Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1)(C)(C)C.Cl.[CH3:32][P:33]1(=[O:44])[O:38][CH2:37][C:36]2([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][O:34]1.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH:19][C:20](=[O:29])[C:21]1[CH:22]=[CH:23][C:24]([CH2:27][N:41]2[CH2:42][CH2:43][C:36]3([CH2:35][O:34][P:33]([CH3:32])(=[O:44])[O:38][CH2:37]3)[CH2:39][CH2:40]2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CBr)cc1
Reactant: CP1(=O)OCC2(CCNCC2)CO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CP1(=O)OCC2(CCN(Cc3ccc(C(=O)Nc4cc(-c5cccs5)ccc4N)cc3)CC2)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[2-(4-Bromomethyl-benzoylamino)-4-thiophen-2-yl-phenyl]-carbamic acid tert-butyl ester (150 mg, 0.31 mmol), 3-methyl-2,4-dioxa-9-aza-3-phosphaspiro[5.5]undecane 3-oxide hydrochloride (89 mg, 0.37 mmol), and DIEA (107 μL, 0.62 mmol) were combined in DMF (4 mL) and stirred at room temperature for 18 h. The solution was diluted with saturated NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography of the crude (0-10% MeOH/CH2Cl2) afforded the desired product as a colorless solid. The solid was dissolved in a mixture of CH2Cl2 (4 mL) and TFA (1 mL) and stirred at room temperature for 2 h. The solution was diluted with 1,2-DCE and evaporated. The crude was taken up in EtOAc, washed with saturated NaHCO3 and brine, dried (MgSO4), and evaporated. The residue was triturated with EtOAc and filtered to afford the desired product as a colorless solid 1H NMR (DMSO-d6, 600 MHz) δ 9.69 (s, 1H), 7.94 (d, J=7.6 Hz, 2H), 7.44 (s, 1H), 7.41 (d, J=7.8 Hz, 2H), 7.33 (d, J=5.2 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.22 (d, J=3.5 Hz, 1H), 7.02 (t, J=4.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 5.13 (s, 2H), 4.16-4.04 (m, 4H), 3.54 (s, 2H), 2.43-2.37 (m, 2H), 2.34-2.28 (m, 2H), 1.68-1.62 (m, 2H), 1.52 (d, J=17.0 Hz, 3H), 1.42-1.38 (m, 2H). MS: cal'd 512 (MH+), exp 512 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:15])[CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCOC1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C1CCOCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
A mixture of 4-methylaminopiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol), tetrahydropyran-3-one (187 mg, 1.87 mmol), 4 Å powdered molecular sieves (550 mg) and DIPEA (323 μl, 241 mg, 1.87 mmol) in DCM (10 mL) was stirred at room temperature for 30 min before the addition of sodium triacetoxyborohydride (396 mg, 1.87 mmol). The reaction mixture was stirred at room temperature for 16 h then diluted with DCM and washed with H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording 4-[Methyl(tetrahydropyran-4-yl)amino]piperidine-1-carboxylic acid tert-butyl ester as an oil (101 mg, 36%). 1H NMR (CDCl3, 300 MHz): δ 4.24-4.07 (m, 2 H); 4.06-3.96 (m, 2 H); 3.43-3.32 (m, 2 H); 2.78-2.63 (m, 4 H); 2.25 (s, 3 H); 1.77-1.60 (m, 8 H); 1.46 (s, 9 H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]([O:25][CH2:26][CH2:27][OH:28])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[OH:28][CH2:27][CH2:26][O:25][C:24]1[C:15]([O:14][CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([C:4](=[O:29])[C:3]([OH:30])=[O:2])=[CH:10][CH:9]=2)=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCCO)cc1
Yield: 69 %

Procedure:
A mixture of 4-[[2-[3-(2-hydroxyethoxy)-2-naphthalenyloxy]ethyl]oxy]-alphaoxobenzeneacetic acid methyl ester (0.6 g) in hot methanol (10 mL) plus enough tetrahydrofuran to dissolve the solids, was treated with 1N sodium hydroxide (4 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2 N hydrochloric acid, and extracted with dichloromethane-tetrahydrofuran. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.4 g of 4-[[2-[3-(2-hydroxyethoxy)-2-naphthalenyloxy]ethyl]oxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 176°-177° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:13]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:13]([N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:10](=[O:12])[CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CNCC(C)C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(CC(C)C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of N-Boc-glycine (1.0 g, 5.7 mmol) in DMF (10 ml) were added diisobutylamine (0.10 ml, 11.4 mmol), DIPEA (1.9 ml, 11.4 mmol) and TBTU (2.7 g, 8.5 mmol). The mixture was stirred for 1 hr at room temperature, quenched with saturated aqueous sodium bicarbonate (15 ml), and extracted with EtOAc (20 ml). The organic phase was washed with brine (15 ml), dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (30% EtOAc in hexanes) to provide tert-butyl 2-(diisobutylamino)-2-oxoethylcarbamate (1.6 g, 98%) as a colorless oil. [M+H]+ 287.3, HPLC purity: 90%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C@@:11]([CH2:16][CH:17]([CH2:19][OH:20])[OH:18])([C@H:12]([CH2:14][OH:15])[OH:13])[O:10][C:8](=[O:9])[C:7]=1[OH:21])[CH2:2][CH2:3][CH3:4].C(=O)([O-])O.[Na+].[CH2:27]1[O:29][CH:28]1[CH2:30][OH:31]>CS(C)=O>[CH2:1]([O:5][C:6]1[C@@:11]([CH2:16][CH:17]([CH2:19][OH:20])[OH:18])([C@H:12]([CH2:14][OH:15])[OH:13])[O:10][C:8](=[O:9])[C:7]=1[O:21][CH2:27][CH:28]([CH2:30][OH:31])[OH:29])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC1=C(O)C(=O)O[C@]1(CC(O)CO)[C@@H](O)CO
Reactant: OCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCOC1=C(OCC(O)CO)C(=O)O[C@]1(CC(O)CO)[C@@H](O)CO
Temperature: 80 °C
Reaction time: 18 h
Yield: 19.9 %

Procedure:
Under an argon atmosphere, 3-O-butylglyceryl ascorbic acid (4.98 g) obtained in Example 6 was stirred in DMSO(10 mL), and further, sodium hydrogen carbonate (0.33 g) was added. Thereafter, glycidol (1.46 g) was added and the mixture was heated up to 80° C. and stirred for 18 hours, followed by extraction with n-butnol. The extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 6.23 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:20/3/0.4), and concentration was performed under reduced pressure to obtain 3-O-butylglyceryl-2-O-glyceryl ascorbic acid (1.23 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH:10]=[CH2:11])=[CH:4][CH:3]=1.[ClH:13].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([C:28]2([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>CO>[ClH:13].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([C:28]2([F:34])[CH2:29][CH2:30][N:31]([CH2:11][CH2:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[O:12])[CH2:32][CH2:33]2)[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC1(c2cccc(OCc3ccccc3)c2)CCNCC1
Reactant: C=CC(=O)Nc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(CCN1CCC(F)(c2cccc(OCc3ccccc3)c2)CC1)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 52 h
Yield: 64 %

Procedure:
To a solution of N-(4-bromophenyl)acrylamide (340 mg, 1.50 mmol) in methanol (10 mL) was added 4-(3-benzyloxyphenyl)-4-fluoropiperidine hydrochloride (321 mg, 1.00 mmol) followed by sodium bicarbonate (840 mg, 10.0 mmol) and the resulting suspension stirred at room temperature for 52 hours. After this time the reaction was filtered and the filtrate concentrated under reduced pressure. The residue was treated with ethyl acetate (10 mL) and the resulting suspension re-filtered and concentrated under reduced pressure. The resulting solid was treated with 10% hydrogen chloride in methanol (10 mL) and the solution re-concentrated. Subsequent trituration with ethyl acetate (10 mL) afforded 3-[4-(3-benzyloxyphenyl)-4-fluoropiperidin-1-yl]-N-(4-bromophenyl)propionamide hydrochloride in 64% yield as a light yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:39])[CH2:6][N:7]1[C:16]2[C:11](=[C:12]([F:21])[CH:13]=[CH:14][C:15]=2[O:17][CH2:18][CH2:19][CH3:20])[C:10](=[O:22])[C:9]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32]C3CCCCO3)=[CH:25][CH:24]=2)=[CH:8]1)[CH3:3]>C(O)C>[F:21][C:12]1[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH3:20])=[C:16]2[C:11]=1[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=1)=[CH:8][N:7]2[CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:39]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OCCOC4CCCCO4)cc3)cn(CC(=O)OCC)c12
Agent: Cl
Solvent: CCO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OCCO)cc3)cn(CC(=O)OCC)c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
2N hydrochloric acid (6.3 ml) was added to an ethanol solution (20 ml) of ethyl(5-fluoro-4-oxo-8-propoxy-3-{4-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl}-4H-quinolin-1-yl)acetate (840 mg, 1.59 mmol) and stirred at 50° C. for 2 hours. The resulting mixture was cooled to room temperature and then concentrated under reduced pressure. Ethyl acetate and water were added to the residue, followed by separation. The thus-obtained organic layer was washed with an aqueous saturated sodium chloride solution, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=30:1→15:1). The purified product was concentrated under reduced pressure, giving a pale yellow oily substance of ethyl {5-fluoro-3-[4-(2-hydroxyethoxy)phenyl]-4-oxo-8-propoxy-4H-quinolin-1-yl}acetate (627 mg, yield: 89%).
Reaction SMILES: F[C:2]1C=C(C=CC=1)NC.[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].[CH2:18]([N:21]1[C@H:26]([CH3:27])[CH2:25][N:24]([C@H:28]([C:43]2[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=2)[C:46](Cl)=[O:47])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][Si](C(C)(C)C)(C)C)[CH:30]=2)[C@@H:23]([CH3:52])[CH2:22]1)[CH:19]=[CH2:20]>>[CH2:18]([N:21]1[C@H:26]([CH3:27])[CH2:25][N:24]([C@H:28]([C:43]2[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=2)[C:46]([N:14]([C:13]2[CH:15]=[CH:16][CH:17]=[C:11]([F:10])[CH:12]=2)[CH3:2])=[O:47])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[C@@H:23]([CH3:52])[CH2:22]1)[CH:19]=[CH2:20]
Reactant: CNc1cccc(F)c1
Reactant: Nc1cccc(F)c1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(C)c3cccc(F)c3)c2)C[C@H]1C

Procedure:
3-Fluoro-N-Methylaniline [NMR (200 MHz, DMSO-d6): δ 2.76 (s, 3H); 3.42 (s, 1H); 6.51-6.92 (m, 3H); 7.28 (dt, J1 =7.3 Hz, J2 =8.0 Hz, 1)], was prepared from 3-fluoroaniline, coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert -butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide as a light yellow powder.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8])(=O)=O.[OH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23]
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 3,3,3-trifluoropropyl tosylate (4.057 gm; 15.12 mmol), 3-hydroxybenzaldehyde (1.85 gm; 15.12 mmol), and K2CO3 (4.15 gm; 30.0 mmol) in DMF (80 mL) and heat at 100° C. After 18 hours, cool to room temperature, dilute with water (200 mL) and extract with dichloromethane (2×200 mL). Combine organic extracts and wash sequentially with water (100 mL), 0.1 M NaOH (2×100 mL), saturated sodium bicarbonate (100 mL) and saturated brine (100 mL), dry (MgSO4), and concentrate. Chromatography on silica gel (0–20% ethyl acetate in hexane) to give the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:18][C:19]1[C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccnc4Cl)cc3c2C1

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 15.9 mg (0.101 mMol) 2-chloro-3-pyridinecarboxylic acid, the title compound was recovered as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][O:27][C:28](=[O:31])[CH2:29]Br>CC(C)=O>[CH3:26][O:27][C:28](=[O:31])[CH2:29][N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:10]1
Reactant: COC(=O)CBr
Reactant: Fc1ccc(-c2n[nH]c(-c3ccc(F)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reaction time: 24 h
Yield: 91.1 %

Procedure:
26.5 g 3,5-bis-(4-fluoro-phenyl)-1H-(1,2,4)triazole, 62.6 g K2CO3 and 15.7 g 2-bromoacetic acid methyl ester were mixed in 1 L acetone and stirred for 24 h under reflux. K2CO3 was filtered and the solvent was removed to yield 30.8 g of the desired product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[C:10]1([CH3:20])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH:18]=O.C1(C)C=CC=CC=1>O>[CH3:20][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[CH:18]=[N:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: Cc1cc(C)c(C=O)c(C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c(C=NCc2ccc(Cl)nc2)c(C)c1
Yield: 99.1 %

Procedure:
A mixture of 5-aminomethyl-2-chloropyridine (14.25 g), mesitaldehyde (14.8 g) and toluene (100 ml) was heated under reflux for 3 hours. The water which was formed during the reaction was trapped by Dean and Stark constant water separator. The toluene was distilled off from the mixture under reduced pressure, so as to obtain N-(2,4,6-trimethylbenzylidene)-2-chloro-5-pyridylmethylamine (27 g). m.p. 47°-48° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][O:11][CH:12]2[C:23]3[C:24](=[O:25])[C:19]([O:26][Si](C(C)(C)C)(C)C)([CH2:20][CH2:21][CH:22]=3)[C:18]#[C:17][CH:16]=[CH:15][C:14]#[C:13]2)=[CH:8][CH:7]=1)=[O:4].FC(F)(F)S(O)(=O)=O>CCOCC.C(OCC)(=O)C>[OH:26][C:19]12[C:24](=[O:25])[C:23](=[CH:22][CH2:21][CH2:20]1)[CH:12]([O:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:35][CH:34]=1)[C:13]#[C:14][CH:15]=[CH:16][C:17]#[C:18]2
Reactant: COC(=O)Cc1ccc(COC2C#CC=CC#CC3(O[Si](C)(C)C(C)(C)C)CCC=C2C3=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)Cc1ccc(COC2C#CC=CC#CC3(O)CCC=C2C3=O)cc1
Yield: 60 %

Procedure:
The silyl ether (8a) was dissolved in 4 mL of anhydrous ether and treated with 100 mL of trifluoromethanesulfonic acid, diluted with ethyl acetate and washed with saturated bicarbonate. The organic fraction was dried over MgSO4 and the residue combined with compound 8b obtained above and chromatographed over silica gel (2:1 hexane/ethyl acetate) to give 50 mg (60%) of compound 8b as a colorless oil:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:13])=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:8]=1)#N.[CH3:14][N:15]([CH3:28])[S:16]([C:19]1C=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O)(=[O:18])=[O:17].[CH:29]1([CH:35]=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([CH:35]2[NH:13][C:6]3[CH:5]=[CH:4][C:3]([C:1]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[S:16](=[O:18])(=[O:17])[N:15]([CH3:14])[CH3:28])=[CH:8][C:7]=3[S:9](=[O:11])(=[O:10])[NH:12]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CN(C)S(=O)(=O)c1ccccc1B(O)O
Reactant: O=CC1CCCCC1
Product: CN(C)S(=O)(=O)c1ccccc1-c1ccc2c(c1)S(=O)(=O)NC(C1CCCCC1)N2

Procedure:
5-Iodo-2-aminobenzenesulfonamide (see compound 37) was transformed by Method H (using 2-(N,N-dimethylsulfamoyl)phenylboronic acid) and Method G (using cyclohexanecarboxaldehyde). M.p. 290-300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([C:16](=[O:18])[CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH:24]=O.COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=[CH:24][C:23]3[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:21]([O:20][CH3:19])[CH:22]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1cccnc1Nc1ccc(Cl)c(Cl)c1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1cc(C=CC(=O)c2cccnc2Nc2ccc(Cl)c(Cl)c2)cc(OC)c1OC
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To a solution of 1-(2-(3,4-dichlorophenylamino)pyridin-3-yl)ethanone (100 mg, 0.355 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 3,4,5-trimethoxybenzaldehyde (68.67 mg, 0.355 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (7g) (137 mg, 84% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O.O>[C:23]([O:22][C:21](=[O:27])[NH:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([NH:13][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[O:12])[CH2:19][CH2:18]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 1H-indazole-5-carboxylic acid (200 mg, 1.23 mmol) obtained in Reference Example 1 in N,N-dimethylformamide (15 ml) were added trans-tert-butyl 4-aminocyclohexylcarbamate (317 mg, 1.48 mmol), triethylamine (0.172 ml, 1.23 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (355 mg, 1.85 mmol) and hydroxybenzotriazole (200 mg, 1.48 mmol), and the resulting mixture was stirred at room temperature for 1 hour. After the reaction solution was heated at 50° C. for 1 hour, water was added thereto at 0° C. The resulting solid was filtered and then dried under reduced pressure to obtain trans-tert-butyl-4-[(1H-indazol-5-ylcarbonyl)amino]cyclohexylcarbamate (435 mg, 98%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[Br:10][C:11]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:12]=1[NH:13][CH2:14][CH3:15].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Br:10][C:11]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:12]=1[N:13]([CH2:14][CH3:15])[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: CCNc1ccc(C(C)C)cc1Br
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1nc(C)nc(Cl)n1)c1ccc(C(C)C)cc1Br
Yield: 67.7 %

Procedure:
Part B: 2,4-Dichloro-6-methyl-1,3,5-triazine (3 g, 18.29 mmol), 2-bromo-N-ethyl-4-isopropylaniline (6.07 g, 25.07 mmol) and diisopropylethylamine (3.2 g, 25.07 mmol) were dissolved in dioxane (60 mL) under N2 and refluxed three hours. The solvent was stripped and the residue was purified using flash chromatography (CH2Cl2, silica). to provide N-(2-bromo-4-isopropylphenyl)-N-ethyl-4-chloro-6-methyl-1,3,5-triazine-2-amine (4.58 g) as a clear oil in 68% yield.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[N:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O>C1COCC1.O.CO>[C:18]([C:15]1[N:14]=[CH:13][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1)#[N:19]
Reactant: CCOC(=O)C1CCN(c2ccc(C#N)nc2)CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)cn1
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a stirred solution of 6′-cyano-3,4,5,6-tetrahydro-2H-[1,3]bipyridinyl-4-carboxylic acid ethyl ester (1.61 g, 6.20 mmol) in THF (30 mL), H2O (30 mL) and MeOH (3 mL) was added LiOH.H2O (326 mg, 7.76 mmol). Stirring was continued overnight at RT before the organic solvent were removed under vacuo. The pH of the was adjusted to 5 with acetic acid, and the product extracted with EtOAc, dried over Na2SO4. The resulting solid was suspended in heptane, filtered off, washed with cold Et2O to give 1.40 g (99%) of 6′-cyano-3,4,5,6-tetrahydro-2H-[1,3]bipyridinyl-4-carboxylic acid. ES-MS m/e: 230.1 (M−H+)