Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11]I)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:21][S-:22].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][S:22][CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N[C@H](CCI)c1ccc(Cl)c(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Yield: 60 %

Procedure:
A solution of 366 (810 mg, 1.88 mmol) and sodium methanethiolate (158 mg, 2.26 mmol) in DMSO (4 mL) was stirred at 50° C. overnight. The mixture was poured into water, extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo to afford 395 mg (60%) of (R)-tert-butyl 1-(3,4-dichlorophenyl)-3-(methylthio)propylcarbamate (372).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].[C:17]1(=[O:31])[N:21]([CH2:22][C:23](Cl)=[O:24])[C:20](=[O:26])[C:19]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:18]12>ClCCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:23](=[O:24])[CH2:22][N:21]3[C:20](=[O:26])[C:19]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:18]4[C:17]3=[O:31])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:12]
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: CN1C(=O)CCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CN1C(=O)CCc2cc(C(=O)CN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 85 °C
Reaction time: 6 h
Yield: 48.4 %

Procedure:
To a stirred solution of 1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin (17.7 g) and aluminum chloride (44.5 g) in 1,2-dichloroethane (26 ml) was added dropwise a solution of 2-phthalimidoacetyl chloride (25 g) in 1,2-dichloroethane (45 ml). The reaction mixture was stirred for 6 hours at 85° C. and then 22 hours at 60° C. After cooling, the mixture was poured into ice water and extracted with chloroform. The extract was washed successively with water, an aqueous solution of sodium bicarbonate and water, dried and evaporated. The residue was triturated with ethyl acetate and the resultant precipitates were collected by filtration, washed with ethyl acetate and dried to give 18.51 g of 1-methyl-2-oxo-6-phthalimidoacetyl-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]([NH:11][NH:12][C:13](=O)[CH3:14])=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[S:26][C:13]([CH3:14])=[N:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NNC(=O)CNC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: Cc1nnc(CNC(=O)OC(C)(C)C)s1
Yield: 79.3 %

Procedure:
To a 37.5 mL THF solution of tert-butyl[2-(2-acetylhydrazino)-2-oxoethyl]carbamate (496 mg, 2.15 mmol) was added Lawesson's reagent (900 mg, 2.23 mmol). The resulting reaction mixture was heated to reflux for 3 hr. The reaction was concentrated and chromatographed on silica gel eluting with a gradient solvent mixture of AcOEt & dichloromethane to give the title compound as white crystalline solid (391 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:5]=1[C:6]([OH:8])=[S:7])([O-:3])=[O:2].[N+](=[CH2:16])=[N-]>CO>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:5]=1[C:6]([O:8][CH3:16])=[S:7])([O-:3])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: Cc1ccc([N+](=O)[O-])c(C(O)=S)c1
Solvent: CO
Product: COC(=S)c1cc(C)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To an ice cold solution of 52.1 g. of 2-nitro-5-methylthiobenzoic acid in 250 ml. of methanol was added an ethereal solution of diazomethane until thin layer chromatography indicated the reaction was complete. The resulting solution was evaporated to dryness and used as such. In one case the crude product was crystallized from methanol to give yellow needles of methyl 2-nitro-5-methylthiobenzoate, mp 53°-54°.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]([C:14]2[CH2:18][CH2:17][O:16][N:15]=2)=[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO>[Cl:3][C:4]1[C:13]([C:14]2[CH2:18][CH2:17][O:16][N:15]=2)=[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOCC2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C1=NOCC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
At 40-45° C., a solution of 32.8 g of sodium hydroxide in 330 ml of methanol was slowly added dropwise to a mixture of 170.0 g (0.54 mol) of methyl 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoate and 1 l of methanol. The suspension was stirred at 50° C. for 5 hours. The solvent was distilled off, the residue was taken up in 1.5 1 of water and the aqueous phase was extracted three times with ethyl acetate. The aqueous phase was acidified with hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases were subsequently washed neutral with water, dried and concentrated. 148.8 g (91% of theory) of 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoic acid were obtained.
Reaction SMILES: C[C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([F:21])[C:14]=1[Cl:22])(C([O-])=O)[C:3]([O:5][C:6](C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[CH2:2][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([F:21])[C:14]=1[Cl:22]
Reactant: CC(C)(C)OC(=O)C(C)(C(=O)[O-])c1ccc(C#N)c(F)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C#N)c(F)c1Cl
Reaction time: 20 h

Procedure:
To a solution of t-butyl methyl(2-chloro-4-cyano-3-fluorophenyl)malonate (4.8 g, 15 mmol) in DCM (50 mL) was added TFA (50 mL) at room temperature and the mixture was aged for 20 hours. LC-MS and TLC (20% ethyl acetate/hexanes) indicated lack of starting malonate diester, but still some mono-acid/mono-ester intermediate. The volatiles were removed in vacuo and the residue was taken up in methanol and heated to reflux for 1 hour. The volatiles were again removed in vacuo and the residue was purified on a CombiFlash Rf (40 gm, 10-40% ethyl acetate/hexanes) to give several main fractions of clean title product by NMR. 1H-NMR (500 MHz, CDCl3) δ ppm 3.734 (s, 3H), 3.860 (s, 2H), 7.234 (d, J=8.0 Hz, 1H), 7.512 (dd, J=6.1 and 8.0 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][CH3:6])[CH2:3][OH:4].[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>O1CCCC1>[OH:4][CH2:3][CH:2]([NH:1][C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7])[CH2:5][CH3:6]
Reactant: C=C1CC(=O)O1
Reactant: CCC(N)CO
Solvent: C1CCOC1
Product: CCC(CO)NC(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
34 ml (0.36 mol) of 2-amino-1-butanol were added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 46.97 g (0.27 mol, 76% yield) of a colorless oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:2].[CH2:28]([C@H:30]1[O:32][CH2:31]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:28][C@H:30]4[CH2:31][O:32]4)=[C:17]([CH2:23][CH3:24])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:25])[N:5]=1)[CH3:27]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1O
Reactant: ClC[C@@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@H]1CO1
Reaction time: 24 h
Yield: 74.8 %

Procedure:
To a solution of 4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (500 mg, 1.36 mmol) in isopropanol (15 mL) and 3 N aq. NaOH (6 mL), (S)-epichlorohydrine (378 mg, 4.09 mmol) is added. The orange solution is stirred at rt for 24 h before another portion of (S)-epichlorohydrine is added. Stirring is continued for 24 h, the mixture is diluted with EA, washed with sat. aq. NaHCO3-solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give diethyl-{4-[3-((R)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridin-2-yl}-amine (430 mg) as a yellow oil; LC-MS: tR=0.96 min; [M+1]+=423.21.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:21][C:20]([F:23])([F:22])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[C:27]([Cl:32])[CH:26]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][C:27]=2[Cl:32])[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:19][C:20]([F:22])([F:23])[CH2:21]1)=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CC(F)(F)C1
Reactant: Fc1ccc(S)c(Cl)c1
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(F)cc2Cl)C[C@H]1C(=O)N1CC(F)(F)C1

Procedure:
The title compound was prepared in analogy to Example 68/69, step 8, using (1R,2R,4R)-2-(3,3-Difluoro-azetidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (Example 117, step 3) and 4-fluoro-2-chloro-benzenethiol. Light yellow solid. MS (EI): 422.7 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[O:29]([C:31]#[N:32])[K]>O.CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][N:25]([C:31]([NH2:32])=[O:29])[CH2:24][C:23]4=[O:28])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(N3CCNCC3=O)cc2)nn1)c1ccc(Cl)s1
Reactant: N#CO[K]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)N1CCN(c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)C(=O)C1
Temperature: 25 °C

Procedure:
5-Chloro-N-((1-(4-(2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (23 mg, 0.055 mmol, prepared as shown in Example 60) was dissolved in 2 mL water and 0.5 mL DMSO. To it was added KOCN (23 mg, 0.28 mmol). The mixture was stirred at RT over the weekend. The title compound was the major product in this reaction and was isolated using direct reverse phase prep HPLC. MS found for C19H18ClN7O3S (M+H)+ 460.1, 462.1 (Cl pattern).
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:10][N:11]([C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1)[NH2:12]>O1CCOCC1>[CH3:1][NH:2][C:3]([NH:12][N:11]([CH3:10])[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:15][N:14]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CN(N)c1ncc(C(F)(F)F)cc1Cl
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: C1COCCO1
Product: CNC(=C[N+](=O)[O-])NN(C)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 33.7 %

Procedure:
500 mg of N-methyl-1-methylthio-2-nitroetheneamine, 770 mg of 1-methyl-1-(3-chloro-5-trifluoromethyl-2-pyridyl)hydrazine and 7 ml of 1,4-dioxane were stirred for about 4 hours under heating and refluxing and then cooled to room temperature, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain 370 mg of N-methyl-1-(2-methyl-2-(3-chloro-5-trifluoromethyl-2-pyridyl)hydrazino)-2-nitroetheneamine (Compound No. 35) having a melting point of from 159 to 160° C. (decomposed).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[CH:9][C:10]=1[F:11])[CH:2]=[CH2:3].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[F:11])[O:12][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(O)ccc1F
Reactant: O=Cc1ccc(F)cc1
Product: C=CCOc1cc(Oc2ccc(C=O)cc2)ccc1F

Procedure:
The product from Example 305C and 4-fluorobenzaldehyde were processed as in Example 61C to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C:22]1[N:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CCNC(=O)OC(C)(C)C)N1CCC(=O)CC1
Reactant: N#Cc1cccc(CN)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(CCNC(=O)OC(C)(C)C)N1CCC(NCc2cccc(C#N)n2)CC1
Yield: 77 %

Procedure:
Using general procedure A, [3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (0.361 g, 1.34 mmol), 6-aminomethyl-pyridine-2-carbonitrile (0.178 g, 1.34 mmol), sodium triacetoxyborohydride (0.425 g, 2.01 mmol) and acetic acid (0.2 ml, cat.) in CH2Cl2 (15 ml) at rt for 16 h gave the crude product as a pale yellow oil. Purification by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 86:12:2, v/v/v) afforded (3-{4-[(6-cyano-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.400 g, 77%) as a colorless oil. 1H NMR (CDCl3) δ 0.93 (d, 3H, J=6.0 Hz), 1.40 (s+m, 13H), 1.65 (m, 1H), 1.92 (m, 2H), 2.13 (br t, 1H, J=9.0 Hz), 2.45 (m, 2H), 2.69-2.81 (m, 3H), 3.07 (m, 1H), 3.30 (m, 1H), 3.97 (s, 2H), 5.95 (br s, 1H), 7.56 (d, 1H, J=9.0 Hz), 7.59 (d, 1H, J=9.0 Hz), 7.77 (t, 1H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:34]([O:36][C:37](=[O:42])[CH2:38][CH2:39][CH2:40][NH2:41])[CH3:35].C(N(CC)CC)C>O1CCCC1>[CH2:34]([O:36][C:37](=[O:42])[CH2:38][CH2:39][CH2:40][NH:41][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:35]
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. Then, under nitrogen atmosphere, 4-aminobutyric acid ethyl ester hydrochloride (3.19 g, 0.019 mole) and triethylamine (1.92 g, 0.019 mole) were added simultaneously and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to dryness and the residue was partitioned between methylene chloride and water. The combined methylene chloride layers were extracted with dilute sodium hydroxide, then with water. The methylene chloride layer was separated, dried, and evaporated to dryness (5.3 g) (76% crude yield). A 2-g sample was recrystallized from absolute ethanol, and dried under high vacuum overnight to give 1.47 g, mp. 169°-71° C.
Reaction SMILES: [CH2:1]([OH:7])[C@@H:2]([OH:6])[CH2:3][CH2:4][OH:5].[CH3:8][C:9]([CH3:11])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:8][C:9]1([CH3:11])[O:6][C@@H:2]([CH2:3][CH2:4][OH:5])[CH2:1][O:7]1
Reactant: CC(C)=O
Reactant: OCC[C@H](O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@H](CCO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To (S)-(−)-1,2,4-butanetriol (30 g, 283 mmol), acetone (200 ml) and p-toluenesulfonic acid monohydrate (1.4 g, 7.36 mmol) were added and the mixture was stirred at room temperature overnight. To the reaction mixture, triethylamine (4 ml) was added and the mixture was concentrated. The residue was purified by silica gel column chromatography (silica gel 350 g, elution solvent: ethyl acetate/heptane=18/82→6/4) to obtain the title compound (30.2 g, yield: 73%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH:18][NH2:19]>C(Cl)Cl>[CH3:17][NH:18][NH:19][C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: CNN
Solvent: ClCCl
Product: CNNC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Added a solution of N,N-dicyclohexylcarbodiimide (I M in CH2Cl2, 5 ml, 5 mmol) to a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (1 g, 4.36 mmol) and N-methyl hydrazine (0.3 g, 6.51 mmol) in CH2Cl2 (20 ml) then stirred for 1 hour. The precipitated solid was filtered, mother liquors were concentrated and residue purified by chromatography on silica gel eluting with 3% v/v MeOH/CH2Cl2 to yield (R)-tert-butyl 3-(2-methylhydrazinecarbonyl)piperidine-1-carboxylate as a white solid (0.85 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].FC(F)(F)C(O)=O.C(Cl)Cl>C([SiH](CC)CC)C>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:26])([F:27])[F:28]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(C(O)c3ccccc3C(F)(F)F)sc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
5-Bromo-6-{hydroxy[2-(trifluoromethyl)phenyl]methyl}-1-isobutyl-3-methyl-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (33.47 g) was dissolved in triethyl silane (100 mls) and cooled to 0° C. before trifluoroacetic acid (100 mls) was added dropwise. After complete addition the resultant thick suspension was diluted by the addition of DCM (100 mls) and the reaction was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and partitioned between DCM and 50% aqueous sodium hydrogen carbonate. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated in vacuo. The resultant off white solid was stirred vigorously with isohexane for 1 hour before being collected by filtration to yield 27.286 g (84.5%) of the subtitle compound.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[C@H:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:16][CH:17]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][NH:39][CH3:40])=[CH:32][C:31]=1[CH3:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[C@H:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:16][CH2:17][N:39]([CH2:38][CH2:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([F:29])=[C:31]([CH3:41])[CH:32]=1)[CH3:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCCCc1ccc(F)c(C)c1
Reactant: Cc1cc(O[C@H](CC=O)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cc(CCCN(C)CC[C@@H](Oc2ccc(F)c(C)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(4-fluoro-3-methylphenoxy)-4-oxobutanal (35 mg, 0.091 mmol) in 3 mL DCE was added 3-(4-Fluoro-3-methylphenyl)-N-methylpropan-1-amine (22 mg, 0.12 mmol) followed by NaBH(OAc)3 (29.5 mg, 0.14 mmol) and AcOH (7.2 mg, 0.12 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 10 mL 5% aqueous NaOH and diluted with ethyl acetate. The mixture was extracted with more ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-].Cl>C1COCC1>[F:33][C:30]([F:31])([F:32])[C:27]1[N:26]=[CH:25][C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:34])=[O:2])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 50 °C

Procedure:
A THF solution of (4-{4-[5-(6-trifluoromethyl-pyridin-3-ylamino)-pyridin-2-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester was treated with 10% aqueous LiOH and heated to 50° C. overnight. Upon reaction completion, the mixture was acidified with concentrated HCl. The resulting precipitate was isolated by filtration to afford the title compound: 1H NMR (400 MHz, DMSO-d6) 1.08-1.19 (m, 1 H) 1.14 (dd, J=12.63, 2.27 Hz, 1 H) 1.44-1.56 (m, 1 H) 1.50 (dd, J=12.51, 2.65 Hz, 1 H) 1.75 (br. S., 1 H) 1.84 (d, J=10.61 Hz, 4 H) 2.14 (d, J=6.82 Hz, 2 H) 2.54 (m, 1 H) 7.33 (d, J=8.34 Hz, 2 H) 7.65 (d, J=2.53 Hz, 1 H) 7.68-7.74 (m, 1 H) 7.70 (d, J=8.34 Hz, 1 H) 7.89 (d, J=8.59 Hz, 1 H) 7.95 (d, J=8.59 Hz, 2 H) 8.46 (d, J=2.78 Hz, 1 H) 8.54 (d, J=2.53 Hz, 1 H) 9.20 (s, 1 H); (M+H)+ 456.3. Alternatively, the methyl ester can be dissolved in a mixture of THF and water, and treated with aqueous sodium hydroxide (4 equiv). The mixture can then be stirred at 50 degrees for 12 hours, at which point the THF is removed under reduced pressure to yield an opaque, white slurry, which affords the title compound as the corresponding sodium salt upon filtration. 1H NMR (DMSO-d6, 500 MHz) δ 10.05 (s, 1 H), 8.59 (d, 1 H, J=2.8 Hz), 8.54 (s, 1 H), 7.92 (d, 2 H, J=8.2 Hz), 7.86 (d, 1 H, J=8.8 Hz), 7.75 (dd, 1 H, J=8.7, 2.7 Hz), 7.69 (s, 2 H), 7.27 (d, 2 H, J=8.5 Hz), 2.45 (m, 1 H), 1.84 (m, 4 H), 1.67-1.80 (m, 3 H), 1.41 (m, 2 H), 1.02 (m, 2 H); MS m/z 456 (M−Na+2H)+.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([CH:14]3[CH2:17][N:16]([C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:19])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:30]I>CN(C=O)C>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([CH:14]3[CH2:15][N:16]([C:18]([N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH3:30])=[O:19])[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(NCC1CCCCC1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC1CCCCC1)C(=O)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
To a stirred solution of 3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]-N-(cyclohexylmethyl)azetidine-1-carboxamide (26 mg, 0.069 mmol) in dry DMF (1 ml) at 0° C. under a nitrogen atmosphere was added sodium hydride (4.1 mg of a 60% dispersion in mineral oil, 0.103 mmol). The resulting suspension was stirred at 0° C. for 30 min. Methyl iodide (4.3 μl, 0.069 mmol) was added and the reaction mixture allowed to warm to RT and was stirred for 16 hrs. The reaction mixture was poured onto ice-water, extracted with EtOAc (3×5 ml), the combined organics washed with brine (5 ml), dried (MgSO4), filtered and concentrated at reduced pressure. Purification by preparative HPLC provided the title compound (5.6 mg, 21% yield) as colourless oil.