Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1>C1COCC1.CO>[OH:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
Sodium borohydride (5.7 g, 0.15 mol) was added in portions to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (15 g, 75 mmol) in THF/MeOH (150 mL/30 mL) at −10° C. The reaction mixture was stirred for 30 min at −10° C. and then poured into ice-water (300 mL). The resulting mixture was extracted with EtOAc (300 mL×3) and the combined extracts were dried over anhydrous sodium sulfate and concentrated to afford tert-butyl 4-hydroxypiperidine-1-carboxylate (13.2 g, 87% yield).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>C(Cl)Cl>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([S:10]([Cl:9])(=[O:12])=[O:11])=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
108 grams of anisole (1.0 mol) was added to 700 ml of CH2Cl2 in a one-liter round bottom flask and cooled to 0°-5° C. While using ice-bath cooling to maintain the temperature below 10° C., 280 grams of chlorosulfonic acid (1.5 mol) was added dropwise with magnetic stirring over a 4 hour period. The solution was then carefully poured over ice (1500 grams) and the organic layer collected. The solution was washed in the cold 10% NaHCO3, and the organic layer collected, then dried over MgSO4 and filtered. The solvent was removed in a rotary evaporator under aspirator vacuum and crude 4-methoxy- benzenesulfonylchloride (72% yield) was obtained as a red oil in a sufficient state of purity to permit its use without further purification.
Reaction SMILES: CCCCCC.C([Li])CCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1.[Br:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH:32]=[O:33])[CH:23]=1.[Cl-].[NH4+]>C1COCC1>[S:12]1[C:13]([CH:32]([C:24]2[CH:23]=[C:22]([Br:21])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[OH:33])=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: O=Cc1cc(Br)c2ccccc2c1
Reactant: c1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1cc(Br)c2ccccc2c1)c1cc2ccccc2s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
Under a nitrogen atmosphere, an n-butyllithium hexane solution (1.6 M, 2.04 ml, 3.27 mmol) was added dropwise to a solution of benzothiophene (0.48 g, 3.58 mmol) in anhydrous THF (10 ml) at −78° C. over 5 minutes. The reaction solution was stirred at −78° C. for 10 minutes, and then at room temperature for 20 minutes. A solution of 4-bromonaphathalene-2-carbaldehyde (0.73 ml, 3.11 mmol) in anhydrous THF (5 ml) was added dropwise to the resulting reaction mixture at −78° C. and stirred at −78° C. for two hours. To the reaction mixture, a saturated ammonium chloride aqueous solution was added and the resulting mixture was extracted with diethyl ether, and the organic layer was washed with a saturated sodium chloride aqueous solution and then dried with anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure and the obtained residue was purified by silica gel flash column chromatography [n-hexane:ethyl acetate (10:1)] to obtain the title compound (1.0 g, 75.6%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)(=[O:22])=[O:21])/[CH:9]=2)=[N:5][N:4]=[N:3]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(OCC)(=O)C>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:19][S:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)(=[O:22])=[O:21])=[CH:9][C:8]=1[S:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1
Reactant: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nnnc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Yield: 99.5 %

Procedure:
13 mg (E)-N-(3-(1-methyl-1H-tetrazol-5-ylthio)-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (13d) was dissolved in 50 ml ethyl acetate, to which was added 27 mg sodium hydrosulfite solid followed by 10 ml water. The mixture was shaken in a separation funnel until the yellow organic phase turned colorless. The organic phase was separated and washed with water and brine. Dried over Na2SO4, the organic phase was filtered and the filtrate was concentrated to dryness. The residue was dissolved in dichloromethylene and triturated with hexane. The precipitate was washed with dichloromethylene/hexane (1:1) affording the title compound 13 mg (99%) as a white solid, m.p.: 130° C. (dec.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:30])[N:6]=1.[H-].[Na+].Cl[C:34]1[N:39]=[CH:38][C:37](S(C)(=O)=O)=[CH:36][N:35]=1>C1COCC1.CC(N(C)C)=O>[CH:27]([C:24]1[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:8]2[N:7]([CH3:30])[N:6]=[C:5]([O:4][CH2:3][CH2:2][O:1][C:34]3[N:35]=[C:36]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:37]=[CH:38][N:39]=3)[C:9]=2[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:19])=[O:20])=[N:22][CH:23]=1)([CH3:28])[CH3:29]
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reactant: CS(=O)(=O)c1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2c(OCCOc3nccc(S(C)(=O)=O)n3)nn(C)c2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reaction time: 0.08 h
Yield: 40.6 %

Procedure:
To a solution of N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-5-isopropyl-2-pyridinesulfonamide (Example 40) (112 mg) in anhydrous THF (5 ml) at 0° C. and under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 21.8 mg) and the mixture was stirred for 5 minutes. To the mixture was added 2-chloro-5-(methylsulfonyl)pyrimidine (50 mg) in dimethylacetamide (1 ml). After stirring for 150 min. the reaction mixture was partitioned between ethyl acetate (50 ml) and saturated ammonium chloride solution (50 ml). The ethyl acetate layer was washed with brine (50 ml), dried (MgSO4), filtered and evaporated to dryness. Purification of the residue on a Phenomenex Magellen™ column using a 0.1M NH4OAc:MeCN gradient (95:5 to 60:40) over 5min. and then an isocratic flow (60:40) for 15 minutes gave the title compound as a white solid (31 mg).
Reaction SMILES: [CH3:1][C@:2]1([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)CCC[C@:4]2(OC2)[CH2:3]1.[CH3:22][C:23]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:27]=1)([CH3:25])[CH3:24].CC(C)([O-])C.[K+]>CN1C(=O)CCC1>[CH3:25][C:23]([C:26]1[O:30][N:29]=[C:28]([N:31]2[CH2:35][C@@:34]3([CH2:37][CH2:4][CH2:3][C@@:2]([CH2:10][N:11]4[C:15]5[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=5[N:13]=[CH:12]4)([CH3:1])[CH2:36]3)[O:33][C:32]2=[O:38])[CH:27]=1)([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(C)(C)C)on1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1cc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)no1
Temperature: 125 °C
Yield: 17.6 %

Procedure:
1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (150 mg, 0.533 mmol), 1,1-dimethylethyl [5-(1,1-dimethylethyl)-3-isoxazolyl]carbamate (320 mg, 1.333 mmol) and potassium tert-butoxide (78 mg, 0.693 mmol) were added to a 10 mL microwave vial while nitrogen purging. Then, NMP (3 mL) was added and the vial was capped and heated to 125° C. for 16 h. The reaction was filtered and purified to give 42 mg (13.3%) of 1-({(5S,7S)-3-[5-(1,1-dimethylethyl)-3-isoxazolyl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl}methyl)-1H-benzimidazole-6-carbonitrile. 1H NMR (400 MHz, MeOH-d4) δ 8.43 (br. s., 1H), 8.19 (s, 1H), 7.82 (d, J=8.28 Hz, 1H), 7.58 (d, J=8.28 Hz, 1H), 6.56 (s, 1H), 4.19 (s, 2H), 3.66-3.79 (m, 2H), 2.04 (d, J=5.77 Hz, 1H), 1.95 (d, J=14.05 Hz, 1H), 1.78-1.90 (m, 1H), 1.65-1.78 (m, 2H), 1.40-1.63 (m, 3H), 1.32 (s, 9H), 1.18 (s, 3H). MS (m/z) 448.3 (M+H+).
Reaction SMILES: O[C:2]1([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CC([O-])(C)C.[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C1COCC1>[C:9]([O:8][C:6]([N:4]1[CH2:5][C:2]2([O:15][CH2:14][C:13]2([CH3:17])[CH3:16])[CH2:3]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC(O)(C(C)(C)CO)C1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCC2(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
To a solution of tert-butyl 3-hydroxy-3-(1-hydroxy-2-methylpropan-2-yl)azetidine-1-carboxylate (0.20 g, 0.82 mmol) in THF (4 ml) was added in rapid succession, KOtBu (0.19 g, 1.72 mmol) and p-toluenesulfonylchloride (0.16 g, 0.82 mmol) and the solution stirred at room temperature for 90 mins. Water (10 ml) was added and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated to give an oil. The oil was purified by flash column chromatography eluting with 30 to 70% ethylacetate/hexanes to give the title compound as a colorless oil 0.13 g, 70%. 1H NMR (CDCl3, 400 Mhz) 1.25 (6H, s), 1.45 (9H, s), 3.89 (2H, d), 4.12 (2H, d), 4.20 (2H, s).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][CH:23]([NH2:28])[C:24]([F:27])([F:26])[F:25].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:28][C@@H:23]([CH3:22])[C:24]([F:27])([F:26])[F:25])=[O:18])=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(N)C(F)(F)F
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
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: CCCCc1noc(C)c1COc1ccc(C(=O)N[C@@H](C)C(F)(F)F)cn1
Yield: 67.9 %

Procedure:
To a stirred solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) in DMF (2 mL) at room temperature under argon was added L-2,2,2-trifluoro-1-(methyl)ethylamine (ABCR F07820EFA, 42.9 mg, 0.38 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (121.7 mg, 0.38 mmol) and N,N-diisopropylethylamine (222.6 mg, 1.72 mmol). After 2.5 h the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=1:0 to 2:1) afforded the title compound (89 mg, 67%) as a light yellow oil. MS: m/e=384.3 [M−H]−.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[NH2:24])[C:17]([O:19][CH3:20])=[O:18].O>C1COCC1>[CH3:20][O:19][C:17]([C:16]1[CH:21]=[CH:22][C:23]2[NH:24][C:1](=[O:2])[NH:13][C:14]=2[CH:15]=1)=[O:18]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1′-carbonyldiimidazole (5 g) in THF (20 ml) was added to a solution of methyl 3,4-diaminobenzoate (CAS Reg. No. 36692-49-6, 5 g) in THF (50 ml). The mixture was stirred at room temperature for 2 h. Water (150 ml) was added. The mixture was filtered and the residue dried to give the title compound (5.6 g) as a light yellow powder. MS (m/e, ISP neg. ion)=191.2 [M−H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].C([Li])CCC.C[O:23][B:24](OC)[O:25]C.Cl>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH3:9])=[C:2]([B:24]([OH:25])[OH:23])[CH:3]=2)=[CH:11][CH:12]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1B(O)O
Temperature: -78 °C
Yield: 69.1 %

Procedure:
3-Bromo-4′-chloro-4-ethylbiphenyl (10 g, 0.03 mol) is dissolved in tetrahydrofuran (250 ml), and the temperature is cooled to −78° C. n-Butyllithium (1.33 molar solution in hexanes, 34.6 ml) is added dropwise over 30 minutes, maintaining the temperature at around −78° C. The reaction mixture is stirred for one and a half hours, then trimethylborate (4.9 g, 0.05 mol) is added dropwise and the reaction mixture is stirred for two hours. A solution of 2N aqueous hydrochloric acid (100 ml) is added dropwise, and once the addition is complete the mixture is stirred for two hours. The mixture is concentrated to remove most of the tetrahydrofuran, then diluted with water and extracted with diethyl ether. The organic extracts are washed with water and brine, combined, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is further purified by flash column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 4′-chloro-4-ethylbiphen-3-ylboronic acid (5.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=O)[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:4][CH:3]=1.[CH3:26][NH:27][NH2:28].O>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[N:28][NH:27][CH3:26])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:4][CH:3]=1
Reactant: CNN
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3cc(C=O)oc23)c1=O
Solvent: C1CCOC1
Solvent: O
Product: CNN=Cc1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
0.4 g (1.0 mmol) of 3-(4-chloro-2-formylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil was dissolved in 5 ml of tetrahydrofuran, and 0.1 g (21.7 mmol) of monomethylhydrazine was added thereto under cooling with ice, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.2 g (yield: 47.6%) of the desired product as a pale yellow glassy substance. Refractive index: unmeasurable, 1H-NMR (solvent, CDCl3): 2.90(3H,s), 3.52(3H,s), 6.18(1H,bs), 6.40(1H,s), 6.85(1H,s), 7.05 (1H,d), 7.25(1H,s), 7.29(1H,d) ppm
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)[CH2:11][CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)[CH2:11][CH3:12]
Reactant: CCCc1ccc(C=O)cc1
Reactant: N#Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCc1ccc(C=Nc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 5.9 g. of p-aminobenzonitrile and 7.4 g. of p-n-propylbenzaldehyde in 100 ml. of benzene is treated with 150 mg. of p-toluenesulfonic acid and reacted as described in Example 1. After evaporation, there remian 12.5 g. of a yellowish oil which crystallizes with cooling. Purification is carried out by several recrystallizations from isopropanol as described in Example 1. The p-[(p-n-propylbenzyliden)amino]benzonitrile which is obtained has a melting point of 64.8°-65.5°C. and a clearing point of 77.6°C. UV (ethanol): ε280 = 24300 (shoulder at 310 nm). The nuclear magnetic resonance, mass spectrum, infrared and microanalysis data confirm the structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:26](OCC)=[O:27])=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1.[C:31]([Li])([CH3:34])([CH3:33])[CH3:32].[Cl-].[NH4+]>C1COCC1.CCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)=[CH:12][C:11]=1[C:26](=[O:27])[C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(=O)C(C)(C)C)c2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carboxylate (524 mg) in THF (10 mL) was added a solution (1.6 M, 1.6 mL) of tert-butyllithium in pentane at −78° C., and the mixture was stirred at −78° C. for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (268 mg) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21](O)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].Cl.[F:26][CH:27]1[CH2:30][NH:29][CH2:28]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH:1]([C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([N:29]3[CH2:30][CH:27]([F:26])[CH2:28]3)=[O:22])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Reactant: FC1CNC1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)c1nc2cc(NC(=O)c3c(C(=O)N4CC(F)C4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 86.5 %

Procedure:
A mixture of 5-(2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 213 μmol), 3-fluoroazetidine hydrochloride (71.3 mg, 640 mmol), propylphosphonic anhydride (50% in ethyl acetate, 314 μl, 533 μmol) and diisopropylethylamine (223 μl, 1.28 mmol) in tetrahydrofuran (4 ml) was stirred for 2.5 days (weekend) at 25° C. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 4-(3-fluoro-azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-isopropyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (71 mg, 86.4%) as a white solid. mp: 226-227° C., MS: m/z=384.0 (M−H+)
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:40])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[C:21]=3[NH:26][C:27]([O:29][CH:30]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[F:39])[CH3:31])=[O:28])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)C.Cl>CO.O>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:30]([O:29][C:27]([NH:26][C:21]2[C:22]([CH3:25])=[N:23][O:24][C:20]=2[C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][C:6]([OH:40])=[O:5])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)=[O:28])[CH3:31])=[C:33]([F:39])[CH:34]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccc(Cl)cc3F)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)OC(C)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Excess lithium hydroxide was added to a solution of (4′-{-4-[1-(4-chloro-2-fluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester (0.100 g, 0.19 mmol) in methanol and water, and the reaction was stirred at room temperature overnight. The mixture was acidified with 1N aqueous HCl and extracted with EtOAc, and the combined organic layers were dried, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[O:19]1[CH:23]=[C:22]([C:24](O)=[O:25])[N:21]=[CH:20]1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:22]3[N:21]=[CH:20][O:19][CH:23]=3)=[O:25])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1cocn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3cocn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and oxazole-4-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=353.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[C:10](=O)[CH2:9]1.[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[C:10](=[N:29][NH:28][C:25]([NH2:27])=[NH:26])[CH2:9]1
Reactant: O=C1CC(c2ccccc2Cl)Cc2[nH]nc(Nc3ccccc3)c21
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2Cl)Cc2[nH]nc(Nc3ccccc3)c21
Yield: 90.3 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-phenylamino-4,5,6,7-tetrahydroindazol-4-one (0.4 g), aminoguanidine hydrochloride (0.16 g), concentrated hydrochloric acid (0.31 ml), water (0.31 ml) and ethanol (20 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethylacetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid (5 ml) and concentrated. Precipitated crystals were recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-phenylamino-4,5,6,7-tetrahydroindazole hydrochloride (Compound 146) (0.23 g) as colorless crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[N:9]=[CH:8][C:7]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6]1)=[S:4].I[CH3:16]>CO>[CH3:16][S:4][C:3]([N:5]1[N:9]=[CH:8][C:7]2([CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6]1)=[N:2][CH3:1]
Reactant: CI
Reactant: CNC(=S)N1CC2(C=N1)CCOCC2
Solvent: CO
Product: CN=C(SC)N1CC2(C=N1)CCOCC2
Temperature: 50 °C
Yield: 0.2 %

Procedure:
0.50 g (1 mol equiv.) 8-Oxa-2,3-diaza-spiro[4.5]dec-3-ene-2-carbothioic acid methylamide was dissolved in 10 mL methanol; 1.2 mL (10 mol equiv.) iodomethane was added and the reaction mixture was heated at 50° C. for 5 hours. Volatiles were removed under reduced pressure, and the residue was taken up in DCM and extracted with 5% aqueous NaHCO3. The organic layer was washed twice with water, dried over Na2SO4, filtered and evaporated to dryness to yield 0.43 g (99%) N-methyl-8-oxa-2,3-diaza-spiro[4.5]dec-3-ene-2-carboximidothioic acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 1.53-1.60 (m, 2H), 1.80-1.88 (m, 2H), 2.47 (s, 3H), 3.26 (s, 3H), 3.56-3.64 (m, 2H), 3.68 (s, 2H), 3.83-3.89 (m, 2H), 6.73 (s, 1H).