Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[F:24])[CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)cnc1C
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(Cc3ccccc3F)c3ccccc3c2=O)cnc1C
Yield: 92.3 %

Procedure:
Compound 4g was prepared following the procedure described in Step 3 of Example 1. 63 mg (0.23 mmol) of 3-(5,6-dimethyl-pyridine-3-carbonyl)-1H-quinolin-4-one 3c, 11 mg (0.27 mmol) of 60% sodium hydride and 51 mg (0.27 mmol) of 2-fluorobenzyl bromide were combined in 1 mL N,N-dimethylformamide at rt for 1 h. The product was purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 50 min. The HPLC fractions containing pure product were combined and the combined solutions was lyophilized with 1 mL of 1 M HCl to give 82 mg of a pale yellow solid 4g as its HCl salt: LC-MSD, m/z for C24H19FN2O2 [M+H]+=387.5, HPLC retention time: 1.2 min; 1H NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 2.9 (s, 3H), 5.55 (s, 2H), 7.05-7.2 (m, 3H), 7.3-7.4 (m, 1H), 7.45-7.55 (m, 2H), 7.65-7.75 (m, 1H), 8.35-8.45 (m, 2H), 8.6 (s, 1H), 8.85 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[Si:22]([O:29][CH2:30][C:31](=[CH2:35])[C:32](O)=[O:33])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[Si:22]([O:29][CH2:30][C:31](=[CH2:35])[C:32]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:33])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Product: C=C(CO[Si](C)(C)C(C)(C)C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (80 mg, 0.28 mmol) was added tetrahydrofuran (2.8 mL), TEA (59.2 μL, 0.425 mmol), 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)prop-2-enoic acid (80 mg, 0.37 mmol) and 1-propanephosphonic acid cyclic anhydride (169 μL, 0.283 mmol). The reaction was stirred at 25° C. overnight before being quenched by pouring into a separatory funnel containing aqueous sodium bicarbonate (5%). The solution was extracted with ethyl acetate (×3) and the organic layers were combined and dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was then purified by silica chromatography by MPLC using 1-8% CH2Cl2MeOH. Concentration of the desired fractions afforded the title compound as a colorless solid. LRMS (ESI) calc'd for C25H33N4O4Si [M+H]+, 481; found 481.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18](O)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.[Si]([O:28][CH2:29][C@H:30]([C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[NH2:31])(C(C)(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O.CO>[OH:28][CH2:29][C@@H:30]([NH:31][C:18]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1)=[O:19])[C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Reactant: Cc1ccc([C@H](N)CO[Si](C)(C)C(C)(C)C)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1ccc(-c2cc(C(=O)N[C@H](CO)c3ccc(C)nc3)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (37 mg, 0.12 mmol) in N,N-dimethylformamide (1 mL) were added (S)-2-(tert-butyldimethylsilyloxy)-1-(6-methylpyridin-3-yl)ethanamine (80 mg, 0.27 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. LC-MS indicated the reaction was complete. To the reaction mixture were added MeOH (2 mL) and 12N aq. HCl (0.5 mL). The mixture was stirred at rt for 2 hrs and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, MeCN-water[10 mM Et2NH]) to afford the final product as a light color solid.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[CH2:5]([Li])[CH2:6][CH2:7]C.[CH2:10]([N:17]1[CH2:21][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C@H](C(N2[C@@H](CC3C=CC=CC=3)COC2=O)=O)C1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:21][C@@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C@H:2]([C:1]([CH2:5][CH2:6][CH3:7])=[S:4])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCS
Reactant: [Li]CCCC
Reactant: CCOC(=O)[C@H]1CN(Cc2ccccc2)C[C@H]1C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Solvent: C1CCOC1
Product: CCCC(=S)[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OCC
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cooled (−78° C.) solution of 5.7 g (75.0 mmol) of propanethiol in 250 mL THF was added 34.4 mL n-butyllithium (1.6M, 55.0 mmol) and the solution was stirred for 45 min at −78° C. under nitrogen and then warmed to −10° C. To the resulting white suspension was added a solution of 9.6 g (22.0 mmol) of (S)-N-[(1-Benzyl)-4-(R)-(ethoxycarbonyl)-3-(S)-pyrrolidinylcarbonyl]-4-benzyl-2-oxazolidinone in 250 mL THF. The reaction was stirred for 30 min and then removed from the bath and allowed to warm to rt over 1 h. The clear solution was partitioned between 1.5 L of ether and 500 mL of 1M NaOH and the layers were separated. The aqueous layer was washed with ether and the combined organic fractions were washed with sat'd NCl solution, dried over MgSO4, filtered, and the filtrate was concentrated.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](SC)=[N:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.Cl.[C:30]1([N:36]2C=CN=C2N2CCN([C@@H]3CN[C@H](C(N4CCSC4)=O)C3)CC2)C=CC=[CH:32][CH:31]=1.C(N)C#C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:31]([CH3:32])=[CH:30][N:36]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([C@@H]1C[C@H](N2CCN(c3nccn3-c3ccccc3)CC2)CN1)N1CCSC1
Reactant: CSC(=Nc1ccccc1)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: C#CCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: Cc1cnc(N2CCN(C(=O)OCc3ccccc3)CC2)n1-c1ccccc1

Procedure:
1-Benzyloxycarbonyl-4-[(methylthio)phenyliminomethyl]piperazine [product of Example 224 (2), 2.70 g] and propargylamine (2.3 mL) were dissolved in 1-butanol (25 mL), and p-toluenesulfonic acid monohydrate (156 mg) was added thereto. The mixture was refluxed for 20 hr. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with chloroform, and the extract was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-benzyloxycarbonyl-4-(5-methyl-1-phenyl-2-imidazolyl)piperazine (1.82 g) as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.C(OCC)(=O)C.O>Cl.CO.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(-n2cccc2)cc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(N)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 72.2 %

Procedure:
To a solution of methyl 3-nitro-5-(pyrrol-1-yl)benzoate (35.8 g) in concentrated hydrochloric acid (79 ml) and methanol (73 ml) was added portionwise iron (48.6 g). After stirring for 3.5 hours at room temperature, the reaction mixture was poured into a mixture of ethyl acetate and water and filtered. The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was pulverized from petroleum ether and diisopropyl ether to give methyl 3-amino-5-(pyrrol-1-yl)benzoate (22.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:11][CH3:12])[CH2:6][CH:5]([C:7]([O:9]C)=O)[CH2:4]1.Cl.[CH3:14][NH:15][O:16][CH3:17].C([Mg]Cl)(C)C>C1COCC1>[CH3:17][O:16][N:15]([CH3:14])[C:7]([CH:5]1[CH2:4][C:3]([O:2][CH3:1])([O:11][CH3:12])[CH2:6]1)=[O:9]
Reactant: COC(=O)C1CC(OC)(OC)C1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CC(OC)(OC)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
Methyl 3,3-dimethoxycyclobutanecarboxylate (11.65 g, 66.9 mmol) was dissolved in THF (134 mL) and treated with N,O-dimethylhydroxylamine hydrochloride (10.12 g, 103.7 mmol). The mixture was cooled to 0° C. and treated with isopropylmagnesium chloride (2 M solution in THF, 100.3 mL, 200.7 mmol) and stirred for 2 h. The reaction was quenched with saturated ammonium chloride solution (75 mL), diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 20-100% ethyl acetate in heptane to afford the desired product (9.16 g, 67%). Rf 0.06 (20% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 3.61 (s, 3H), 3.20 (s, 3H), 3.19 (s, 3H), 3.15 (s, 3H), 2.39 (d, J=9.0 Hz, 4H). ESI MS found for C9H17NO4 m/z [204.1 (M+1)].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21]O[CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1.[NH2:35][NH2:36].CC#N.[OH2:40]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]3[C:11]([C:12]([NH2:13])=[N:35][NH:36]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:40][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCOC(c4nc(-c5cccc(Cl)c5)c[nH]4)C3)nc(N)n2)cc1F
Reactant: NN
Reactant: O
Solvent: CC#N
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC(c3nc(-c4cccc(Cl)c4)c[nH]3)C2)n1
Reaction time: 1 h
Yield: 30.2 %

Procedure:
A mixture of 4-(2-amino-6-{2-[4-(3-chlorophenyl)-1H-imidazol-2-yl]-4-morpholinyl}-4-pyrimidinyl)-2-fluorobenzonitrile (310 mg, 0.651 mmol) and hydrazine (1.03 mL, 32.6 mmol) in ethanol (4 mL) was heated under microwave conditions with stirring for 1 hour. The mixture was concentrated, and the resulting residue was purified by Prep-HPLC using CH3CN in water (10 mmol ammonium hydrogen carbonate in water) from 40% to 60% in 9 minutes to afford the title compound (96 mg) as a yellow solid. LC-MS (ES) m/z=488 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.07-3.15 (m, 1H), 3.17-3.23 (m, 1H), 3.69-3.75 (m, 1H), 4.04-4.06 (m, 1H), 4.30-4.34 (m, 1H), 4.60-4.64 (m, 1H), 4.72-4.75 (m, 1H), 5.38 (s, 2H), 6.20 (s, 2H), 6.71 (s, 1H), 7.21-7.30 (m, 1H), 7.34-7.47 (m, 1H), 7.60-7.63 (m, 1H), 7.69-7.72 (m, 1H), 7.74-7.76 (m, 2H), 7.83-7.85 (m, 1H), 7.99 (s, 1H), 11.52 (s, 1H), 12.43-12.70 (m, 1H).
Reaction SMILES: ClC(Cl)(Cl)C([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:36](O)=[O:37])=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=4[Cl:35])=[CH:20][CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:8])(C)C.[Cl:44][C:45]1[CH:55]=[CH:54][CH:53]=[CH:52][C:46]=1[CH2:47][NH:48][CH:49]1[CH2:51][CH2:50]1>>[CH:7]([OH:8])=[O:6].[Cl:44][C:45]1[CH:55]=[CH:54][CH:53]=[CH:52][C:46]=1[CH2:47][N:48]([CH:49]1[CH2:50][CH2:51]1)[C:36]([C:15]1[C@@H:14]2[NH:9][C@H:10]([CH2:17][C:16]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[Cl:35])=[CH:20][CH:19]=1)[CH2:11][N:12]([C:39](=[O:41])[CH3:40])[CH2:13]2)=[O:37]
Reactant: CC(=O)N1CC2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Reactant: Clc1ccccc1CNC1CC1
Product: CC(=O)N1C[C@H]2CC(c3ccc(OCCOc4cc(F)ccc4Cl)cc3)=C(C(=O)N(Cc3ccccc3Cl)C3CC3)[C@@H](C1)N2
Product: O=CO

Procedure:
Synthesized according to typical procedures H and E from bicyclononene BN10 and (2-chlorobenzyl)cyclopropylamine. LC-MS: Rt=0.90; ES+: 638.22.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Br(O)(=O)=O.Br(O)(=O)=O.[CH2:42]([N:49]1[CH2:54][C@@H:53]2[CH2:55][C@H:50]1[CH2:51][NH:52]2)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH2:42]([N:49]1[CH2:54][C@@H:53]2[CH2:55][C@H:50]1[CH2:51][N:52]2[CH2:32][C:29]1[CH:30]=[N:31][C:26]([C:24]2[NH:25][C:21]([CH:13]([C:10]3[CH:11]=[CH:12][C:7]([S:4]([CH:1]4[CH2:3][CH2:2]4)(=[O:6])=[O:5])=[CH:8][CH:9]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:22][CH:23]=2)=[CH:27][CH:28]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [O-][Br+2]([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CN4C[C@@H]5C[C@H]4CN5Cc4ccccc4)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in 1,2-dichloroethane (5 mL) were added (1S,4S)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane dibromate (350 mg) and triethylamine (310 μL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (280 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the title compound (172 mg, yield 63%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). MS: 637 (MH+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[CH:10]=O)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[NH2:21].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1/[CH:10]=[N:21]/[C:14]1[C:13]([Cl:12])=[CH:18][C:17]([F:19])=[CH:16][C:15]=1[Cl:20])=[N+:2]=[N-:3]
Reactant: Nc1c(Cl)cc(F)cc1Cl
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=Nc1ccncc1/C=N/c1c(Cl)cc(F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Titanium tetrachloride (1M, 4.0 mL, 4.15 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (1.0 g, 6.75 mmol), 2,6-dichloro-4-fluorophenylamine (1.22 g, 6.75 mmol) and triethylamine (2.8 mL, 20.3 mmol) in DCM (24 mL), under nitrogen. The reaction was stirred for 30 minutes at 0° C., warmed to room temperature, stirred for an additional 2 h, and concentrated under reduced pressure. The residue was dissolved in toluene and filtered though a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid (2.09 g, quant.). This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=2)=[O:10])=[CH:4][N:3]=1.[CH3:32][NH:33][CH3:34]>C(O)C>[CH3:32][N:33]([C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=[C:13]3[CH:12]=2)=[O:10])=[CH:4][N:3]=1)[CH3:34]
Reactant: O=C(Nc1cnc(Cl)nc1)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1ncc(NC(=O)c2cc3cc(C(F)(F)F)cnc3n2Cc2cccc(F)c2)cn1

Procedure:
In a sealed tube, a mixture of 0.2 g (0.44 mmol) of N-(2-chloropyrimidin-5-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared in the preceding stage, and 1.3 mL (8.89 mmol) of an aqueous solution of dimethylamine at 40%, the whole in solution in 15 mL of ethanol, is heated at 110° C. for 20 h. After this time, the reaction mixture is allowed to return to room temperature, then a white precipitate is collected by filtration, washed with water and dried at reduced pressure to obtain 0.14 g of the expected product.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](OC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:19][NH2:20]>CCO>[C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH:19][NH2:20])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: COC(=O)C(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCO
Product: NNC(=O)C(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of methyl 2,2-diphenylacetate (0.5 g, 1 equiv) in anhydrous EtOH (150 mL) was added hydrazine hydrate (8 mL) and heated to reflux. Stirring was then continued for 1 hour. The reaction mixture was then cooled and the solvents removed under reduced pressure. The crude oil was diluted with EtOAc and washed with H2O and the organic phase dried over Na2SO4, filtered, and the solvents removed under reduced pressure to yield a yellow oil (0.97 g, 97%) that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>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.C(O)C>[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:17]2[C:16]([CH3:19])=[N:15][N:14]3[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)=[CH:10][C:11]([N:20]4[CH2:24][CH2:23][CH2:22][C@H:21]4[CH2:25][OH:26])=[N:12][C:13]=23)=[CH:30][CH:29]=1
Reactant: Cc1nn2c(-c3ccc(F)c(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2c(C)nn3c(-c4ccc(F)c(F)c4)cc(N4CCC[C@H]4CO)nc23)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
(S)-(1-(7-(3,4-Difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (74 mg), 4-methylphenylboronic acid (27 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (7 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred overnight under argon atmosphere at 85° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure, concentrated and purified by column chromatography to yield the target compound (41 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.C(Cl)(=O)C([Cl:9])=O.[NH2:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:22]/[O:23][CH3:24])/[C:19](O)=[O:20])[N:17]=1>O1CCCC1>[ClH:9].[CH3:1][N:2]([CH:3]=[N:12][C:13]1[S:14][CH:15]=[C:16](/[C:18](=[N:22]/[O:23][CH3:24])/[C:19]([Cl:9])=[O:20])[N:17]=1)[CH3:5]
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)Cl)c1csc(N=CN(C)C)n1
Product: Cl
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 42.4 %

Procedure:
Dimethylformamide (1.6 g, 22 mmol) and 10 ml of tetrahydrofuran were mixed, to which 3.06 g (24 mmol) of oxalyl chloride were added dropwise under ice-cooling. After completion of the dropwise addition, the resulting mixture was stirred for further 10 minutes and was then cooled to -15° C. To the mixture so obtained, were added 2.0 g (10 mmol) of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid and 10 ml of tetrahydrofuran, followed by stirring for 80 minutes. The reaction mixture was concentrated under reduced pressure. Slurry was collected by filtration under a nitrogen gas stream and then dried at room temperature, whereby 1.32 g of the title compound were obtained (yield: 43%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:5].CS(O[CH:20]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]1)(=O)=O.O>CN(C=O)C>[CH:24]([OH:26])=[O:25].[CH3:5][N:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:20]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23]2)=[C:9]([CH3:14])[CH:8]=1)[CH3:3]
Reactant: Cc1cc(CN(C)C)ccc1O
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CN(C)C)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Product: O=CO
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.35 g, 8.7 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 4-[(dimethylamino)methyl]-2-methylphenol—commercially available—(1.1 g, 6.7 mmol) in DMF (5 mL) was added drop-wise over 10 minutes. The mixture was stirred for 30 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.84 g, 7.3 mmol) in DMF (5 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (100 mL) was added and the mixture was extracted three times with EtOAc (50 mL). The combined organic phases were dried through a phase separator and the solvent was removed by evaporation. The residue was purified by preparative chromatography on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-50% acetonitrile in water/acetonitrile/formic acid (95/5/0.2), 100 mL/min. Fractions were collected, pooled and concentrated in vacuo. DCM was added and the solution was filtered through a phase separator and concentrated by evaporation. There was obtained 1.93 g (91%) of 16A as a colourless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.37 (s, 3H), 2.62 (s, 6H), 3.97 (s, 2H), 3.92-4.04 (m, 2H), 4.24-4.35 (m, 2H), 4.81-4.92 (m, 1H), 6.59 (d, 1H), 6.62 (s, 1H), 7.35 (d, 1H), 8.42 (s, 1H).