Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:5][N:4]([S:6]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)(=[O:8])=[O:7])[CH2:3]1.[F:15][C:16]([F:23])([F:22])[S:17]([O:20]C)(=[O:19])=[O:18]>C(Cl)Cl>[F:15][C:16]([F:23])([F:22])[S:17]([O-:20])(=[O:19])=[O:18].[F:14][C:2]1([F:1])[CH2:5][N:4]([S:6]([N:9]2[CH:13]=[CH:12][N+:11]([CH3:16])=[CH:10]2)(=[O:8])=[O:7])[CH2:3]1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: O=S(=O)(N1CC(F)(F)C1)n1ccnc1
Solvent: ClCCl
Product: C[n+]1ccn(S(=O)(=O)N2CC(F)(F)C2)c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 165.8 %

Procedure:
To a solution of 1-(3,3-difluoroazetidin-1-ylsulfonyl)-1H-imidazole (0.500 g, 2.24 mmol) in DCM (5 mL) at about 0° C. was added methyl trifluoromethanesulfonate (0.27 mL, 2.46 mmol) dropwise over about 3 min. The reaction mixture was stirred at about 0° C. for about 2 h. The solid was collected by vacuum filtration, washed with DCM (10 mL), and dried under vacuum to give 1-(3,3-difluoroazetidin-1-ylsulfonyl)-3-methyl-1H-imidazol-3-ium trifluoromethanesulfonate (0.79 g, 90%) as a white solid: LC/MS (Table 1, Method c) Rt=1.12 min; MS m/z 238 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[Li]CCCC.[CH3:14][C:15]([S@:18]([N:20]=[C:21]1[CH2:24][O:23][CH2:22]1)=[O:19])([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:21]2([NH:20][S@@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH2:24][O:23][CH2:22]2)[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc(I)c1
Reactant: CC(C)(C)[S@@](=O)N=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)NC1(c2cncc(Br)c2)COC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a solution of 3-bromo-5-iodopyridine (0.14 g, 0.493 mmol) in THF (2 mL) cooled at −78° C. was added nBuLi (462 μl, 0.74 mmol) dropwise over 5 min. The reaction mixture was stirred at −78° C. for 15 min, then (R)-2-methyl-N-(oxetan-3-ylidene)-propane-2-sulfinamide (0.1 g, 0.567 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 10 min then allowed to warm up to RT. The mixture was quenched with water (2 mL) and extracted with EtOAc (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 100% EtOAc-heptane gradient to give the title compound (0.096 g, 58%) as a light yellow oil. MS: 333.0 and 335.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]1.C[Mg]Cl.CC1(C)CCCC(C(=O)C)C1.[C:27]([O:31][CH2:32][C:33](O)=[O:34])(=[O:30])[CH2:28][CH3:29].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:27]([O:31][CH2:32][C:33]([O:11][C:8]([CH:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:12])([CH3:1])[CH2:3]1)([CH3:10])[CH3:9])=[O:34])(=[O:30])[CH2:28][CH3:29]
Reactant: CCC(=O)OCC(=O)O
Reactant: CC1(C)CCCC(C(C)(C)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)C1CCCC(C)(C)C1
Agent: C[Mg]Cl
Solvent: ClCCl
Product: CCC(=O)OCC(=O)OC(C)(C)C1CCCC(C)(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
4-dimethyl-aminopyridine (122 mg, 1.0 mmol) and 2-(3,3-dimethylcyclohexyl)-2-propanol (2.6 g, 15 mmol), [which is obtainable from methylmagnesium chloride and 1-(3,3-dimethylcyclohexyl)-ethanone by a Grignard reaction] are added successively to a solution of 81% (propionyloxy) acetic acid (2.7 g, 16.5 mmol) in CH2Cl2 (15 ml). The reaction solution is now cooled to 0° C. and dicyclohexylcarbodiimide (3.4 g, 16.5 mmol), dissolved in CH2Cl2 (5 ml) is added. After 1 h at 0° C., the cooling is removed, and the reaction mixture is stirred for a further 16 h at room temperature. The precipitate that has precipitated is, then, filtered off, and the filtrate is freed from solvent in a rotary evaporator. The resulting crude product is taken up in n-pentane (20 ml) and the precipitate that forms is again filtered off. The filtrate is also washed twice with 0.5 M HCl and twice with saturated NaHCO3 solution, and the organic phase is then dried over Na2SO4, filtered off, and concentrated in a rotary evaporator. After purification by flash chromatography (cyclohexane/EtOAc=10:1, Rf=0.23) and subsequent bulb tube distillation (BTD: 221° C., 1.3 mbar), 3.1 g (73%) 2-[1-(3,3-dimethylcyclohexyl)-1-methylethoxy]-2-oxoethyl propionate is obtained as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[NH:8][CH2:7]/[C:6]/2=[CH:16]\[C:17]([NH:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24]C)=[O:23])=[O:18].[Li+].[OH-]>CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[NH:8][CH2:7]/[C:6]/2=[CH:16]\[C:17]([NH:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([OH:24])=[O:23])=[O:18]
Reactant: COC(=O)c1ccccc1NC(=O)/C=C1\CNC(=O)c2cc(OC)c(OC)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1OC)/C(=C/C(=O)Nc1ccccc1C(=O)O)CNC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a stirred solution of (Z)-methyl 2-(2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetamido)benzoate (140 mg, 0.35 mmol) in MeOH (4 mL) and THF (8 mL) was added 2N LiOH (0.7 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight then the reaction was quenched by addition of 1N HCl and the solvent was removed under reduced pressure. The mixture was diluted with water, cooled and the precipitate collected by filtration to afford (Z)-2-(2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetamido)benzoic acid (125 mg, 93%). 1H-NMR (400 MHz, DMSO-d6) δ 3.80, (s, 3H), 3.84 (s, 2H), 3.85 (s, 3H), 7.00 (s, 1H), 7.10 (m, 1H), 7.22 (d, J=6.0 Hz, 1H), 7.56 (m, 1H), 7.61 (s, 1H), 7.90 (dd, J=8.0, 1.6 Hz, 1H), 8.57 (dd, J=8.4, 0.8 Hz, 1H), 11.38 (d, J=5.6 Hz, 1H), 13.54 (br s, 1H); LC-MS (ES-API); rt 8.27 min; m/z calculated for C20H18N2O6[M+H]+ 383.1, found 383.1.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:38]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][CH2:39]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[C:42]([CH:38]4[CH2:41][CH2:40][CH2:39]4)=[O:43])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)C1CCC1)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by cyclobutanecarbonyl chloride (42 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 154 mg, 85%; 1H NMR (mix of rotomers, 400 MHz, DMSO-D6) δ ppm 8.52 (2 H, d, J=6.06 Hz), 7.66 (2 H, d, J=6.06 Hz), 7.30 (2 H, dd, J=8.46, 5.68 Hz), 7.15 (2 H, t, J=8.97 Hz), 6.52 (1 H, s), 5.08-5.33 (2 H, m), 4.42-4.57 (0.5 H, m), 4.38 (1 H, d, J=13.39 Hz), 3.95 (3 H, s), 3.64-3.79 (0.5 H, m), 3.36-3.48 (0.5 H, m), 3.24-3.34 (0.5 H, m), 3.03-3.20 (1 H, m), 2.55-2.76 (4 H, m), 2.01-2.28 (4 H, m), 1.39-1.99 (6 H, m); m/z (APCI+) for C28H32N5O2F 490.2 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([O-:25])=[O:24].[CH3:19][S:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH3+:7])=[CH:10][CH:11]=1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NS(C)(=O)=O)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C[NH3+])cc1
Product: O=C([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
(4-Methanesulfonylaminobenzyl)carbamic acid t-butyl ester 8-2 (500 mg) was dissolved in anhydrous dichloromethane (30 ml) and the solution was cooled to 0° C., followed by slowly adding trifluoroacetic acid (5 ml) thereto. The mixture was stirred at 0° C. for 1 hour and 30 minutes and then, after confirming the completion of the reaction using TLC, concentrated under reduced pressure to yield an orange colored residue. The residue was washed with ether and filtered to yield the compound 8-3 (420 mg, 80%) as a pink solid.
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)O1.[H-].[Na+].[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1>>[N:10]1([C:6]2[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[C:6]3[C:5]4[C:25](=[CH:24][CH:28]=[CH:15][CH:4]=4)[CH2:26][C:2]=3[C:7]=2[C:8]#[N:9])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(-c2cc(N3CCCC3)c(C#N)c(=O)o2)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(-c2cc(N3CCCC3)c(C#N)c3c2-c2ccccc2C3)cc1

Procedure:
A mixture of 2-oxo-4-(pyrrolidin-1-yl)-6-p-tolyl-2H-pyran-3-carbonitrile (280 mg), indanone-2 (132 mg) and NaH (39 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 182-184° C.; ESMS 351 (M++1); IR (KBr) 2205 cm−1 (CN); 1H NMR (200 MHz, CDCl3) δ 1.99-2.06 (m, 4H, 2CH2), 2.48 (s, 3H, CH3), 3.63-3.72 (m, 4H, 2CH2) δ 4.03 (s, 2H, CH2), 6.45 (s, 1H, ArH), 6.80 (d, J=7.6 Hz, 1H, ArH), 7.03-7.18 (m, 2H, ArH), 7.27-7.36 (m, 4H, ArH), 7.47 (d, J=7.0 Hz, 1H, ArH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:22][CH3:23])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:38])[C:30]=1[C:31](=O)[C:32]([O:34]CC)=O.CC(O)=O>COCCO.CCOC(C)=O>[Cl:38][C:29]1[CH:28]=[N:27][CH:26]=[C:25]([Cl:24])[C:30]=1[C:31]1[C:32](=[O:34])[N:22]([CH3:23])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])=[CH:13][CH:14]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCN(CC)C(=O)c1ccc(Nc2ncc(N)c(NC)n2)cc1
Reactant: CCOC(=O)C(=O)c1c(Cl)cncc1Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: COCCO
Product: CCN(CC)C(=O)c1ccc(Nc2ncc3nc(-c4c(Cl)cncc4Cl)c(=O)n(C)c3n2)cc1
Yield: 27.6 %

Procedure:
A mixture of 0.50 g (1.6 mmol) of 5-amino-2-[[4-(diethylaminocarbonyl)-phenyl]amino]-4-(methylamino)pyrimidine, 0.8 g (3.2 mmol) of ethyl 2-(3,5-dichloropyridin-4-yl)-2-oxoacetate, and 0.5 mL of HOAc in 20 mL of 2-methoxyethanol is heated under reflux for 16 hours. Workup in EtOAc, followed by chromatography on silica, eluting with EtOAc/hexane (3:2), gives 0.22 g (28%) of the title compound (Compound 13): mp (i-Pr2O) 230–231° C.
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].CCN(CC)CC.Cl.[CH:13]1([CH:18]([NH2:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[CH:13]1([CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[NH:25][C:1](=[O:2])[CH3:3])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: NC(c1ccccn1)C1CCCC1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(c1ccccn1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
AcCl (0.10 g, 1.25 mmol) was added to a stirred suspension of Et3N (0.35 mL, 0.25 g, 2.5 mmol, 2.2 eq.) and (rac)-1-cyclopentyl-1-(2-pyridinyl)methylamine HCl salt (0.25 g, 1.14 mmol) in CH2Cl2 (5 mL). The resulting mixture was stirred at rt for 2 h. The reaction mixture was washed with H2O (10%, 3×3 mL) and was dried over Na2SO4 and was concentrated under reduced pressure yielding the crude product (0.20 g) as a clear yellow oil which quickly crystallized. 1H NMR (300 MHz, CDCl3) δ ppm 8.53 (d, J=5.0 Hz, 1H), 7.62 (dt, J=1.5, 7.5 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.16 (d, J=5.0 Hz, 1H), 6.72 (br d, J=7.0 Hz, 1H), 4.93 (t, J=9.0 Hz, 1H), 2.37-2.20 (m, 1H), 2.00 (s, 3H), 1.80-1.10 (m, 8H); HPLC: Daicel Chiralpak AD-H, 80:20 v/v heptane-EtOH (+0.2% Et2NH), 1.0 mL min−1, 210 nm, Rt=9.5 min, Rt=19.2 min.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][OH:18])[CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[C:19]1(=[O:25])[O:24][C:22](=O)[CH2:21][CH2:20]1.C(N([CH2:31][CH3:32])CC)C>CN(C)C=O>[C:19]([CH2:20][CH2:31][CH2:32][O:1][C@@H:2]([CH2:17][O:18][CH2:22][CH2:21][CH2:20][C:19]([OH:24])=[O:25])[CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)([OH:25])=[O:24]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1nc2c(ncn2COC[C@@H](O)CO)c(=O)[nH]1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2COC[C@H](COCCCC(=O)O)OCCCC(=O)O)c(=O)[nH]1

Procedure:
A solution of (S)-9-(2,3-dihydroxy-1propoxymethyl)guanine (1.37 g, 5 mmol), 2.0 g of succinic anhydride, and 2.8 ml of anhydrous triethylamine in dry dimethylformamide (75 ml) is heated in an oil bath at 60° . When the reaction is complete (24 hours) the mixture is cooled and evaporated to dryness in vacuo. The residue is resuspended in ice-water (50 ml) and the pH is adjusted to 2 with 2N-HCl. The precipitate is filtered, thoroughly washed with ice-water, and dried in vacuo. The precipitate is then recrystallized from methanol.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[C:7]2[C:8](=[C:13]([CH3:17])[N:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1>>[OH:2][CH2:1][CH2:3][NH:4][C:6]1[C:7]2[C:8](=[C:13]([CH3:17])[N:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: Cc1cc(Cl)c2nn(C)c(C)c2n1
Reactant: NCCO
Product: Cc1cc(NCCO)c2nn(C)c(C)c2n1

Procedure:
The title compound was prepared from ethanolamine and 7-chloro-2,3,5-trimethylpyrazolo[4,3-b]pyridine in an analogous manner to the preparation of Example 2 giving a white crystalline solid, m.p. 186°-189° C. after recrystallisation from ether/methanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=[N:6][CH:7]=1.[Li]C(C)(C)C.C[O:27][B:28](OC)[O:29]C.Cl>C1COCC1>[CH:19]1[C:20]2[N:8]([C:4]3[CH:3]=[C:2]([B:28]([OH:29])[OH:27])[CH:7]=[N:6][CH:5]=3)[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: COB(OC)OC
Reactant: Brc1cncc(-n2c3ccccc3c3ccccc32)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1cncc(-n2c3ccccc3c3ccccc32)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 9-(5-bromopyridin-3-yl)-9H-carbazole (2B) (1.7 g, 5.3 mmol) in THF (20 mL) was added a solution of tert-BuLi (1.7M in hexanes, 6.8 mL, 11.6 mmol) at about −78° C. The crude mixture was then stirred at about −78° C. for about 40 min, then a freshly distilled trimethylborate (0.89 mL, 8 mmol) was added. The resulting solution was stirred at RT overnight, then a 5% HCl aqueous solution (50 mL) was added and the whole was stirred for about 20 hours. The mixture was extracted with ethyl acetate (250 mL) three times, the organic phase was collected; dried over Na2SO4, concentrated and recrystallized with hexanes/dichloromethane to give product 2C, a light yellow solid (0.9 g, 60% yield).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:17][C:18]1([CH3:32])[C:23](=O)[CH2:22][CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19]1.C(OCC)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:17][C:18]1([CH3:32])[CH2:19][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:22]/[C:23]/1=[N:9]\[C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@@H](/N=C1\CCN(C(=O)OC(C)(C)C)CC1(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of (R)-1-phenylethanamine (2.56 g, 21.12 mmol) and triethylamine (14.7 mL, 106 mmol) in dichloromethane (40 mL) was cooled in an ice bath and titanium tetrachloride (8.80 mL, 8.80 mmol) was added dropwise giving a light brown mixture. The cold bath was removed and tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (4.00 g, 17.60 mmol) was added as solid in one portion and the resulting mixture was allowed to stir at rt overnight. To the resulting mixture was added 75 mL of diethyl ether and the mixture was stirred at rt for 15 min then filtered through a pad of CELITE® to remove the solids and the filter cake was rinsed with additional ether (30 mL×2). The resulting clear yellow filtrate was concentrated on a rotovap to afford a yellow liquid as the title compound (5.80 g, 17.6 mmol, quantitative). This material was used directly without any further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16](Cl)=[N:17][OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH2:15][C:16]1[CH:21]=[C:20]([C:22]2[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=2)[O:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1cccc(OCc2ccccc2)c1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3cccc(OCc4ccccc4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-benzyloxy-phenyl)-acetohydroximoyl chloride (200 mg, 0.724 mmol) described in Manufacturing Example 61-1-4 and 3-ethynyl-pyridin-2,6-diamine (61.5 mg, 0.462 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (252 μL, 1.81 mmol). This mixture was stirred for 4 hours at room temperature. This mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (138 mg, 51%).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH2:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCNC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.9 %

Procedure:
Trityl chloride (13.1 g, 47.0 mmol) was added to a stirred suspension of 3-piperidone hydrochloride (5.79 g, 42.7 mmol) and triethylamine (14.9 ml, 107 mmol) in CH2Cl2 (100 ml) and the reaction was stirred for 16 h under N2 at room temperature. The resulting mixture was filtered and the filtrate washed sequentially with H20 and 5% aqueous citric acid, dried over MgSO4 and evaporated under reduced pressure. Trituration with pentane afforded the subtitle compound as a colourless solid (4.8 g, 33%). Rf 0.23 (CH2Cl2/pentane 2/3, v/v). 1H NMR (CDCl3) δ: 2.05 (2H, m), 2.35 (2H, m), 2.45 (2H, m), 2.85 (2H, s), 7.06-7.55 (15H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])OC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.CN(CCCCCCCCCCCC)C>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: NCc1cccnc1
Agent: CCCCCCCCCCCCN(C)C
Solvent: Cc1ccccc1C
Product: O=C(NCc1cccnc1)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 4 h
Yield: 80.3 %

Procedure:
196.13 g (1 mole) of methyl N-(4-nitrophenyl)-carbamate, 108.14 g (1 mole) of 3-aminomethyl-pyridine and 106.7 g (0.5 mole) of N,N-dimethyl-n-dodecylamine are dissolved in 3 liters of xylene. The reaction mixture is refluxed, and the spures of water present are removed from the mixture together with the alcohol formed in a Dean-Stark trap. The end-product starts to separate from the mixture within 15-20 minutes from the beginning of boiling. The mixture is boiled for 4 hours, thereafter the suspension is filtered at about 100° to 110° C. The filter cake is washed twice with 100 ml of hot xylene, each, and with a small amount of acetone, and then dried in vacuo. 218.6 g (80.3%) of N-(4-nitrophenyl)-N'-(3-pyridylmethyl)-urea are obtained; m.p.: 221°-223° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([O:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[F:39])=[O:29])=[CH:24][CH:25]=2)[C:20]([NH2:40])=[N:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:40][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[F:39])=[O:29])[CH:22]=2)[N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[N:19]=1)=[O:6]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(NC(=O)NCc3cc(F)ccc3F)ccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1nc(NC(=O)c2cccc(Cl)c2)c2cc(NC(=O)NCc3cc(F)ccc3F)ccc21
Temperature: 90 °C
Reaction time: 24 h
Yield: 34 %

Procedure:
7.1 93 mg of 3-chlorobenzoyl chloride are added to a mixture of 200 mg of tert-butyl-3-amino-5-[3-(2,5-difluorobenzyl)ureido]indazole-1-carboxylate (0.48 mmol, preparation analogous to Example 1.1), 2.0 ml of pyridine, 8 mg of 4-(dimethylamino)pyridine and 100 μl of dioxane, and the mixture is stirred at 90° C. for 24 hours. After cooling, the batch is evaporated, and the residue is purified by column chromatography on silica gel (eluent:heptane/EA 3:2), giving 90 mg of tert-butyl 3-(3-chlorobenzoylamino)-5-[3-(2,5-difluorobenzyl)ureido]indazole-1-carboxylate (34%), MS-FAB (M+H+)=556.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:21]1([C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:13][CH2:12][N:11]3[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2ccccc2)c1
Yield: 136.1 %

Procedure:
The 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from Example 54b (1.03 g, 3 mmol), phenylboronic acid (920 mg, 7.5 mmol), Pd(0) (100 mg) and Na2CO3 (4 mL of a 2 M solution) were mixed in 20 mL of toluene, and the mixture was stirred at reflux for 3 hours. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel, eluting with CHCl3:MeOH 100:2, to afford 1.39 g of the title compound. MS (CI/NH3) m/z 341 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.38 (s, 9H), 2.32 (m, 2H), 3.89 (m, 2H), 4.21 (m, 1H), 4.41 (m, 1H), 4.54 (m, 1H), 7.40 (m, 3H), 7.50 (m, 2H), 8.10 (m, 1H), 8.54 (m, 1H), 8.20 (m, 1H).