Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([C:42](=[O:44])[CH3:43])[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
Rac-cis-(3,5-Bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone (200 mg, 0.41 mmol) was dissolved in methylene chloride (5 mL). Triethyl amine (0.173 mL, 1.24 mmol) and acetyl chloride (0.035 mL, 0.49 mmol) were added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and chromatography on silica gel with methylen chloride/triethyl amine 99:1 gave the desired product (122 mg, 56%) as a light yellow foam, MS: m/e=528.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.[C:17](OCC)(OCC)(OCC)[CH3:18]>C(OC(=O)C)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=[C:17]2[CH3:18])=[CH:10][CH:11]=1)#[N:16]
Reactant: N#Cc1ccc(Nc2ccncc2N)cc1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2cnccc2n1-c1ccc(C#N)cc1

Procedure:
A mixture of 3-amino-4-[N-(4-cyanophenyl)amino]pyridine (see part (b)) (9.31 g, 44.3 mmol), triethyl orthoacetate (40 ml) and acetic anhydride (30 ml) was heated under reflux for 2 hours under nitrogen, cooled, then concentrated under reduced pressure The brown residue was dissolved in 1M hydrochloric acid and washed with ethyl acetate (200 ml). The aqueous layer was rendered basic with saturated aqueous ammonia and extracted with dichloromethane (3×200 ml). The combined extracts were washed with water, dried (MgSO4) and concentrated to give the title compound (6.5 g), as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([CH3:13])[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([CH3:13])[CH2:11][CH2:10][N:9]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CCNC1c1ccc(F)cc1
Product: Cc1ccc(S(=O)(=O)N2CCC(C)C2c2ccc(F)cc2)cc1

Procedure:
The title compound, off-white solid, m.p. 112° C. and MS: m/e=354.2 (M+) was prepared in accordance with the general method of example 1e from (2RS,3RS)-2-(4-fluoro-phenyl)-3-methyl-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][CH2:8][CH2:9][S:10]([CH2:13][CH2:14][CH2:15]O)(=[O:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[Br:19]CCCS(C)(=O)=O>>[Br:19][CH2:15][CH2:14][CH2:13][S:10]([CH2:9][CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:18])[CH3:17])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)CCCBr
Reactant: CC(C)(C)[Si](C)(C)OCCCS(=O)(=O)CCCO
Product: CC(C)(C)[Si](C)(C)OCCCS(=O)(=O)CCCBr

Procedure:
Intermediate 24 (485 mg) was prepared from Intermediate 20 (1.18 g, 4 mmol)) according to an analogous procedure to that described for Intermediate 14.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:22](OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]2[C:3]=1[CH:9]=[N:22][NH:5]2
Reactant: Cc1c(N)cccc1Br
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Brc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a solution of 3-bromo-2-methylaniline (5 g, 27 mmol) in chloroform (1 mL) was added acetic anhydride (5 g, 27 mmol) at 0° C. and the mixture was stirred at room temperature for 1 h. Potassium acetate (0.75 g, 7.8 mmol) and isoamyl nitrite (0.78 g, 58 mmol) were added and the reaction mixture was refluxed for 18 h. The volatiles were removed under reduced pressure and water (0.65 mL) was added. The mixture was concentrated, diluted with concentrated hydrochloride acid (1 mL) and heated at 50° C. for 2 h. After being cooled to room temperature, aqueous sodium hydroxide solution (50%) was added until pH=10. The aqueous mixture was extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, evaporated and purified on silica gel column (3% ethyl acetate in petroleum ether) to give the desired product (2.69 g, 34% yield) as a solid. MS (ESI): m/z 197.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8](Cl)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.CN.[CH2:13]([N:15](CC)CC)C>C1COCC1>[CH3:13][NH:15][C:8]([C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1nccnc1Cl
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To a solution of 3-chloropyrazine-2-carboxylic acid chloride (350 mg, 2.0 mmol) in THF (10 mL) was added methylamine (300 mg, 10 mmol) and triethylamine (303 mg, 3.0 mmol). The reaction mixture was stirred at RT for 3 h. The reaction solution was concentrated under reduced pressure to give the desired compound (200 mg, yield 100%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([O:10][CH3:11])=[C:7]([CH:9]=1)[NH2:8].FC(F)(F)C1C=CC(OC)=C([N:22]=[C:23]=[O:24])C=1.[C:29]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([OH:31])=[O:30]>>[C:29]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([OH:31])=[O:30].[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([O:10][CH3:11])=[C:7]([NH:8][C:23]([NH:22][C:34]2[CH:43]=[CH:44][CH:45]=[C:32]([C:29]([OH:31])=[O:30])[CH:33]=2)=[O:24])[CH:9]=1
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Agent: Nc1ccc(Oc2cccc(C(=O)O)c2)cc1
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cccc(C(=O)O)c1

Procedure:
Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl) urea, which was coupled with 4-fluoroaniline according to Method D1c.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:27][C:28]([F:45])([F:44])[C@@H:29]([O:31][C:32](=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1)[CH3:30]>>[F:27][C:28]([F:45])([F:44])[C@@H:29]([O:31][C:32]([N:23]1[CH2:24][CH2:25][CH:20]([C@@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:33])[CH3:30]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Product: C[C@H](OC(=O)N1CCC([C@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (S)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described in Example 1. LC (method 3): tR=1.54 min; Mass spectrum (ESI+): m/z=518 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:54][CH3:55])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:34][C:35]2[CH:36]=[C:37]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=2)[O:38][CH2:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])[C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:54][CH3:55])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]([CH2:34][C:35]2[CH:36]=[C:37]([CH:47]=[C:48]([C:50]([F:53])([F:51])[F:52])[CH:49]=2)[O:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1cc(CN(Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)c2ncc(N3CCOCC3)cn2)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(OCCCC(=O)O)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Ethyl 4-(3-{[(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenoxy)butyrate (88 mg) is dissolved in a mixed solvent of ethanol (1 ml) and tetrahydrofuran (1 ml) and thereto is added a 1M-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is made acidic with 10% aqueous citric, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 4-(3-{[(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-phenoxy)butyric acid (71 mg). MS (m/z): 747 [M+H]+
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)=[O:11].[F-].[K+]>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:15]2[CH:16]=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][CH:14]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Br)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccc(C=O)cc2)cc1
Yield: 100.1 %

Procedure:
4-Bromobenzonitrile (73 mg, 0.40 mmol) reacted with 4-formylphenylboronic acid (90 mg, 0.60 mmol) using 0.5/1.0 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (70 mg, 1.21 mmol) in THF solvent at 40° C. to give the title compound (83 mg, 97%) as a white solid: 1H-NMR (500 MHz, CDCl3): δ 10.10 (s, 1H), 8.01 (d, 2H, J=8.25 Hz), 7.80-7.74 (m, 6H). 13C{1H}-NMR (125 MHz, CDCl3): δ 191.57, 144.90, 144.14, 136.14, 132.78, 130.41,128.03, 127.91, 118.52, 112.17. GC/MS(EI): m/z 207 (M+), 206.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][C@@H:23]4[CH2:25][O:24]4)=[C:16]([CH2:26][CH3:27])[CH:15]=3)[N:10]=2)[CH:6]=[C:5]([CH3:28])[N:4]=1)[CH3:2].[NH3:29]>CO>[NH2:29][CH2:25][C@@H:23]([OH:24])[CH2:22][O:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([C:11]2[N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH3:28])[N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=3)[O:13][N:12]=2)=[CH:15][C:16]=1[CH2:26][CH3:27]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(OC[C@@H]4CO4)c(CC)c3)no2)cc(C)n1
Reactant: N
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@H](O)CN)c(CC)c3)no2)cc(C)n1

Procedure:
(S)-2-ethyl-4-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine is treated with ammonia in MeOH as described in Example 46 step b) to give (R)-1-amino-3-{2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-propan-2-ol.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[C:9]([C:17]4[O:18][C:19]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:20][C:21](=[O:23])[CH:22]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14]2)=[CH:5][CH:4]=1.[BrH:30]>C(Cl)(Cl)Cl>[Br:30][CH2:2][C:3]1[CH:16]=[C:15]2[C:6]([S:7][C:8]3[C:9]([C:17]4[O:18][C:19]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:20][C:21](=[O:23])[CH:22]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=c1cc(-c2cccc3c2Sc2ccc(CO)cc2C3)oc(N2CCOCC2)c1
Reactant: Br
Solvent: ClC(Cl)Cl
Product: O=c1cc(-c2cccc3c2Sc2ccc(CBr)cc2C3)oc(N2CCOCC2)c1
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 2-(7-Hydroxymethyl-9H-thioxanthen-4-yl)-6-morpholin-4-yl-pyran-4-one (3)(240 mg, 0.59 mmol) in chloroform (10 mL) was saturated with hydrogen bromide by bubbling hydrogen bromide gas through the reaction mixture until the solution became cloudy. After 18 hours, hydrogen bromide gas was again bubbled through the reaction mixture. The reaction mixture was washed with saturated NaHCO3 and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The brown coloured solid was dried under vacuum at 50° C. to give the crude title compound (assumed 100%) which was used without any further purification. m/z (LC-MS, ESP): 470.2 [M+H]+ (1:1, bromine isotope ratio present), R/T=3.86 mins
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)([CH3:6])[CH3:5])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[N:13]1[C:14]2[C:9](=[CH:8][C:7]([C:4]([NH2:1])([CH3:5])[CH3:6])=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CC(C)(N=[N+]=[N-])c1ccc2ncccc2c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(N)c1ccc2ncccc2c1
Reaction time: 6 h
Yield: 15.9 %

Procedure:
To 6-(2-azidopropan-2-yl)quinoline (0.100 g, 2.67 mmol) in ethanol (3 ml), palladium on carbon (10 mg, 10% w/w) was added and stirred under a hydrogen atmosphere using hydrogen filled balloon. After 6 h, the reaction mass was filtered through celite, washed with methanol and concentrated to afford the title compound as brown liquid (0.079 g, 90%). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.82 (dd J=4.2, 1.6 Hz, 1H), 8.31 (d, J=8.9 Hz, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.99 (dd, J=8.9, 2.1 Hz, 1H), 7.93 (d, J=8.9 Hz, 1H), 7.49 (q, J=4.2 Hz, 1H), 2.06 (s, 2H), 1.46 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:16]=3[S:17][C:18]=2Br)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:27][O-:28].[Na+].CO.O>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[C:16]=3[S:17][C:18]=2[O:28][CH3:27])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1c(Br)sc2c1CCCC2=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1sc2c(c1S(=O)(=O)N(C)CC(O)c1ccc(F)cc1)CCCC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-bromo-7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid [2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-amide (the compound of Preparation Example 58) (80 mg) in methanol (3 mL) was added a solution of 28% sodium methoxide/methanol (0.8 mL). After stirring at room temperature for 3 hours, the reaction solution was poured into water, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. The residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (58 mg) was obtained as a light brown candy-like substance.
Reaction SMILES: FC1C=CC=C([N+:8]([O-:10])=[O:9])C=1F.[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14](NC(=O)OC(C)(C)C)[CH2:13]1>C(#N)C.C(N(CC)C(C)C)(C)C>[N+:8]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=[N+]([O-])c1cccc(F)c1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])N1CCCCC1
Yield: 189532 %

Procedure:
A mixture of 1,2-difluoro-3-nitrobenzene (2.38 g, 0.015 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (3.0 g, 0.015 mmol) and N,N-diisopropylethylamine (5.2 ml, 0.030 mmol) was heated in acetonitrile (20 mL) at 80° C. overnight. The solvents were removed in vacuo, and chromatographic purification (ethyl acetate-hexanes) of the residue gave a nitropiperidine as orange oil (3.7 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29])=[O:17].O.O[Li].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29])=[O:17]
Reactant: COC(=O)c1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1

Procedure:
Methyl 4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-nitrobenzoate (5.4 gr, 11.6 mmol) was dissolved in THF (78 mL) and water (52 mL) and treated at room temperature with LiOH hydrate (730 mg) for 24 hours. THF was evaporated and the resulting aqueous phase was treated with 5% KHSO4 aqueous solution (100 mL). The so obtained precipitated was filtered off and dried under vacuum at 60° C. affording the title compound without any further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:21]=[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:23]([C:24]([O:26]C)=[O:25])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.Cl>O1CCOCC1.O.O>[CH2:1]([O:8][C:9]1[C:14]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:21]=[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:23]([C:24]([OH:26])=[O:25])=[C:11]2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(C)S(C)(=O)=O)c(OCc3ccccc3)cc12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)O)c2cc1OCc1ccccc1)S(C)(=O)=O
Yield: 96.2 %

Procedure:
To a solution of methyl 5-(benzyloxy)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylate (3 g, 6.2 mmol) in dioxane/H2O (1/1, 60 mL) was added LiOH.H2O (781 mg, 19 mmol), and the mixture was heated to reflux for 3 hours, and concentrated in vacuo. The residue obtained was dissolved in H2O, 1 N HCl was added until pH reached 3, and the resulting precipitate was collected by filtration, washed with water, dried to afford 5-(benzyloxy)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)pyrazolo[1,5-a]pyridine-3-carboxylic acid (2.8 g, yield: 96%). 1H-NMR (DMSO-d6, 400 MHz) δ 12.4 (s, 1H), 8.97 (s, 1H), 7.74˜7.77 (m, 2H), 7.59 (s, 1H), 7.54 (d, J=7.2 Hz, 2H), 7.29˜7.43 (m, 3H), 7.26 (t, J=8.8 Hz, 2H), 5.32 (s, 2H), 3.54 (s, 3H), 3.20 (s, 3H), 3.00 (s, 3H). MS (M+H)+: 470.
Reaction SMILES: C(OC(=O)[C@H:5]([CH2:7][CH2:8][C:9](OCC)=O)[NH2:6])C.S(Cl)(Cl)=O.Cl.C(OC(=O)[C@H:24](CCC(OCC)=O)[NH2:25])C.[CH2:34]([N:36](CC)[CH2:37]C)C>CN(C)C1C=CN=CC=1>[N:25]1[C:24]2[N:6]=[CH:5][CH:7]=[CH:8][C:9]=2[CH:37]=[N:36][CH:34]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: c1cnc2ncncc2c1

Procedure:
Those compounds of the present invention where R2 is prop-1,3-diyl are prepared by first preparing a benzoic acid derivative described above having a p-propen-1-yl group using the oxazoline described in Meyers, Acc. Chem. Res., 14, 375 (1978), which is incorporated herein by reference. Acid hydrolysis (5N HCl, reflux, 36 hours) affords 4-allylbenzoic acid which is converted to the corresponding diethyl-L-glutamate derivative by initial treatment with thionyl chloride (4.0 eqv., benzene, reflux, 4 hours) followed by diethyl-L-glutamate hydrochloride (2.1 equivalents), 4-dimethylamino-pyridine (0.01 eqv.) and triethylamine (18 hours). Coupling to either the pyrrolo- or pyrido[2,3-d]pyrimidine, at least by Alternative 2, affords the compounds of the present invention where R2 is a propen-1,3-diyl.
Reaction SMILES: [CH2:1]([C:3]([OH:36])([CH2:34][CH3:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:31][CH3:32])([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33])[CH3:2].[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45](Br)[CH:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45]([C:18]2[CH:19]=[CH:20][C:15]([C:12]([CH2:13][CH3:14])([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([CH2:34][CH3:35])([OH:36])[CH2:1][CH3:2])=[C:7]([CH3:33])[CH:8]=3)[CH2:31][CH3:32])=[CH:16][C:17]=2[CH3:30])[CH:46]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C
Temperature: 89.5 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
Degassed N,N-dimethylformamide (0.37 mL) was added to 3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol (Example 29; 30.6 mg, 0.0621 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 21.1 mg, 0.0917 mmol), tetrakis(triphenylphosphine)palladium (0) (9.0 mg, 0.0078 mmol) and potassium phosphate (29.4 mg, 0.138 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 85 to 94° C. for three hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=1/1) to give the title compound (29.5 mg, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=O)[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[N:14]=[N:15][C:16]([NH:19][NH2:20])=[CH:17][CH:18]=1.BrC(Cl)(Cl)C(Br)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C(N(CC)CC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]2[N:15]([C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:20][N:19]=2)[N:14]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: COc1cccc(N=C=O)c1
Agent: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc(Nc2nnc3ccc(Cl)nn23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-methoxyphenyl isocyanate and 3-chloro-6-hydrazinopyridazine in acetonitrile was stirred at room temperature for 30 minutes, and 1,2-dibromo-1,1,2,2-tetrachloroethane was added and the mixture was stirred at room temperature for further 2 hours. This reaction solution was combined with triethylamine and triphenylphosphine with cooling in ice, and stirred at room temperature for 3 days. Then, the reaction solution was concentrated under reduced pressure, purified by a standard method to obtain 6-chloro-N-(3-methoxyphenyl)-1,2,4-triazolo[4,3-b]pyridazin-3-amine. Dat (F:276).