Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[CH:4]=[O:5].[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cccc1Br
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: O=Cc1c(Cl)cccc1-c1ccncc1
Yield: 50.5 %

Procedure:
2-Chloro-6-bromobenzaldehyde (200 mg, 0.91 mmol), pyridine-4-boronic acid (125 mg, 1.0 mmol), dichlorobis(triphenylphosphine)palladium (II) (5 mol %, 30 mg), acetonitrile (2 mL) and aqueous sodium carbonate (2 molar solution, 2 mL) were combined in a microwave vial and sealed with a crimp seal. The mixture was microwaved at 150° C. for 5 min. The crude reaction mixture was then poured over Celite and washed with acetonitrile. The mixture was concentrated under reduced pressure and taken up in ethyl acetate. This organic solution was successively washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 98:2 methylene chloride:methanol to provide 2-chloro-6-(4-pyridyl)benzaldehyde (100 mg, 51% yield). NMR (300 MHz, CDCl3): 10.3 (s, 1H), 8.65 (m, 2H), 7.55 (m, 2H), 7.2 ppm (m, 3H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([C:11]1[CH:12]=C([CH:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=1)C(O)=O)([CH3:10])([CH3:9])[CH3:8]>CN(C)C=O.ClCCl>[C:20]([C:18]1[CH:17]=[C:1]([CH:12]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:19]=1)[C:2]([Cl:4])=[O:3])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (0.542 g, 0.37 ml, 4.27 mmol) was added dropwise to a solution of 3,5-di-tert-butylbenzoic acid (0.200 g, 0.853 mmol) and dichloromethane (4 ml). N,N-Dimethylformamide (1 drop) was added and the colorless solution stirred at RT for 3 h. The solution was concentrated to afford 3,5-di-tert-butylbenzoyl chloride as a yellow oil.
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=[C:10]([CH3:14])[N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C(#N)C.C(Cl)(Cl)Cl>[CH3:17][N:18]([CH3:20])[CH:19]=[N:2][S:1]([C:5]1[O:13][C:12]2[CH:11]=[C:10]([CH3:14])[N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc2oc(S(N)(=O)=O)cc2cn1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Cc1cc2oc(S(=O)(=O)N=CN(C)C)cc2cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a suspension of 2-sulfamoyl-6-methylfuro[3,2-c]pyridine (3.65 g, 17.2 mmol) in acetonitrile (80 ml), under a nitrogen atmosphere, was added N,N-dimethylformamide dimethyl acetal (2.6 ml, 19.6 mmol). This reaction was stirred for 1.5 hours at room temperature and then diluted with chloroform and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered through a charcoal pad and the solvent evaporated. The residue was triturated with diethyl ether and the product collected (4.31 g, 93% yield) and used as is. A small portion was crystallized from ethyl acetate for microanalysis, mp. 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([O:25]CC)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31].[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([C:18]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:31])([F:32])[F:33]
Reactant: CCOC(=O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(c2cc(OCC(F)(F)F)c(Cl)c(-c3ccc(C(F)(F)F)cc3)c2)CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.6 %

Procedure:
The ethyl 1-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylate (80 mg) dissolved in 10 mL of MeOH/THF/H2O (10 mL/10 mL/5 mL) and 57 mg LiOH added. The reaction mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography over silica gel (hexane/EtOAc 9:1) gave 1-(6-Chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclopentane carboxylic acid (45 mg) as a white solid. 1H-NMR (500 MHz, CDCl3): 7.74 (d, 2H), 7.55 (d, 2H), 7.08 (s, 1H), 4.44 (q, 2H), 2.66 (m, 2H), 1.98 (m, 2H), 1.78 (m, 4H).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.Cl.[C:15]1([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)CC(C)C>[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:25][CH2:24]1)(=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1ccccc1)N1CCNCC1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Product: O=C(c1ccccc1)N1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol), phenylpiperazin-1-ylmethanone hydrochloride (115.5 mg; 0.51 mmol) and triethylamine (141.3 μl; 1.02 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 9 (reaction time 6 h) and worked up. The crystals obtained after purification by column chromatography are dissolved in acetonitrile and water and freeze-dried; yield: 47 mg (27%), crystals;
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@:8]([CH2:27][O:28]C(=O)C)([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@H:6]1[N:32]1[CH:47]=[CH:46][C:36]([NH:37][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:35][C:33]1=[O:34])(=O)C.C[O-].[Na+].Cl>CO>[CH2:11]([O:10][C@@H:9]1[C@@:8]([CH2:27][OH:28])([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:7][C@@H:6]([N:32]2[CH:47]=[CH:46][C:36]([NH:37][C:38](=[O:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[N:35][C:33]2=[O:34])[C@@H:5]1[OH:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of nucleoside 54 (3.4 g, 5.3 mmol) in methanol (20 cm3) was added sodium methoxide (0.663 g, 11.66 mmol). The reaction mixture was stirred at room temperature for 10 min and then neutralised with 20% aqueous hydrochloric acid. The solvent was partly evaporated and the residue was extracted with dichloromethane (3×50 cm3). The combined organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×20 cm3) and was dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98.5:1.5, v/v) as eluent to give compound 55 as a white solid material (1.6 g, 54%). δH (CDCl3) 9.95 (1H, br s, NH), 8.33 (1H, d, J 7.4, 6-H), 7.98 (2H, m, Bz), 7.60-7.12 (14H, m, Bn, Bz, 5-H), 6.17 (1H, d, J 1.6, 1′-H), 4.78 (1H, d, J 11.8, Bn), 4.48-4.27 (5H, m, Bn, 2′-H, 3′-H), 3.85 (1H, d, J 11.8, 5′-H,), 3.66-3.61 (2H, m, 5′-Hb, 1″-H), 3.47 (1H, d, J 10.4, 1″-Hb). δC (CDCl3) 167.5, 162.31 (C-4, C═O), 155.36 (C-2), 145.34 (C-6), 137.49, 137.08, 133.09, 133.01, 128.94, 128.67, 128.48, 128.30, 128.01, 127.90, 127.80 (Bn, Bz), 96.53 (C-5), 93.97, 89.35 (C-1′, C-4′), 76.06, 75.28, 73.70, 72.76, 70.26, 62.44 (C-2′, C-3′, Bn, C-5′, C-1″). FAB-MS m/z 558 [M+H]+.
Reaction SMILES: [CH:1]1([C:4](=[O:21])[CH2:5][C:6]([C:8]2[CH:18]=[CH:17][C:11]3[S:12][CH:13]=[C:14]([O:15][CH3:16])[C:10]=3[C:9]=2[O:19][CH3:20])=[O:7])[CH2:3][CH2:2]1.[CH:22](OCC)(OCC)[O:23][CH2:24][CH3:25].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:21])[C:5](=[CH:22][O:23][CH2:24][CH3:25])[C:6]([C:8]2[CH:18]=[CH:17][C:11]3[S:12][CH:13]=[C:14]([O:15][CH3:16])[C:10]=3[C:9]=2[O:19][CH3:20])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: COc1csc2ccc(C(=O)CC(=O)C3CC3)c(OC)c12
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc2scc(OC)c2c1OC)C(=O)C1CC1

Procedure:
A mixture of 5-(3-cyclopropyl-1,3-dioxoprop-1-yl)-3,4-dimethoxybenzo[b]thiophene (0.5 g) and triethyl orthoformate (0.73 g) was heated under reflux with acetic anhydride (10 ml) for 3 hours. After cooling and addition of toluene the solution was evaporated to dryness to yield 5-(3-cyclopropyl-2-ethoxymethylene-1,3-dioxoprop-1-yl)-3,4-dimethoxybenzo[b]thiophene as a red oil.
Reaction SMILES: C(#N)C.CC(O[CH2:8][C:9]1[CH2:18][S:17][C@@H:12]2[C@H:13]([NH2:16])[C:14](=[O:15])[N:11]2[C:10]=1[C:19]([OH:21])=[O:20])=O.[SH:22][C:23]1[O:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:35])[CH:29]=2)=[N:26][N:27]=1.B(F)(F)F.CCOCC.N>O>[NH2:16][C@@H:13]1[C:14](=[O:15])[N:11]2[C:10]([C:19]([OH:21])=[O:20])=[C:9]([CH2:8][S:22][C:23]3[O:24][C:25]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:35])[CH:29]=4)=[N:26][N:27]=3)[CH2:18][S:17][C@H:12]12
Reactant: Oc1ccc(-c2nnc(S)o2)cc1O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Agent: N
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnc(-c4ccc(O)c(O)c4)o3)CS[C@H]12
Temperature: 50 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
To 520 ml of acetonitrile 16.3 g (60 mmol) of 7β-aminocephalosporanic acid and 13.9 g (66 mmol) of 2-mercapto-5-(3,4-dihydroxyphenyl)-1,3,4-oxadiazole and 45.4 ml (360 mmol) of boron trifluoride diethyl etherate were added, and stirred at 50° C. for 3 hours. The reaction solution was cooled and poured into 450 ml of cold water. The mixture was stirred at room temperature for 1 hour and adjusted to pH2.0 with a 25% aqueous ammonia. The mixture was stirred at not more than 5° C. for 1 hour, and the precipitates were collected by filtration. The precipitates were washed with water and ethyl acetate and dried to obtain 21.3 g (yield: 84.1%) of the above identified compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[SH:21]>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: N#Cc1cnc2ccsc2c1Cl
Solvent: CN(C)C=O
Product: N#Cc1cnc2ccsc2c1Sc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) and 2,4-dichlorothiophenol (202.9 mg, 1.13 mmol) in 5 mL of N,N-dimethylformamide is stirred at room temperature for 1 hour, and then concentrated in vacuo. The resulting residue is treated with water and stirred for 1 hour. The precipitate is filtered, washed with water, air dried, and then purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane to provide 249.0 mg of 7-[(2,4-dichlorophenyl)thio]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 126-128° C.; 1H NMR (DMSO-d6) δ 7.47 (dd, J=6, 2 Hz, 1H), 7.54 (d, J=6 Hz, 1H), 7.73 (d, J=4 Hz, 1H), 7.88 (d, J=2 Hz, 1H), 8.43 (d, J=4 Hz, 1H), 9.09 (s, 1H); MS 336.9, 339.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](NC)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.[CH:27]([N:30](C(C)C)CC)(C)C.[NH:36]1[CH:40]=[C:39]([C:41]([OH:43])=O)[CH:38]=[N:37]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O1CCCC1>[F:1][C:2]([F:26])([F:25])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:27][NH:30][C:41]([C:39]5[CH:38]=[N:37][NH:36][CH:40]=5)=[O:43])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1
Reactant: CNc1ccc2c(c1)OCCc1sc(-c3ncnn3CC(F)(F)F)nc1-2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cn[nH]c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: O=C(NCc1ccc2c(c1)OCCc1sc(-c3ncnn3CC(F)(F)F)nc1-2)c1cn[nH]c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-methylamine in tetrahydrofuran was added diisopropylethylamine followed by 1H-pyrazole-4-carboxylic acid and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate. The reaction was stirred at room temperature for about 3 hours. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate and extracted 3 times with ethyl acetate. The organic layers were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give was reacted with to give 106. MS (ESI+) 476.1. 1H NMR (400 MHz, DMSO) δ 13.03 (br, 1H), 8.60 (m, 1H), 8.32-8.22 (m, 2H), 8.07 (s, 2H), 7.15 (dd, J=16.3, 8.3, 1H), 7.00 (s, 1H), 5.84 (q, J=8.7, 2H), 4.43 (d, J=5.9, 2H), 4.36 (t, J=4.9, 2H), 3.45 (t, J=4.9, 2H)
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:6]=2[CH:5]=[CH:4][NH:3]1.CO.C1COCC1.[OH-].[Na+]>O>[O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: CCC(CC)n1cc(-c2csc(C(=O)OC)c2)c2c(=O)[nH]ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)n1cc(-c2csc(C(=O)O)c2)c2c(=O)[nH]ccc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a solution of methyl 4-(4-oxo-1-(pentan-3-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxylate (23.5 mg) obtained in Example 7 in a mixed solvent of methanol (1 mL)/THF (1 mL)/water (1 mL) was added 8N aqueous sodium hydroxide solution (0.021 mL) at 0° C. The reaction mixture was stirred at 90° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (23.0 mg).
Reaction SMILES: [CH2:1]=[O:2].Br[CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:9][CH:8]=1)[CH3:6].[Mg]>C1COCC1>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH:5]([CH3:6])[CH2:4][CH2:1][OH:2])=[CH:8][CH:9]=1
Reactant: CC(CBr)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Reaction time: 120 h

Procedure:
0.3 g. of paraformaldehyde is added to Grignard solution prepared from 3.11 g. of 4-(1-bromo-2-propyl)-2',4'-difluorobiphenyl and 0.26 g. of magnesium powder in 40 ml. of THF and the mixture is allowed to stand for 5 days. It is worked up in the customary manner, using ice/dilute hydrochloric acid, to give 3-(2',4'-difluoro-4-biphenylyl)butan-1-ol.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:17]=[C:16]([CH2:27][CH:28]([C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)[C:29]#[N:30])[CH:15]=2)[CH:10]=[CH:11][C:12]=1[Cl:13].[Cl-].[NH4+].[N-:40]=[N+:41]=[N-:42].[Na+]>O.C(O)=O>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[N:18]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:17]=[C:16]([CH2:27][CH:28]([C:29]3[NH:42][N:41]=[N:40][N:30]=3)[C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)[CH:15]=2)[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COc1ccc(-n2nc(CC(C#N)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: O
Product: COc1ccc(-n2nc(CC(c3cccc(C)c3)c3nnn[nH]3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 90 °C
Yield: 63 %

Procedure:
To a 48-mL pressure vessel (Chemglass) were added N,N-dimethylformamide (25.0 mL), 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionitrile (2.76 g, 5.97 mmol, 1.0 equiv), ammonium chloride (1.58 g, 29.8 mmol, 5.0 equiv) and sodium azide (1.94 g, 29.8 mmol, 5.0 equiv). The screw-cap vessel was sealed and then placed in an oil bath heated to 90° C. for 48 h. The reaction mixture was cooled to room temperature, pH-adjusted with formic acid, diluted with water (100 mL), and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with water (3×50 mL) then brine (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (5% methanol/dichloromethane) to yield the title compound (1.9 g, 63%). HPLC: Rt=3.09 (Method A). MS (ESI): mass calculated for C26H22Cl2N6O, 504.12; m/z found, 505.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 7.57 (d, J=8.5 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.23-7.16 (m, 3H), 7.09-7.07 (m, 3H), 7.01 (dd, J=8.5, 2.2 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 6.46 (s, 1H), 4.86 (dd, J=9.0, 6.6 Hz, 1H), 3.77 (s, 3H), 3.62 (dd, J=14.8, 9.3 Hz, 1H), 3.35 (dd, J=14.8, 6.6 Hz, 1H), 2.28 (s, 3H).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.F[C:18](F)(F)[C:19]([OH:21])=[O:20].[CH2:24]([Cl:26])Cl>>[CH2:10]([N:4]1[CH2:3][C:10]([C:11]2[CH:16]=[CH:15][C:24]([Cl:26])=[CH:13][CH:12]=2)=[C:18]([C:19]([OH:21])=[O:20])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Product: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (201.6 g, 849 mmol) in CH2Cl2 (600 mL) was added dropwise over a 30 minutes period to a stirred solution of 3-(4-chlorophenyl)-2-propionic acid ethyl ester (125.9 g, 566 mmol) and trifluoroacetic acid (4.3 mL, 114 mmol) in CH2Cl2 (400 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 4 h. It was then concentrated and the reaction mixture was taken up in dioxane (1.2 L). Then 1N NaOH (146 mL) were added and the mixture was stirred at ambient temperature for 72 h. The volatiles were removed and the residue was extracted with TBDME and water. The organic phases were extracted with water and the combined aqueous phases were acidified with aqueous HCl (10%). Upon stirring at ambient temperature over night a precipitation formed which was isolated, washed with water and ethanol and dried under high vacuum to yield the title product (148 g, 76%) as a colorless solid. ES-MS m/e: 314.8 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1.Br[CH2:31][CH:32]1[CH2:34][CH2:33]1.O.[OH-].[Cs+].[ClH:38]>CN(C=O)C>[ClH:38].[ClH:38].[CH:32]1([CH2:31][N:1]2[CH:5]=[C:4]([CH2:6][N:7]3[C:15]4[C:10](=[C:11]([NH:16][C:17]([C:19]5[N:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:22]6=[N:21][CH:20]=5)=[O:18])[CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:28][CH3:29])=[N:8]3)[CH:3]=[N:2]2)[CH2:34][CH2:33]1
Reactant: CCc1nn(Cc2cn[nH]c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: BrCC1CC1
Agent: Cl
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cnn(CC3CC3)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a solution of N-(1-((1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 0.052 mmol; prepared according to Example 21, Step A) in dry DMF (0.5 mL) was added (bromomethyl)cyclopropane (7.0 mg, 0.052 mmol) and cesium hydroxide hydrate (8.7 mg, 0.052 mmol). The mixture was stirred at ambient temperature for 60 minutes. The mixture was filtered, washed with methanol and ethyl acetate, and concentrated under reduced pressure. The residue was purified using preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane. The product was dissolved in a mixture of dichloromethane and methanol. Hydrogen chloride (0.52 mmol; 2M solution in diethyl ether) was added and the solvent was removed under reduced pressure, followed by high vacuum to give N-(1-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride (5.6 mg). MS (APCI), positive scan, m/z=440.2 (M+H).
Reaction SMILES: [P:1]([O-:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1>CN(C=O)C.O>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]1[O:25][CH2:24][CH2:23][CH2:22][P:1](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=P(CCCOC1CCCCO1)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dibenzyl phosphite (1.70 mL, 7.63 mmol) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil) (0.381 g, 9.53 mmol) in dry DMF (11.4 mL) at 25° C. under N2. After 15 min 2-(3-bromopropoxy)tetrahydro-2H-pyran (1.29 mL, 7.63 mmol) was added and the mixture was stirred at 25° C. for 5 h. The reaction mixture was diluted with water (20 mL) and extracted with Et2O (2×40 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to afford dibenzyl [3-(tetrahydro-2H-pyran-2-yloxy)propyl]phosphonate. Rf=0.06 (20% EtOAc/hexanes). LCMS calc.=427.17; found=427.15 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22](OCC)=[O:23].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38](Cl)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:34]=[CH:35][CH:36]=1>>[CH3:20][C:13]1[NH:12][C:11]2[CH:21]=[C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=3)[C:22](=[O:23])[C:10]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:28])([F:27])[F:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reactant: COc1cccc(N=C(Cl)c2ccccc2)c1
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3cccc(OC)c3)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-(3-methoxyphenyl)-benzimidoyl chloride (2.2 g, 8.7%).