Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[S:3]1.Br[CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[OH:17][CH2:16][CH2:15][CH2:14][N:6]1[C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: OCCCBr
Reactant: O=Cc1ccc2[nH]c(=O)sc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc2c(c1)sc(=O)n2CCCO
Temperature: 65 °C
Yield: 128.3 %

Procedure:
2-oxo-2,3-dihydro-1,3-benzothiazole-6-carbaldehyde (120 mg, 0.67 mmol), 3-bromopropan-1-ol (85 μL, 0.94 mmol), potassium carbonate (278 mg, 2.01 mmol) and potassium iodide (55 mg, 0.33 mmol) were suspended in acetonitrile (2 mL) and the whole mixture was heated at 65° C. for 48 h. Then, the solids were filtered off and washed with acetonitrile and the resulting filtrate was evaporated to dryness to afford the title compound as a solid (204 mg of 77% purity by HPLC, 99% yield) which was used without further purification.
Reaction SMILES: P(Cl)(Cl)[Cl:2].O[CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([N:20]=1)=[C:18]1[N:21]=[CH:22][CH:23]=[CH:24][C:17]1=[C:16]1[C:11]=2[N:12]=[C:13]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:15]1>C(Cl)(Cl)Cl>[Cl:2][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([N:20]=1)=[C:18]1[N:21]=[CH:22][CH:23]=[CH:24][C:17]1=[C:16]1[C:11]=2[N:12]=[C:13]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:15]1
Reactant: CCOC(=O)c1nc2c3cccnc3c3nc(CO)ccc3c2nc1C(=O)OCC
Reactant: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc2c3cccnc3c3nc(CCl)ccc3c2nc1C(=O)OCC
Temperature: 25 °C
Yield: 25.6 %

Procedure:
Phosphorus trichloride (473 mg, 3.44 mmol) was added to a solution diethyl 7-(hydroxymethyl)dipyrido[3,2-f:2′,3′-h]quinoxaline-2,3-dicarboxylate (350 mg, 0.86 mmol) in CHCl3 (150 ml). The reaction mixture was heated under reflux for 6 h and allowed to cool down to room temperature afterwards. The reaction was quenched by addition of concentrated Na2CO3 solution (150 ml). The layers were separated and the water was extracted by CH2Cl2 (3×150 ml) and CHCl3 (1×50 ml). The organic layer was dried over K2CO3. The solvent was removed under reduced pressure to give the crude product. Purification was achieved by chromatography on alumina (gradient elution: CH2Cl2 to 2% CH3OH—CH2Cl2) The product was obtained as a yellow glass (95 mg, 0.22 mmol, 26%). 1H NMR (300 MHz, CDCl3): δ 1.45 (6H, t, J=7.2, OCH2CH3), 4.53 (4H, q, J=7.2, OCH2), 5.07 (2H, s, CH2Cl), 7.78 (1H, dd, J=8.1, 4.5, H11), 8.05 (1H, d, J=8.4, H6), 9.31 (1H, dd, J=4.5, 1.8, H10), 9.50 (1H, dd, J=8.1, 1.8, H12), 9.53 (1H, d, J=8.7, H5). 13C NMR (75 MHz, CDCl3): δ14.4 (CH3), 47.3 (CH2Cl), 63.2 (OCH2), 123.8 (C11), 124.6 (C6), 125.6 (q Ar), 126.6 (q Ar), 134.5 (C12), 135.7 (C5), 140.1 (q Ar), 140.4 (q Ar), 144.3 (q Ar), 144.4 (q Ar), 147.6 (q Ar), 148.1 (q Ar), 153.8 (C10), 161.0 (C7), 165.0 (CO), 165.1 (CO). m/z (ES+) 447 (MNa+).
Reaction SMILES: [Na].[NH:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17](S(=O)(=O)[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5][N:4]=[N:3]1.[OH-:24].[Na+].Cl>>[NH:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([O:24][C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5][N:4]=[N:3]1
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Product: O=c1c2ccccc2oc2cc(-c3nnn[nH]3)ccc12

Procedure:
3-(5-Tetrazolyl)thioxanthone-10,10-dioxide sodium salt (U.K. patent specification No. 1,447,031; 45.0 g) was stirred and boiled under reflux with 2-normal sodium hydroxide solution for 61/2 hours. The solution was acidified by pouring into excess hydrochloric acid solution and the precipitated product filtered off and recrystallised from dimethylformamide to give the title compound (14.95 g), m.pt. 296° C. (decomposes).
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@H:2]([C:7]([NH:9][C@H:10]([C:13](C(OCC)=O)=[O:14])[CH2:11][CH3:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:30]([NH2:32])[CH3:31]>C(Cl)(Cl)Cl.CO>[NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[C@H:2]([C:7]([NH:9][C@H:10]([C:13]([NH:32][CH2:30][CH3:31])=[O:14])[CH2:11][CH3:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CCOC(=O)C(=O)[C@H](CC)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: CCN
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCNC(=O)[C@H](CC)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Yield: 64 %

Procedure:
This compound was synthesized from protected α-ketoester derived from Z—Leu—Abu—CO2Et and ethylamine in 64% yield by the procedure described in Example 1. Single spot on TlC, Rf=0.36 (CHCl3/CH3OH 50;1); mp 130-132° C. Anal. calcd. for C21H31N3O5:405.45; C, 62.20; H, 7.71; N, 10.36. Found: C, 61.92; H, 7.62; N, 10.31. NMR (CDCl3) ok. MS (FAB) m/e=406 (M+1).
Reaction SMILES: [C:1]([OH:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.S(Cl)([Cl:14])=O>CN(C)C=O>[C:1]([Cl:14])(=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Cl)c1

Procedure:
This intermediate was prepared by either of two methods. In the first, a mixture of 100 g of m-anisic acid (0.658 mole), 250 g thionyl chloride (2.10 mole), and 5 mL of dimethylformamide was heated under reflux in a round-bottom flask with desiccant in the top of the condenser for exclusion of atmospheric moisture. Excess thionyl chloride was distilled from the product using a rotary film-evaporator at about 26.6 kPa pressure. The m-anisoyl chloride was then isolated by fractional distillation through a 25 cm Vigreux column at 109° C. and 1.6 kPa pressure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[C:15]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([N:23]1[CH2:28][CH2:27][C:26]2([CH2:13][C:12](=[O:14])[C:3]3[CH:4]=[C:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=3[O:1]2)[CH2:25][CH2:24]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1cc(S(C)(=O)=O)ccc1O
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Product: CS(=O)(=O)c1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3ccccc3)CC1)O2

Procedure:
2'-Hydroxy-5'-methanesulfonylacetophenone and 1-benzoyl-4-piperidone were condensed according to the method of Example 434 to give the ketone as a white solid, m.p. 155°-157° C.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14](=[O:20])[CH2:15][CH2:16][CH:17]=[C:18]=[CH2:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClC1C=CC=CC=1Cl>[CH2:9]1[C:8]2=[CH:7][C:1]3[C:6]([C:13]([C:14](=[O:20])[CH2:15][CH2:16][CH:17]=[C:18]=[CH2:19])=[C:12]2[CH2:11][CH2:10]1)=[CH:5][CH:4]=[CH:3][CH:2]=3
Reactant: C=C=CCCC(=O)C#CCCC/C=C/c1ccccc1
Solvent: Clc1ccccc1Cl
Product: C=C=CCCC(=O)c1c2c(cc3ccccc13)CCC2
Temperature: 225 °C
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
To a 2-5 mL MWI vial equipped with a stir bar was added the ene-allene-yne 1 (50 mg, 0.19 mmol) in o-dichlorobenzene (2.5 mL), and the reaction was irradiated with stirring at 225° C. for 10 min until complete by TLC. The reaction was then transferred directly to a silica gel cartridge and purified by silica gel column chromatography (25 g silica cartridge, 0-3% Et2O/pentane) to yield 2 as a light yellow oil (34 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].Cl.Cl[CH2:21][CH2:22][CH2:23][NH2:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:21][CH2:22][CH2:23][NH2:24])[C:7]=1[CH2:13][CH3:14]
Reactant: NCCCCl
Reactant: CCc1n[nH]c(CC)c1Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Product: CCc1nn(CCCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 150 °C
Yield: 84 %

Procedure:
The pyrazole of Example 11 (200 mg, 0.71 mmol) was mixed with 3-chloropropylamine hydrochloride (138 mg, 1.06 mmol). The resulting mixture was heated neat at 150° C., for 24 hours under a nitrogen atmosphere. After cooling, the reaction mixture was partitioned between dichloromethane (30 ml) and saturated aqueous sodium hydrogencarbonate solution (30 ml). The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (90:10:0, by volume) gradually changing to dichloromethane:methanol:ammonia (90:10:1, by volume) to afford the title compound (203 mg) as a brown oil.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:31]=2)[C:16]([NH:18][C:19]2[C:28]([CH3:29])=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=2[CH3:30])=[O:17])[CH2:6]1.CO>C1COCC1>[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:31]=2)[C:16]([NH:18][C:19]2[C:20]([CH3:30])=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][C:28]=2[CH3:29])=[O:17])[CH2:6]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCCC(CO)C2)cc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
A solution of aqueous 4N NaOH (2.00 ml) is added to a stirred solution of methyl 4-[[5-[3-(hydroxymethyl)-1-piperidyl]-2-methyl-benzoyl]amino]-3,5-dimethyl-benzoate (0.3 g, 0.73 mmol) in THF:MeOH (10 ml:5 ml). After 16 hours at ambient temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with 1N HCl, and extracted with 10% IPA in CH2Cl2. The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as a light brown solid (0.27 g, 90%). Mass spectrum (m/z): 397.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:22][CH2:23][C@@H:24]([N:29]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:7]2=1.O.NN>CCO>[NH2:29][C@@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:15]1[C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:7]2[C:6]3[C:11](=[C:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[C:10](=[O:12])[N:9]([CH3:13])[C:8]=2[CH:14]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)c(C(F)(F)F)cc21
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)c(C(F)(F)F)cc21
Temperature: 45 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a solution of (S)-2-(1-((4,6-dimethyl-5-oxo-9-(trifluoromethyl)-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (50 mg, 0.019 mmol) in EtOH (4 mL) was added hydrazine hydrate (6.52 mg, 0.130 mmol). The reaction mixture was allowed to stir at 45° C. for 2 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Symmetry C-18 column (19.0×250 mm) 7.0 micron; mobile phase A: Ammonium acetate in water; mobile phase B: acetonitrile; flow rate: 16.0 mL) to afford the (S)-8-((2-amino-4-methylpentyl)oxy)-4,6-dimethyl-9 (trifluoromethyl)benzo[c][2,7]naphthyridin-5(6H)-one (5 mg, 0.012 mmol, 64% yield) as an off-white solid. LC/MS (ESI) m/e 408.2 [(M+H)+, calcd for C21H25F3N3O2 408.2] LC/MS retention time (method B): tR=1.25 min. HPLC retention time (method A): tR=10.10 min HPLC retention time (method B): tR=10.69 min; 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.66 (s, 1H), 8.63 (d, J=5.6 Hz, 1H), 8.22 (d, J=5.6 Hz, 1H), 7.19 (s, 1H), 4.42-4.38 (m, 1H), 4.28-4.20 (m, 1H), 3.83 (s, 3H), 3.58-3.49 (m, 1H), 3.11 (s, 3H), 1.90-1.82 (m, 1H), 1.68-1.62 (m, 1H), 1.58-1.53 (m, 1H), 1.10-1.00 (m, 6H).
Reaction SMILES: [O:1]1[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:2]1[C:3](OC)=[O:4].[BH4-].[Na+]>O1CCCC1>[O:1]1[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:2]1[CH2:3][OH:4]
Reactant: CCCCCCCCCCCCCCC[C@H]1O[C@@H]1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC[C@H]1O[C@@H]1CO
Yield: 75 %

Procedure:
In 500 ml of tetrahydrofuran were suspended 62.4 g (0.2 mol) of the methyl (2S,3R)-2,3-epoxyoctadecanoate (V-1) prepared in Example 3-(3) and 7.4 g (0.2 mol) of NaBH4, followed by heat refluxing for 3 hours. After confirming disappearance of the compound (V-1) by TLC, tetrahydrofuran was evaporated. To the residue were added 20 ml of water and then 500 ml of a saturated ammonium chloride aqueous solution to adjust to pH 5 to 6, and the mixture was extracted with 500 ml of ethyl acetate. After drying, ethyl acetate was removed by evaporation, and the resulting crude crystals were recrystallized from heptane to obtain 42.6 g (0.15 mol; yield: 75%) of (2R,3R)-2,3-epoxyoctadecanol (melting point: 77 to 78° C.). Optical rotation [α]D25 =+24.5° (c=0.285, CHCl3)
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19]>CO>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH:6]2[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]2)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: NCCCCCCN
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Solvent: CO
Product: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reaction time: 2 h

Procedure:
162.75 g (1.05 moles) of 2,2,6,6-tetramethyl-4-piperidone dissolved in 200 cc of methanol, 58 g (0.5 moles) of hexamethylenediamine dissolved in 70 cc of methanol, and 0.5 g of Pt (at 10% on carbon) were introduced into a 1 liter autocalve. The mixture was hydrogenated at 80° C and 50 atm pressure for 2 hours.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([N:7]2[CH:11]=[C:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[CH2:23][CH2:22][C@:21]([CH2:26][CH3:27])([C:24]#[N:25])[C:20]4=[O:28])[CH:16]=[CH:15][N:14]=3)[CH:9]=[N:8]2)[CH2:4]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1>[CH2:26]([C@:21]1([C:24]#[N:25])[CH2:22][CH2:23][N:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:10]3[CH:9]=[N:8][N:7]([CH:5]4[CH2:6][N:3]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:4]4)[CH:11]=3)[N:18]=2)[C:20]1=[O:28])[CH3:27]
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Nc3cnn(C4CNC4)c3)n2)C1=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3cnn(C4CN(S(C)(=O)=O)C4)c3)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (3R)-1-(2-((1-(azetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile dihydrochloride (83 mg) obtained in Example 185 in tetrahydrofuran (5 mL) were added triethylamine (30 μL) and methanesulfonyl chloride (33 μL) at room temperature, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized (ethyl acetate/hexane) to give the title compound (16 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:11][C:10]2[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[CH:4]=1.C(=O)([O-])O.[Na+].CC1(C)N([O])C(C)(C)CCC1.[O-]Cl.[Na+]>ClCCl.O.C(OCC)(=O)C.CCCCCC>[CH:2]([C:3]1[S:11][C:10]2[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[CH:4]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CO)cc2C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2sc(C=O)cc2C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 6,7-dihydro-2-(hydroxymethyl)thieno[3,2-c]pyridine-5(4H)-carboxylate (1.6 g, 0.006 mol) in dichloromethane (18 ml), sodium hydrogen carbonate (1.06 g) dissolved in water was added and the resulting mixture was cooled to 0° C. Then a catalytic amount of TEMPO followed by NaOCl (18 ml, 10×) were added at 0° C. and the reaction mixture was stirred for 1-2 h at room temperature. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane). Upon completion of the reaction, the reaction mixture were diluted with water (20 ml) and dichloromethane (20 ml). Then the dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane. The combined extract was dried over sodium sulfate, concentrated under reduced pressure and the crude so obtained was purified by column chromatography (silica, 7% ethyl acetate/hexane) to yield the titled compound as a pale yellow solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:28]=1[CH:29]=[CH:30][C:31]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([CH3:2])[CH:4]=1)=[O:32]
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Reactant: O=C(O)C=Cc1cc(F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1cc(F)ccc1F
Yield: 97.8 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (2.0 g), triethylamine (1.1 mL), 2,5-difluorocinnamic acid (1.5 g), WSC.HCl (1.6 g), and methylene chloride (80 mL), to give the captioned compound (2.9 g, 98%) as an oily product.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](=O)[CH3:20])=[CH:14][CH:13]=1>>[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([CH3:10])[S:8][CH:9]=2)[CH3:20])=[CH:14][CH:13]=1
Reactant: Cc1nc(C(O)CN)cs1
Reactant: CC(=O)Cc1ccc(O)cc1
Product: Cc1nc(C(O)CNC(C)Cc2ccc(O)cc2)cs1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with 4-hydroxyphenyl-propan-2-one followed by purification of the base on a silica gel column using chloroform/methanol/ammonia=9:1:1 as eluant.
Reaction SMILES: [CH:1]1([C:5]2[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:51][C:52]1[O:56][N:55]=[C:54]([C:57]([NH2:64])([CH3:63])[CH2:58][S:59]([CH3:62])(=[O:61])=[O:60])[N:53]=1.Br>CN(C=O)C>[CH:1]1([C:5]2[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([NH:64][C:57]([CH3:63])([C:54]3[N:53]=[C:52]([CH3:51])[O:56][N:55]=3)[CH2:58][S:59]([CH3:62])(=[O:61])=[O:60])=[O:13])=[N:9][CH:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CCC2)cn1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3CCC3)cn2)no1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22 %

Procedure:
To a solution of 5-Cyclobutyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 108f, 40 mg, 145 μmol) in dry DMF (1.00 ml) was added DIEA (76.2 μl, 436 μmol) and TBTU (49.0 mg, 153 μmol) and the reaction mixture was stirred at room temperature for 20 minutes. Addition of 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer A) (example 124b, 45.8 mg, 153 μmol) to the reaction mixture and the latter was stirred at room temperature for 2 hours. The crude was directly purified by preparative HPLC without any work-up to yield the title compound (15 mg, 22%); MS (ESI, m/z): 477.5 (M+H+).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:33]([NH:40][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([N:11]2[C:10](=[S:28])[N:9]([C:6]3[CH:7]=[N:8][C:3]([C:1]#[N:2])=[C:4]([C:29]([F:31])([F:30])[F:32])[CH:5]=3)[C:16](=[O:17])[C:12]32[CH2:15][CH2:14][CH2:13]3)=[CH:19][C:20]=1[F:27])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)O)c(F)c3)C2=S)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[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: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)NCc4ccccc4)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
A mixture of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid (Compound 224, 68 mg, 0.14 mmol), benzylamine (22 mg, 0.21 mmol), HATU (70 mg, 0.18 mmol), and DIEA (40 μL, 0.21 mmol) in DMF (3 mL) was stirred at room temperature for 3 h. The crude reaction mixture was purified by reverse phase HPLC (acetonitrile/water:TFA) to afford 51 mg of N-benzyl-4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.22 (d, 1H), 9.12 (t, 1H), 8.75 (d, 1H), 7.87 (t, 1H), 7.49 (dd, 1H), 7.40 (dd, 1H), 7.37-7.31 (m, 4H), 7.29-7.24 (m, 1H), 4.51 (d, 1H), 2.69-2.63 (m, 2H), 2.55-2.44 (m, 2H), 2.03-1.94 (m, 1H), 1.62-1.56 (m, 1H). LCMS [M+1]+ 554.5.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].F[C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CN(C=O)C>[CH2:21]([N:6]1[C:5]2[CH:12]=[CH:13][C:2]([CH3:1])=[CH:3][C:4]=2[C:9](=[O:10])[O:8][C:7]1=[O:11])[C:20]1[CH:23]=[CH:24][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)oc(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of Compound 11 (5 g, 28 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 1.24 g, 31 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat 4-fluorobenzyl bromide (3.81 mL, 31 mmol) was added, and the solution further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 6.3 g (79%) of white solids. M.P. 153° C. 1H NMR (DMSO-d6): δ 2.32 (s, 3H), 5.24 (s, 2H), 7.14-7.17 (m, 3H), 7.44 (m, 2H), 7.54 (dd, J=1.7, 8.2 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H). Anal. (C16H12FNO3) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].BrC1C=CC(Cl)=CC=1[CH2:20][O:21][CH2:22]OC>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[CH2:4][O:5][CH2:20][O:21][CH3:22]
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Reactant: COCOCc1cc(Cl)ccc1Br
Product: COCOCc1cc(C)ccc1Br

Procedure:
This compound was made from 2-bromo-5-methylbenzoic acid in the same manner as compound 18d: 1H NMR (300 MHz, DMSO-d6) δ (ppm) 2.27 (s, 3H), 3.30 (s, 3H), 4.51 (s, 2H), 4.68 (s, 2H), 7.05 (dd, J=7.9, 2.3 Hz, 1H), 7.30 (d, J=1.5 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H).