyl acetate in hexanes.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: C1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCCC2)c(C#N)c1-c1ccc(OCCO)cc1

Procedure:
At RT, 90 mg (0.17 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 30 μl (0.37 mmol) of pyrrolidine were stirred in 2.3 ml of THF for 30 min. About 12 ml of water were added to the reaction mixture, the suspension formed was freed from THF on a rotary evaporator, and the precipitate formed was filtered off and washed with water and dried under high vacuum. This gave 78 mg (81% of theory) of the desired target compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:29][CH2:28][C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:11]([CH3:10])[CH:12]2[CH2:29][CH2:28][C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]3)[CH2:14][CH2:13]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CNC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cnc(Cl)nc1N(C)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 100 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (300 mg, 1.84 mmol) and tert-butyl 9-(methylamino)-3-azaspiro[5.5]undecane-3-carboxylate (573.32 mg, 2.03 mmol) in ethanol (30 mL) was added N,N-diethylethanamine (372.38 mg, 3.68 mmol). The reaction mixture was stirred at 100° C. overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as yellow oil (165 mg, 22%).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Nc1ccccc1Cl
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccccc1Cl
Yield: 31.4 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (3.00 g, 14.5 mmol) and 2-chloroaniline (2.77 g, 21.7 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (1.44 g, 31%) was obtained.
Reaction SMILES: S(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(C)(=O)=O.[Na+].[I-:26]>C(#N)C>[I:26][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: [I-]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1CCOS(C)(=O)=O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1CCI
Yield: 118.1 %

Procedure:
Ethyl 1-(2-mesyloxyethyl)-3-carboethoxy-4-methylpyrrole-2-acetate (11.6 g) and 27 g of NaI was heated to reflux with 150 ml of acetonitrile for 1 hour. Solvent was removed by distillation and the residue triturated with water. The insoluble product was separated by filtration, air dried and crystallized from methylenechloride/hexane to yield 14.9 g of ethyl 1-(2-iodoethyl)-3-carboethoxy-4-methylpyrrole-2-acetate as a white solid.