Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].CO[C:4](=[O:20])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[NH2:21][NH-]>O1CCOCC1>[ClH:1].[N+:17]([C:14]1[CH:15]=[C:16]2[C:11]([NH:10][CH:9]=[C:8]2[CH2:7][C@@H:5]([C:4]([NH2:21])=[O:20])[NH2:6])=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: [NH-]N
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)[C@@H](N)Cc1c[nH]c2ccc([N+](=O)[O-])cc12

Procedure:
(S)-5-Nitrotryptophan methyl ester hydrochloride (see example 47) was converted to the corresponding amide derivative following the procedure described in example 44 for the 5-hydroxy derivative. The amino amide was then converted to its hydrochloride salt using 4N HCl in dioxane.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:7])[CH:4]([CH3:6])[CH3:5].[H-].[Na+].C(O[C:13]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)=[CH:26][N:25]=1)[CH:19]=[CH:18]2)=O)C>C1COCC1>[C:40]([O:39][C:37]([N:34]1[CH2:33][CH2:32][CH:31]([O:30][C:27]2[CH:26]=[N:25][C:24]([N:20]3[C:21]4[C:17](=[CH:16][C:15]([C:13]5[O:1][N:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:7]=5)=[CH:23][CH:22]=4)[CH:18]=[CH:19]3)=[CH:29][CH:28]=2)[CH2:36][CH2:35]1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCOC(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1
Reactant: CC(C)C(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1noc(-c2ccc3c(ccn3-c3ccc(OC4CCN(C(=O)OC(C)(C)C)CC4)cn3)c2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 22.6 %

Procedure:
To a stirred solution of N′-hydroxyisobutyrimidamide (0.10 g, 1.0 mmol) in dry THF (10 mL), NaH (0.078 g, 3.26 mmol) was added and stirred at 60° C. for 2 h. The reaction contents were brought to room temperature, Ethyl-1-(5-((1-(tert-butoxycarbonyl)piperidin-4-yl) oxy) pyridin-2-yl)-1H-indole-5-carboxylate (0.205 g, 0.440 mmol) was added and stirred at 60° C. for 3 h. The reaction was quenched by methanol at 0° C. and concentrated in vacuo. The resultant residue was dissolved with ethyl acetate and washed with water, the organic layer was separated, concentrated in vacuo and the resulting residue was purified by flash column chromatography to give the title compound (0.050 g, 10.16%).
Reaction SMILES: [C:1]1(Br)[C:10]([F:11])=[C:8]([F:9])[C:6]([F:7])=[C:4]([F:5])[C:2]=1[F:3].C([Li:17])CCC>C1(C)C=CC=CC=1>[C:1]1([Li:17])[C:10]([F:11])=[C:8]([F:9])[C:6]([F:7])=[C:4]([F:5])[C:2]=1[F:3]
Reactant: [Li]CCCC
Reactant: Fc1c(F)c(F)c(Br)c(F)c1F
Solvent: Cc1ccccc1
Product: [Li]c1c(F)c(F)c(F)c(F)c1F
Reaction time: 2 h

Procedure:
1.53 mL (0.0123 mole) of C6F5Br was put in toluene in 50 omL flask. Then, 7.67 mL (0.0123 mole) of n-butyl lithium was taken with syringe and, added dropwisely in dry ice acetone bath at −78° C., and agitated for 2 hours to obtain C6F5Li. 0.64 g (0.002 mole) of Cl2B(C6F4)BCl2 was dissolved in 40 mL of toluene, added slowly to the agitating flask at −78° C. with syringe, and the reaction was performed continuously for 12 hours by elevating the temperature to the room temperature. The remaining solvent was removed under vacuum to produce salts of (Li+)2[(C6F5)3B—C6F4—B[(C6F5)3]2−.
Reaction SMILES: C(O)C.FC(F)(F)S(O[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C:11]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=O)=O.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[N:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:10]([C:33]2[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=2)=[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(c2ccncc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C

Procedure:
To a 1:1 (v/v) ethanol:toluene solution (0.18 M) of 1-(1,1-dimethylethyl) 3-ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (1 eq.) and 4-pyridinylboronic acid (1.1 eq.) was added sodium carbonate (2 M aq. solution, 2.6 eq.). The suspension was evacuated and back-filled with N2. Finally, tetrakis(triphenylphosphine)palladium(0) (0.04 eq.) was added in one rapid portion and the reaction suspension was heated at 80° C. for 18 h. The reaction was then quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 80:20 (v/v) Hex:EtOAc→ EtOAc) afforded the title compound as a golden yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][N:5]([CH3:7])[CH:6]=1.O.[C:10]([OH:18])(=[O:17])[C:11]([CH2:13][C:14](O)=[O:15])=[CH2:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([N:8]2[C:14](=[O:15])[CH2:13][CH:11]([C:10]([OH:18])=[O:17])[CH2:12]2)=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(N)n1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1cc(Br)c(N2CC(C(=O)O)CC2=O)n1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
To a solution of 4-bromo-1-methyl-1H-pyrazol-3-amine (312 mg) in a mixed solvent of water (2.0 mL) and toluene (2.0 mL) was added itaconic acid (245 mg). The reaction mixture was stirred at 120° C. for 5 hr, and the solvent was evaporated under reduced pressure. The residue was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[CH:17][N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:35]([NH:37][CH3:38])[CH3:36].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([N:37]([CH2:35][CH3:36])[CH3:38])[N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCNC
Solvent: C1CCOC1
Solvent: O
Product: CCN(C)c1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.019 ml (0.22 mmol) of N-ethylmethylamine were stirred in 1.5 ml of THF for 30 min. About 15 ml of water were added to the reaction mixture, and the aqueous phase was extracted 3× with ethyl acetate. The combined organic phases were washed once with sodium chloride solution, dried over sodium sulfate, concentrated by evaporation and dried under high vacuum. This gave 63 mg (99% of theory) of the desired target compound.
Reaction SMILES: [OH:1][C:2]1[CH:52]=[CH:51][C:5]([CH2:6][CH:7]2[CH2:18][N:17]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15][N:14]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:13][CH2:12][N:11]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:10][CH2:9][N:8]2[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:55]([CH:57]1[O:59][CH2:58]1)Cl>C1(C)C=CC=CC=1>[O:59]1[CH2:58][CH:57]1[CH2:55][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:18][N:17]([CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15][N:14]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:13][CH2:12][N:11]([CH2:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:10][CH2:9][N:8]2[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:51][CH:52]=1
Reactant: ClCC1CO1
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)C(Cc2ccc(O)cc2)CN(CC(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)C(Cc2ccc(OCC3CO3)cc2)CN(CC(=O)OC(C)(C)C)CC1

Procedure:
12.72 g (18.2 mmol) of 2-[4-hydroxybenzyl)-1,4,7,10-tetrakis-(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (example 9d) is dissolved in 250 ml of toluene and mixed with 350 mg of sodium hydride (80% in paraffin, 18.3 mmol). It is warmed to 80° to 100° C. and mixed by instillation with a solution of 1.74 g (18.2 mmol) of epichlorohydrin in 50 ml of toluene. After refluxing for two hours, it is concentrated by evaporation and purified over a silica gel column. A colorless oil is obtained.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C:6](Cl)(Cl)=[S:7].[NH2:10][C:11]1[C:19]2[S:18][C:17]([Cl:20])=[N:16][C:15]=2[C:14]([Cl:21])=[CH:13][C:12]=1[F:22]>O.ClCCl>[Cl:20][C:17]1[S:18][C:19]2[C:11]([N:10]=[C:6]=[S:7])=[C:12]([F:22])[CH:13]=[C:14]([Cl:21])[C:15]=2[N:16]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1c(F)cc(Cl)c2nc(Cl)sc12
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: Fc1cc(Cl)c2nc(Cl)sc2c1N=C=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 16.9 g calcium carbonate in 100 ml water was added to a solution of 19.4 g thiophosgene in 100 ml dichloromethane. A solution of 40 g 7-amino-2,4-dichloro-6-fluorobenzothiazole in 500 ml dichloromethane was added, dropwise at 5° C., and the mixture stirred for 8 hours at room temperature. The solid was filtered, the phases were separated, and the organic phase dried over magnesium sulfate and concentrated. The residue was purified by column chromatography (eluent: hexane/ethyl acetate). Yield: 16 g=38% of theory m.p.: 80°-81° C.
Reaction SMILES: [Br:1][C:2]([CH2:4]Br)=[CH2:3].[C:6]1([CH2:12][CH:13]=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>[Zn].C1(C)C=CC=CC=1>[Br:1][C:2]([CH2:4][CH:13]([OH:14])[CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:3]
Reactant: O=CCc1ccccc1
Reactant: C=C(Br)CBr
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Product: C=C(Br)CC(O)Cc1ccccc1

Procedure:
49.93 Grams of 2,3-dibromo-1-propene were added dropwise to a mixture of 20.00 g of phenylacetaldehyde, 40 g of toluene, 60 g of 0.01% hydrochloric acid and 16.33 g of zinc powder at 30° C., and the mixture was allowed to react at the same temperature for 3 hours. After the reaction was completed zinc-derived insolubles were filtered off, and the resultant filtrate was separated. The organic phase was washed with a 7% sodium carbonate aqueous solution, and the toluene was distilled off under reduced pressure. The resultant oily substance was purified by silica gel column chromatography to give 24.01 g of 2-bromo-5-phenyl-1-penten-4-ol; nD25 =1.536, FI-MS m/e 240(M+), 242(M+2+).
Reaction SMILES: Cl.[NH2:2]O.[CH3:4][O:5][C:6]1[C:7]([CH3:14])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[OH-].[Na+]>C(O)=O>[CH3:4][O:5][C:6]1[C:7]([CH3:14])=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:2]
Reactant: NO
Reactant: COc1cccc(C=O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: COc1cccc(C#N)c1C
Yield: 80 %

Procedure:
Hydroxylamine hydrochloride (0.75 g, 11 mmol) was added to 3-methoxy-2-methylbenzaldehyde (1.25 g, 8.32 mmol) in formic acid (89-91%) (10 ml), and the mixture heated to reflux for 40 min., cooled, diluted with ice-cold water, basified with 10% aqueous sodium hydroxide solution and extracted with diethyl ether. The organic extract was washed with saturated aqueous sodium chloride (50 ml), dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography over silica gel eluting with 5% diethyl ether in hexane to afford the product as a white solid (0.98 g). M+ 147; 360 MHz 1H n.m.r (CDCl3) 7.26-7.17 (2H, m), 7.02 (1H, d, J 7.9 Hz), 3.86 (3H, s), 2.41 (3H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH3:30][C:31]1(O)[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][C:31]2([CH3:30])[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(O)CCCC1
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Product: CC1(OC(=O)C#C[C@H]2[C@@H](C(=O)O[C@H](C#N)c3cccc(Oc4ccccc4)c3)C2(C)C)CCCC1
Yield: 55.1 %

Procedure:
Using the procedure of Step A of Example 15, 3 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[2-carboxyethynyl]-cyclopropane-carboxylate and 3 g of 1-methylcyclopentanol were reacted. The residue was chromatographed over silica gel and was eluted with an 8-2 n-hexane-ethyl acetate mixture to obtain 2 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[2-(1-methylcyclopentyloxycarbonyl)-ethynyl]-cyclopropane-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:24])([F:23])[F:21])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccc(C)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccc(C)cc1OC)C(F)(F)F

Procedure:
Analogously to Example 7, 14.68 g of ethyl-4-(2-methoxy-4-methylphenyl)-4-methyl-2-oxopentanoate is reacted with 21.6 ml of (trifluoromethyl)trimethylsilane and 9.7 ml of tetrabutylammonium fluoride solution (1 M in THF) in 195 ml of THF to form 13.73 g of ethyl-4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoate. The product is reduced with 2.84 g of lithium aluminum hydride in 560 ml of diethyl ether to form 11.62 g of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol. The oxidation of the diol is carried out analogously to Example 7 under Swern conditions with 3.8 ml of oxalyl chloride, 7.1 ml of DMSO and 26.5 ml of triethylamine to 5.91 g of the title compound.
Reaction SMILES: ClCCCO[C:6]1[C:15]([C:16]#[N:17])=[C:14]([NH:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:28][CH3:29])[CH:12]=2)[N:7]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[I-].[Na+]>COCCOC>[NH:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([NH:18][C:14]3[C:13]4[C:8](=[CH:9][C:10]([O:28][CH2:11][CH2:10][CH2:9][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[C:11]([O:28][CH3:29])[CH:12]=4)[N:7]=[CH:6][C:15]=3[C:16]#[N:17])[CH:27]=2)[CH:23]=[N:24]1
Reactant: C1COCCN1
Reactant: COc1ccc2nc(OCCCCl)c(C#N)c(Nc3ccc4cn[nH]c4c3)c2c1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCN1CCOCC1
Yield: 56 %

Procedure:
The title compound was prepared by the procedure of Example 167 using 0.408 g of (3-chloropropoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 1.4 ml of morpholine, 0.060 g of sodium iodide and 12 ml of ethylene glycol dimethyl ether to give 0.255 g (56%) of the desired product. MP 143-145° C.; HRMS: C25H26N6O3: m/z 458.2084; δ(mu)−1.7
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[CH:10]=[CH:9][C:8]1=[O:17].FC(F)(F)C(O)=O>O>[O:17]=[C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[N:15][CH:14]=[CH:13][CH:12]=2)[N:7]1[CH2:6][CH:2]=[O:1]
Reactant: O=c1ccc2cccnc2n1CC1OCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=CCn1c(=O)ccc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To 1.1 g of 1-(1,3-dioxolan-2-ylmethyl)-1,8-naphthyridin-2(1H)-one, 11 mL of a 90% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 2 hours. Then, 1.1 mL of water was added thereto and the mixture was stirred for 13 hours, and thereto was further added 1.1 mL of water and the mixture was stirred for 3 hours 30 minutes, and stirred at 50 to 70° C. for 1 hour 30 minutes. The solvent was distilled off under reduced pressure, and to the resultant residue, a saturated aqueous sodium hydrogen carbonate solution, water and chloroform were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.75 g of (2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehyde as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:12][N:11]=[C:10]1[S:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:12][N:11]=[C:10]1[S:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCSc1ncc(C(C)C(=O)OCC)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCSc1ncc(C(C)C(=O)O)n1Cc1ccccc1Cl

Procedure:
A solution of ethyl 2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propionate (0.71 g, 1.94 mmol) in water (10 mL) and methanol (5 mL) was treated with potassium carbonate (0.51 g, 3.7 mmol). The reaction mixture was refluxed on a steam bath for 2 hours, the methanol was evaporated, the aqueous layer was washed with diethyl ether, cooled in ice, and adjusted to pH 3.4 with aqueous hydrochloric acid solution. The resulting gummy solid was extracted into methylene chloride, washed with water, dried, and concentrated. The residue was triturated with diethyl ether to give 2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propionic acid; mp 170°-172° C.
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: Cc1ccc(B(O)O)cn1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
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 (S)-tert-butyl (1-(3-bromo-5-((4-(trifluoromethoxy)phenyl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (Stage 102.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.8 min, m/z=472.0 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:19])[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].O[Li].O>C1COCC1.O>[C:15]([O:14][C:12]([N:6]1[C:5]([CH3:19])([C:3]([OH:4])=[O:2])[CH2:9][O:8][C:7]1([CH3:11])[CH3:10])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C1(C)COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(C)(C)OCC1(C)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a stirring solution of 4 (9.392 g, 34 mmol) in THF (65 mL) and H2O (35 mL) under an inert atmosphere was added solid LiOH—H2O (1.426 g, 34 mmol) in one portion. The reaction mixture was heated to 90° C. and stirred 8 h at which point the reaction mixture was cooled to rt. The crude reaction mixture was washed with Et2O (3×50 mL) and the Et2O extracts were discarded. The aqueous solution was then acidified with 2M KHSO4 until a white precipitate began to form on addition, pH=5. The acid was added dropwise until the precipitate persisted and the aqueous solution was extracted with Et2O (50 mL). After extraction, two addition drops of acid were added to the aqueous layer and it was again extracted with Et2O (25 mL). The Et2O extracts were combined and quickly back extracted with 1M NaOH (15 mL). The organic phase was then dried over sodium sulfate and concentrated in vacuo to give 5 (7.458 g, 85%) as a white solid which was used without further purification. Compound was observed as an uneven mixture of rotomers.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([NH:33][CH2:34][CH:35]5[CH2:37][CH2:36]5)[S:31][CH:32]=4)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]([NH:33][CH2:34][CH:35]3[CH2:37][CH2:36]3)[S:31][CH:32]=2)=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3ccc(-c4csc(NCC5CC5)n4)cn3)c2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2c(c1CSc1ccc(-c3csc(NCC4CC4)n3)cn1)CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-{5-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-pyridin-2-ylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.386 g, 0.693 mmol) in anhydrous DCM (16 mL) at room temperature add trifluoroacetic acid (15.9 mL) and stir the solution at room temperature overnight. Concentrate in vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM, load the solution on to a RediSep° column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 95:5 DCM/2M ammonia in methanol over 33 min; 95:5 to 90:10 DCM/2M ammonia in methanol over 33 min; 35 mL/min) to afford 7-chloro-6-{5-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-pyridin-2-ylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.315 g, 99%). MS (ES+) m/z: 457.1 (M+H)+.
Reaction SMILES: [C:1](=[O:8])([S:6][CH3:7])[O:2][CH:3](Cl)[CH3:4].[C:9]([OH:14])(=[O:13])[CH:10]([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C>CCOCC>[C:1](=[O:8])([S:6][CH3:7])[O:2][CH:3]([O:14][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:4]
Reactant: CC(C)C(=O)O
Reactant: CSC(=O)OC(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CSC(=O)OC(C)OC(=O)C(C)C
Temperature: 55 °C
Yield: 97 %

Procedure:
Compound (3) (308 g, 2 mol) was dissolved in isobutyric acid (264 g, 3 mol). This mixture was slowly added to a pre-mixed solution of isobutyric acid (264 g, 3 mol) and diisopropylethylamine (387 g, 3 mol), and the reaction mixture heated to 55° C. for 16 h, diluted with ether (10 L), washed with water (4×5 L), saturated bicarbonate solution (2×5 L) and brine (5 L), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (2) as colorless liquid (400 g, 97% yield). The product was optionally further purified by vacuum distillation (135° C./20 Torr). 1H NMR (CDCl3, 400 MHz): δ 1.17 (d, J=6.8 Hz, 6H), 1.49 (d, J=5.6 Hz, 3H), 2.33 (s, 3H), 2.54 (m, 1H), 6.91 (q, J=5.2 Hz, 1H).