Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.[CH:23](=[O:26])[CH2:24][CH3:25]>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][CH:23]([OH:26])[CH2:24][CH3:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C)c(NC(=O)OC(C)(C)C)c1
Reactant: CCC=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCC(O)Cc1ccc(OC)cc1NC(=O)OC(C)(C)C
Temperature: -20 °C
Yield: 39.3 %

Procedure:
To a solution of (5-methoxy-2-methyl-phenyl)-carbamic acid t-butyl ester (6.95 g, 29.3 mmole) in 100 ml THF cooled at −45° C. was added sec-BuLi (45 ml, 58.5 mmole) slowly to keep temperature lower than −45° C. The reaction mixture was stirred and warmed to −20° C., then cooled to −45° C. and propionaldehyde (2.67 ml, 36.63 mmole) was added. The reaction mixture was stirred and warmed to room temperature for 1 h, quenched with 1N HCl and extracted with EtOAc, dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (10-15% EtOAc in hexane) to give colorless oil (3.40 g, 39%). 1H NMR (CDCl3) δ7.96 (1H, s), 7.44 (1H, s), 6.96-7.00 (1H, m), 6.55 (1H, m), 3.80 (3H, s), 2.60-2.76 (2H, m), 1.93-1.95 (2H, m), 1.50 (9H, s), 0.93-1.01 (4H, m). ESIMS (MNa+): 318.20.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([N:28]([C:30]4[S:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)[N:34]=4)[CH3:29])=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=O)[N:22]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:43]>CN(C=O)C.[Cl-].[Na+].O>[NH2:43][C:25](=[O:27])[CH2:24][CH2:23][C:21]1[N:22]=[C:17]2[CH:16]=[CH:15][C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]3)=[CH:19][N:18]2[C:20]=1[N:28]([C:30]1[S:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:34]=1)[CH3:29]
Reactant: CN(c1nc(-c2ccc(F)cc2)cs1)c1c(CCC(=O)O)nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn12
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1nc(-c2ccc(F)cc2)cs1)c1c(CCC(N)=O)nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 3-(6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-2-yl)propanoic acid (220 mg, 0.38 mmol, 1 eq.) and TEA (211 μL, 1.52 mmol, 4 eq.) in DMF (3 mL) was stirred for 10 min at r.t. Propane phosphonic acid anhydride (226 μL, 0.76 mmol, 2 eq.) followed by ammonium chloride (40.7 mg, 0.76 mmol, 2 eq.) were added and the resulting mixture was stirred at r.t. for 4 days. TEA (211 μL, 1.52 mmol, 4 eq.), propane phosphonic acid anhydride (226 μL, 0.76 mmol, 2 eq.) and ammonium chloride (40.7 mg, 0.76 mmol, 2 eq.) were added and the reaction mixture kept stirring for 2 h. Brine was added (100 mL) and the mixture was extracted with DCM (3×20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel (elution with DCM/MeOH 100/0 to 80/20) to give tert-butyl 4-(2-(3-amino-3-oxopropyl)-3-((4-(4-fluorophenyl)thiazol-2-yl)(methyl)amino)imidazo[1,2-a]pyridin-6-yl)piperidine-1-carboxylate (Gen-10-am).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:14]=[O:15])([O-:3])=[O:2].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=1>>[Br:16][C:17]1[CH:18]=[C:19]([CH:14]([C:5]2[CH:6]=[CH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]=2[N+:1]([O-:3])=[O:2])[OH:15])[CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1ccc2ccccc2c1[N+](=O)[O-]
Reactant: Brc1cccc(I)c1
Product: O=[N+]([O-])c1c(C(O)c2cccc(Br)c2)ccc2ccccc12

Procedure:
The titled compound was prepared from 1-nitro-2-naphthaldehyde and 1-bromo-3-iodobenzene in a procedure similar to that of example 1 (1).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl.[OH-].[Na+]>O.O.Cl[Sn]Cl.C1OCCOCCOCCOCCOCCOC1>[CH2:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH:12]1[O:14][CH2:13]1
Reactant: CC(C)CCCCCO
Reactant: ClCC1CO1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(C)CCCCCOCC1CO1
Temperature: 130 °C
Reaction time: 20 h
Yield: 89.9 %

Procedure:
A reactor equipped with stirrer, reflux condenser, dropping funnel and thermometer is charged with 130.23 g (1.0 mol) of isooctanol (mixture of isomers), 4.51 g (0.02 mol) of SnCl2.2H2O and 5.28 g (0.02 mol) of 18-crown-6 (crown ether) and the charge is heated to 130° C. Then, with efficient stirring, 86.26 ml (1.1 mol) of epichlorohydrin are added over 30 minutes. The reaction is allowed to continue for 20 hours, during which time the temperature rises to about 135° C. The reaction mixture is cooled to 55° C. and then, at this temperature, 88 g (1.1 mol) of a 50% solution of sodium hydroxide are added dropwise with efficient stirring over 30 minutes. After stirring for 5 hours at 55°-60° C. and cooling to room temperature, the suspension is filtered and the filtrate is washed with ethyl acetate. The phases are separated, and the aqueous phase is extracted with 2×100 ml of ethyl acetate. The combined organic phases are washed with as small an amount of 10% KH2PO4 solution as possible and then with water until neutral, dried over magnesium sulfate and filtered. The filtrate is freed from solvent on a rotary evaporator under vacuum (bath temperature 50° C.). Yield: 167.4 g (90% of theory) of yellowish isooctanol glycidyl ether (mixture of isomers) for which the following analytical values are obtained: epoxy value: 3.93 eq/kg (73% of theory); total chlorine content: 2.44%; hydrolysable chlorine content: 232 ppm.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:19][OH:20])=[C:4]([CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH:5]=[N:6][C:7]=1[CH3:8].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][O:1][C:2]2[C:3]([CH2:19][OH:20])=[C:4]([CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[CH:5]=[N:6][C:7]=2[CH3:8])=[CH:24][CH:25]=1)#[N:30]
Reactant: Cc1ncc(COc2ccc(C#N)cc2)c(CO)c1O
Reactant: N#Cc1ccc(CBr)cc1
Product: Cc1ncc(COc2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Yield: 49 %

Procedure:
The coupling of 4-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethoxy)-benzonitrile (13) (1.08 g, 4.0 mmol) and α-bromo-p-tolunitrile (0.9 g, 4.8 mmol), as described in Example, gave 4-(5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethoxy)-benzonitrile (14) (755 mg, 49% yield) as a colorless solid.
Reaction SMILES: S(=O)(=O)(O)O.C(N)=O.[C:9]1([N:15]2[C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:18](=[O:25])[NH:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[C:9]1([N:15]2[C:19]3([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[C:18](=[O:25])[N:17]=[CH:16]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: O=S(=O)(O)O
Solvent: NC=O
Solvent: O
Product: O=C1N=CN(c2ccccc2)C12CCNCC2

Procedure:
As shown in Scheme 2, Compounds (I) wherein R is hydrogen can be prepared from a piperidine-4-one (V) through a compound (VI) according to known procedures as described in U.S. Pat. No. 3,238,216. First, the compound (V) can be reacted with a hydrochloric acid salt of an amino compound (VII) (i.e., XNH2) in the presence of a suitable cyanating agent such as potassium cyanide (KCN), to give the compound (VI). This reaction can be carried out in a suitable reaction inert solvent such as water at 0° to 50° C. for 30 min. to 7 days. Then, the compound (VI) may be treated with sulfuric acid at 0° to 100° C. for 30 min. to 10 hours, followed by reaction with formamide (HCONH2). The reaction with formamide may be carried out at 150° to 250° C. for 30 min. to 20 hours. If a mixture of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one derivative and 1-phenyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one derivative is obtained in this reaction condition, the mixture may be treated with a reducing reagent such as sodium borohydride (NaBH4) to give desired 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one derivative.
Reaction SMILES: [ClH:1].[F:2][CH:3]([F:30])[O:4][C:5]1[CH:6]=[C:7]([S:11]([N:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:17]=2)[CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[ClH:1].[F:30][CH:3]([F:2])[O:4][C:5]1[CH:6]=[C:7]([S:11]([N:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]3[CH2:25][CH2:26][N:27]([CH3:33])[CH2:28][CH2:29]3)[CH:17]=2)[CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccc(N(C)S(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: COc1ccc(N(C)S(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C)CC1

Procedure:
The compound was prepared by reaction of 3-difluoromethoxy-N-[4-methoxy-3-(piperazin-1-yl)-phenyl]-N-methyl-benzenesulfonamide hydrochloride (compound of example 2) with aqueous formaldehyde and sodium triacetoxyborohydride as described for example 5.
Reaction SMILES: C(Cl)CCl.[OH:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH:17]1([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=2[CH:31]=[O:32])[CH2:19][CH2:18]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:17]1([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([O:5][CH2:6][C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[O:27])=[CH:24][C:23]=2[CH:31]=[O:32])[CH2:19][CH2:18]1
Reactant: O=Cc1cc(C(=O)O)ccc1OCC1CC1
Reactant: O=C(CO)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=Cc1cc(C(=O)OCC(=O)OCc2ccccc2)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (2.52 g, 13.16 mmol) was added to a solution of compound benzyl 2-hydroxyacetate (2.02 g, 12.15 mmol), 4-(cyclopropylmethoxy)-3-formylbenzoic acid (2.23 g, 10.13 mmol), and DMAP (247 mg, 2.03 mmol) in DCM (20 ml) at RT under nitrogen atmosphere. The mixture was stirred at RT overnight. The mixture was then diluted with DCM and washed with NaHCO3 sat. sol., HCl 0.1M and brine. The organic phase was dried over Na2SO4, and the solvent was evaporated. 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-formylbenzoate was obtained (3.73 g, quantitative yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[Br:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[Cl:35])=[CH:20][C:16]=1[C:17]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:18]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Br
Reactant: OC1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCOC1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Br
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-bromo-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-bromo-5-(2-chloro-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][CH2:62][C:63]1[C:64]([CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[N:65][CH:66]=[CH:67][CH:68]=1>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:61][CH2:62][C:63]2[C:64]([CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:74])([CH3:76])[CH3:75])=[N:65][CH:66]=[CH:67][CH:68]=2)=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NCc1ncccc1CN
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)c(NCCc2cccc(F)c2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ncccc1CNC(=O)c1ccc(-c2ccccc2C#N)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (0.60 g, 1.66 mmol) in DMF (3 mL) was added DIEA (0.329 mL, 2.53 mmol), HBTU (0.756 g, 2.00 mmol), then tert-butyl (3-(aminomethyl)pyridin-2-yl)methylcarbamate (0.473 g, 2.11 mmol). The reaction mixture was stirred at room temperature for 1 hr. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give tert-butyl (3-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate as a pale yellow solid (545 mg, 57%). LRMS (M+H+) m/z 581.3.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:8][O:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5].[CH3:21][Mg]Br>C1COCC1>[CH:11]1([C:10]2[O:9][N:8]=[C:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[C:4](=[O:5])[CH3:21])[CH2:12][CH2:13]1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1c(-c2ccccc2)noc1C1CC1
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccccc2)noc1C1CC1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 5-cyclopropyl-3-phenyl-isoxazole-4-carboxylic acid methoxy-methyl-amide (4.00 g, 14.7 mmol) in THF (42 mL) cooled to −78° C. was added a solution of methylmagnesium bromide (3 M in diethylether, 9.80 mL, 29.4 mmol) dropwise within 5 min at −78° C. The cooling bath was removed and the reaction mixture was allowed to warm up to room temperature over 2.5 h. The reaction mixture was then re-cooled to −78° C., diluted with a saturated ammonium chloride solution (50 mL), allowed to warm up to room temperature and then diluted with water and extracted with ethyl acetate. The combined organic layers were then washed with brine and then dried over sodium sulphate and evaporated to afford the title compound (3.2 g, 94%) which was obtained as a light yellow solid. MS: m/e=228.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])=[O:39])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH:35]([OH:37])[CH3:36])=[CH:31][N:30]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:52](OC(=O)C)(=[O:54])[CH3:53].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl.N1C=CC=CC=1>[C:52]([O:37][CH:35]([C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][C:23]([N:20]3[CH2:19][CH2:18][CH:17]([CH2:16][C:12]4[N:11]=[C:10]([C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)=[O:43])=[O:39])[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[C:14]([CH3:15])[N:13]=4)[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)=[N:30][CH:31]=1)[CH3:36])(=[O:54])[CH3:53]
Reactant: Cc1nc(CC2CCN(c3ccc(-c4ccc(C(C)O)cn4)cc3)CC2)nc(C(=O)NCC(=O)OCc2ccccc2)c1OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1ccc(-c2ccc(N3CCC(Cc4nc(C)c(OCc5ccccc5)c(C(=O)NCC(=O)OCc5ccccc5)n4)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.6 %

Procedure:
Benzyl [({5-(benzyloxy)-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidin-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.24 g, 0.35 mmol) obtained in Example 12-(3) was dissolved in dichloromethane (30 mL), and acetic anhydride (0.050 mL, 0.52 mmol) and triethylamine (1.8 mL) were added, followed by stirring at room temperature for 12 hours. Acetic anhydride (1.8 mL) and pyridine (0.90 mL) were added to the reaction solution, followed by stirring for further 12 hours, and subsequently a saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with ethyl acetate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.40 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.12 g, 0.17 mmol) as a yellow oil (yield 48%).
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][C:10]1[C:11]([O:42][CH3:43])=[N:12][C:13]([N:17]2[CH2:21][CH:20]([CH2:22]O)[C:19]([NH:30][C:31]([NH:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[S:32])([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH2:18]2)=[N:14][C:15]=1[CH3:16].C(=O)(O)[O-].[Na+]>ClCCl>[F:9][C:10]1[C:11]([O:42][CH3:43])=[N:12][C:13]([N:17]2[CH2:21][CH:20]3[C:19]([C:24]4[CH:29]=[N:28][CH:27]=[CH:26][N:25]=4)([N:30]=[C:31]([NH:33][C:34](=[O:41])[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[S:32][CH2:22]3)[CH2:18]2)=[N:14][C:15]=1[CH3:16]
Reactant: COc1nc(N2CC(CO)C(NC(=S)NC(=O)c3ccccc3)(c3cnccn3)C2)nc(C)c1F
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc(N2CC3CSC(NC(=O)c4ccccc4)=NC3(c3cnccn3)C2)nc(C)c1F
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
1-Chloro-N,N,2-trimethylpropenylamine (492 μL, 3.71 mmol) is added to a stirred solution of N-[[1-(5-fluoro-4-methoxy-6-methyl-pyrimidin-2-yl)-4-(hydroxymethyl)-3-pyrazin-2-yl-pyrrolidin-3-yl]carbamothioyl]benzamide (1.32 g, 2.65 mmol) in dichloromethane (30 mL) at room temperature. The reaction mixture is stirred for 1 hour 30 minutes. Then a saturated aqueous solution of sodium bicarbonate (20 mL) is added followed by dichloromethane (70 mL). The layers are separated and the aqueous layer is re-extracted with dichloromethane (70 mL). The combined organic layers are dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is dissolved in methanol (40 mL) and loaded on an ion exchange column. The column is eluted with methanol (60 mL) then with 7 M ammonia/methanol solution (100 mL). The basic solvent fraction is collected and evaporated under reduced pressure. The isolated residue is further purified by silica gel column chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (820 mg, 64%). ES/MS (m/e): 480 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].C(N(CC)CC)C.C1COCC1.[C:48]1(=[O:52])[O:51][CH2:50][CH2:49]1>C(OCC)(=O)C>[OH:52][CH2:48][CH2:49][C:50]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]1)=[O:51]
Reactant: O=C1CCO1
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1c(C(=O)NC2CCN(C(=O)CCO)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.4 %

Procedure:
To a mixture of the compound of Example 77 (200 mg, 0.423 mmol), triethylamine (423 μL, 3.18 mmol) and THF (10 mL) was added β-propiolactone (39.9 μL, 0.635 mmol) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate). Recrystallization of the obtained solid from ethyl acetate gave the title compound (70.0 mg, 30%) as a white powder.
Reaction SMILES: [N:1]([C:4]1([CH3:20])[CH2:8][CH2:7][CH2:6][CH:5]1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C:4]1([CH3:20])[CH2:8][CH2:7][CH2:6][CH:5]1[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:12])=[O:11]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)NC2CCCC2(C)N=[N+]=[N-])cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC2CCCC2(C)N)cc1

Procedure:
To a solution of N-(2-azido-2-methylcyclopentyl)-4-methylbenzene-1-sulfonamide (52.0 g, 176.87 mmol) in methanol (1100 ml) was added palladium on carbon (10% wt, 10.0 g). The reaction mixture was stirred at room temperature under a balloon of hydrogen gas for 12 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:8](I)=[C:9]2[CH:15]=[CH:14][N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:10]2=[N:11][CH:12]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH:40]=[O:41])[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH:40]([C:8]2[C:7]([Cl:6])=[CH:12][N:11]=[C:10]3[N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:9]=23)[OH:41])[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Reactant: O=CC1CCCN(Cc2ccccc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CCCN(Cc4ccccc4)C3)c(Cl)cnc21
Reaction time: 0.67 h
Yield: 99.8 %

Procedure:
A solution of n-BuLi (1.6 N in heptane, 8.62 mL, 13.8 mmol) was added dropwise to a solution of 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.00 g, 11.5 mmol, Adesis) in THF (135 mL) at about −78° C., keeping the temperature below about −70° C. After stirring for about 40 min, a solution of 1-benzylpiperidine-3-carbaldehyde (4.21 g, 20.7 mmol) in THF (15 mL) was added dropwise and the resulting mixture was stirred at about −75° C. for about 2 h. The reaction was quenched by dropwise addition of saturated aqueous NH4Cl (100 mL) and the THF was removed under reduced pressure. The aqueous phase was extracted into EtOAc (250 mL), washed with brine (200 mL), and concentrated to yield crude (1-benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (5.88 g, quantitative) as a yellow oil that was used directly in the next step without further purification: LC/MS (Table 2, Method a) Rt=1.78 min; MS m/z: 512 and 514 (M+H)+