Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH:9][C:15]([NH:14][CH2:12][CH3:13])=[O:16])[S:8][C:4]=2[CH:3]=1
Reactant: Nc1nc2ccc(Br)cc2s1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
About 0.75 g of 6-bromo-1,3-benzothiazol-2-amine (crude) is dissolved in about 15 mL DMF. About 0.5 mL of ethylisocyanate is added followed by about 0.9 mL triethylamine and the solution is heated to about 80° C. under good agitation. The solution is allowed to stir for about 4 hours then cooled to RT. The solvent is removed in vacuo and the solids are washed well with ether. The product is further purified by column chromatography.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH:13]=O)[C@H:9]([O:11][CH3:12])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][NH:21][C:20]1[CH:22]=[CH:23][C:17]([Br:16])=[CH:18][CH:19]=1)[C@H:9]([O:11][CH3:12])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Br)cc1
Reactant: CO[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CO[C@H](C)[C@@H](CNc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 18.6 %

Procedure:
To a solution of ((1S,2R)-1-formyl-2-methoxy-propyl)-carbamic acid t-butyl ester (1.92 g, 8.8 mmol) and 4-bromoaniline (1.51 g, 8.8 mmol) in dichloroethane (50 mL) was added sodium triacetoxyborohydride (3.73 g, 17.6 mmol) portionwise. After the addition, the resulting mixture was stirred at rt for over night. The reaction mixture was quenched with saturated NaHCO3, and extracted with DCM (4×40 mL). The combined DCM was dried (Na2SO4) and concentrated. The residue was subjected to ISCO (120 g column, 0-40% EtOAc in hexane over 100 min.) to give the titled compound (610 mg). MS (MH+ 373 and 375).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[I:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[C:7]2[C:12]([C:13]=1[I:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1[nH]c2ccccc2c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(I)c2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a mixture of 3-iodoindol-2-carboxylic acid methyl ester (202) (0.604 g, 2 mmol) and NaH (60%, 0.192 g, 2.4 mmol) in DMF (20 mL) was added p-toluenesulfonylchloride (0.381 g, 2 mmol) at room temperature. After stirring for 1 hour, ethyl acetate (50 mL) was added to the reaction mixture. The mixture was washed with brine (3×30 mL). The organic layer was dried with MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography (10% ethyl acetate/hexane V:V) to afford 203 (0.68 g, 76%). 1H NMR (CDCl3): 2.35 (s, 3H), 4.05 (s, 3H), 7.23 (d, 2H, J=8.4), 7.33 (t, 1H, J=7.2), 7.41, (m, 2H), 7.83 (d, 2H, J=8.4), 7.98 (d, 1H, J=8.4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([C:29](=[O:36])[C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2I)[CH:15]=1>>[CH3:11][O:12][C:13](=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)/[C:30](=[C:31](/[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)\[C:32]([CH3:35])([CH3:34])[CH3:33])/[C:29]2=[O:36])[CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)(C)C)c2ccccc2I)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccc(Cl)cc3)C(C)(C)C)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-chlorophenylboronic acid (commercially available) and 3-{[(4,4-dimethyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (400 MHz, MeOD) δppm 1.38 (s, 9H) 3.86 (s, 3H) 4.83 (d, 2H) 6.81 (d, J=7.83 Hz, 1H) 6.99 (d, J=7.83 Hz, 2H) 7.10 (t, J=7.58 Hz, 1H) 7.22 (t, J=7.71 Hz, 1H) 7.33-7.42 (m, 4H) 7.84-7.88 (m, 2H) 7.93 (d, J=7.83 Hz, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.O.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>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][OH:7]
Reactant: OCc1ccccc1B(O)O
Reactant: Brc1nccs1
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: O
Solvent: C1COCCO1
Product: OCc1ccccc1-c1nccs1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a stirred solution of 2-bromothiazole (1.0 g, 6.1 mmol) in dioxane/water (20/5 mL) was added (2-(hydroxymethyl)phenyl)boronic acid (1.4 g, 9.1 mmol), sodium carbonate (1.29 g, 12.2 mmol), and Pd(PPh3)4 under nitrogen. The mixture was heated at reflux for 18 h. After cooling to rt, water (50 mL) was added and aqueous was extracted with DCM (3×50 mL). The combined organic layer was dried and evaporated. The residue was purified by column chromatography to yield (2-(thiazol-2-yl)phenyl)methanol (0.95 g, 5.1 mmol).
Reaction SMILES: [C:1]([C:4]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]([CH3:7])[O:5]1)([OH:3])=O.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([CH3:21])[CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:1]([C:4]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]([CH3:7])[O:5]2)=[O:3])=[C:16]([CH3:21])[CH:15]=1
Reactant: CCOC(=O)C1(C(=O)O)OC1C
Reactant: Cc1cc(Br)ccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)OC1C
Yield: 46.7 %

Procedure:
Ethyl 2-carboxy-3-methyloxiranecarboxylate (5.09 grams, 0.03 mole), prepared in Part B, 4-bromo-2-methylaniline (5.44 grams, 0.03 mole) and 1,3-dicyclohexylcarbodiimide (6.03 grams, 0.03 mole) were reacted in a manner similar to that described in Example LVII to give 4.72 grams (0.014 mole) of N-(4-bromo-2-methylphenyl)-2-ethoxycarbonyl-3-methyloxiranecarboxamide having a melting point of 57° C.-60° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]=[C:6]([C@:8]23[CH2:13][C@H:12]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]3)[O:5][N:4]=1>C(O)C>[C@:8]12([C:6]3[O:5][N:4]=[C:3]([CH3:2])[N:7]=3)[CH2:13][C@H:12]1[CH2:11][NH:10][CH2:9]2
Reactant: Cc1noc([C@]23C[C@H]2CN(C(=O)OC(C)(C)C)C3)n1
Agent: Cl
Solvent: CCO
Product: Cc1noc([C@@]23CNC[C@@H]2C3)n1
Temperature: 50 °C

Procedure:
2.5 M HCl (4.5 mL, 0.0113 mol) was added to (1R,5R)-tert-butyl 1-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (143) (0.75 g, 0.0028 mmol) in 4 mL of ethanol. The solution was heated to 50° C. for 2.5 hours, cooled and condensed to a white solid. The material crystallized from 5 mL hot ethanol and 20 mL t-butyl methyl ether. The solids were isolated by filtration and washed with t-butyl methyl ether (2×5 mL) and dried under vacuum over night to 0.48 g white crystalline solid. The optical purity (99.68%) was determined by HPLC analysis (Chiral Technologies Chiral-AGP, 4.0 mm×150 mm, 0.5% methanol, 20 mM sodium phosphate pH=7). MS (ESI) m/z 166 [M+H]+. 1H NMR (DMSO-d6) δ 1.66-1.69 (m, 1H), 1.73-1.76 (m, 1H), 2.31 (s, 3H), 2.47-2.49 (m, 1H), 3.37-3.41 (m, 2H), 3.70-3.74 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH3:12].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Br
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(F)c(N)cc1Br
Temperature: 0 °C
Yield: 31.9 %

Procedure:
To a stirred solution of 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (18.0 g) in ethanol (300 mL) was added SnCl2.2H2O (51.8 g, 0.230 mol) at room temperature. The mixture was heated at reflux for 3 h. The solvent was evaporated under reduced pressure to give a residue, which was poured into ice water. The aqueous phase was basified with sat. NaHCO3 to pH 7. The solid was filtered off and the filtrate was extracted with dichloromethane (200 mL×3). The combined organics were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc=10/1) to afford 5-bromo-2-fluoro-4-methylaniline (5.0 g, 30% yield for two steps). 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J=8.8 Hz, 1H), 6.86 (d, J=11.6 Hz, 1H), 3.64 (br, 2H), 2.26 (s, 3H). MS (ESI) m/z (M+H+) 204.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][C:14]=1[O:24][CH3:25].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:11])[CH3:1])=[O:22])=[CH:15][C:14]=1[O:24][CH3:25]
Reactant: CC(C)CCCCCCCO
Reactant: COc1cc(CCC(=O)O)ccc1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: COc1cc(CCC(=O)OCCCCCCCC(C)C)ccc1O
Temperature: 50 °C
Yield: 76.5 %

Procedure:
8-Methyl-1-nonanol (752 mg, 4.74 mmol), 3-(4-hydroxy-3-methoxyphenyl)propionic acid (977 mg, 4.98 mmol) and Novozyme 435 (100 mg) were measured and placed in a flask (25 ml). Toluene (5 ml) and anhydrous magnesium sulfate (1 g) were added, and the mixture was stirred with heating in an oil bath at 50° C. for 16 hr. The reaction mixture was allowed to cool to room temperature, toluene (25 ml) was added, and Novozyme 435 and the precipitated insoluble material were removed by filtration. Toluene (50 ml) was added, and the mixture was washed with 5% aqueous sodium hydrogen carbonate solution (25 ml×3) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (chloroform:n-hexane:ethyl acetate=1:1:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give 8-methylnonyl 3-(4-hydroxy-3-methoxyphenyl)propionate (1.22 g, yield 76.2%) as a colorless oil.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>>[O:19]1[CH:8]2[CH:7]1[CH2:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][C:10]=1[CH2:9]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C1=CCc2ccccc2C1
Product: c1ccc2c(c1)CC1OC1C2

Procedure:
Reaction of a 5,8-dihydronaphthalene of formula III or formula IV with m-chloroperbenzoic acid yields a 5,6,7,8-tetrahydro-6,7-epoxynaphthalene having the structure ##STR6## The reaction can be carried out by mixing m-chloroperbenzoic acid with a solution of a 5,8-dihydronaphthalene in an organic solvent, e.g., ethyl acetate. The resulting mixture is added to a mixture of ethyl ether and aqueous sodium bicarbonate, and mixed to form a 5,6,7,8-tetrahydro-6,7-epoxynaphthalene of formula V.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[C:15]1([CH3:24])[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl.Cl[Sn](Cl)(Cl)Cl>[CH3:24][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:6]2[CH:7]=[C:8]3[O:9][CH2:1][O:2][C:3]3=[CH:4][C:5]=2[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccc(C)cc1)OCO2

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (319 mg, 1.64 mmol) in CH2Cl2 (5 mL), SnCl4 (1.0M solution in CH2Cl2 ; 3.5 mL mmol) and 4-toluoyl chloride (260 μL, 1.97 mmol) as an oily solid (90 mg, 18%). 1H NMR (CDCl3) 7.69 (d, 2H, J=8.0), 7.24 (d, 2H, J=8.0), 6.88 (s, 1H), 6.83 (s, (s, 2H), 3.78 (s, 2H), 3.60 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]1[C:15]([N+:24]([O-:26])=[O:25])=[C:16]([CH2:20][C:21]([OH:23])=O)[CH:17]=[CH:18][CH:19]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:30][CH2:29]1>C1COCC1.CCOC(C)=O>[CH2:34]([N:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:21](=[O:23])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[C:15]=2[N+:24]([O-:26])=[O:25])[CH2:29][CH2:30]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)Cc1cccc(F)c1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1cccc(F)c1[N+](=O)[O-])NC1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
17.0 g (102 mmol) CDI were added at RT to 18.3 g (91.9 mmol) (3-fluoro-2-nitro-phenyl)-acetic acid in 500 mL THF and stirred for 30 min. Then 20.0 mL (95.8 mmol) 4-amino-1-benzylpiperidine were added and the mixture was stirred for a further 2 h. The reaction mixture was diluted with EtOAc and the organic phase was washed with water and saturated sodium chloride solution. The organic phase was dried on magnesium sulphate, filtered and evaporated down i. vac. The residue was triturated with DIPE and suction filtered.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]O)[CH2:39][CH2:38]1)[C:35]#[CH:36]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:45][CH2:44][CH2:43][N:40]3[CH2:39][CH2:38][N:37]([CH2:34][C:35]#[CH:36])[CH2:42][CH2:41]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: C#CCN1CCN(CCCO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C#CCN1CCN(CCCOc2cc3ncnc(Cl)c3cc2OC)CC1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 76.8 %

Procedure:
4-Chloro-7-hydroxy-6-methoxyquinazoline (300 mg, 1.42 mmol), (prepared as described for the starting material in Example 4), was suspended in dichloromethane (15 ml). Triphenylphosphine (523 mg, 2 mmol) and 3-(4-prop-2-yn-1-ylpiperazin-1-yl)propan-1-ol (267 mg, 1.46 mmol) were added. Diisopropyl azadicarboxylate (340 μl, 1.71 mmol) was then added dropwise. The reaction mixture was stirred for 1.25 hours at ambient temperature and then loaded directly onto a silica column, and eluted with methylene chloride/methanol (90/8 followed by 90/10) to give 4-chloro-6-methoxy-7-[3-(4-prop-2-yn-1-ylpiperazin-1-yl)propoxy]quinazoline (409 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1CCCC1>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH:20]=[C:21]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc2cc[nH]c2c1
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cc(Cl)ccc23)CC1
Yield: 72.2 %

Procedure:
A stirred solution of 6-chloroindole (455 mg, 3.0 mmol), t-butyl-4-oxo-1-piperidinecarboxylate (650 mg, 3.3 mmol), and pyrrolidine (0.62 mL, 7.4 mmol) in ethanol (10 mL) was heated at reflux for 16 hours. Solvent was evaporated and the residue was recrystallized from ethyl acetate and hexanes to afford a yellow solid (721 mg, 72%).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[Br:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:9]([O:26][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH2:19][Br:18])=[CH:21][CH:22]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O)c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(COC(=O)c1ccc(CBr)cc1)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
Triethylamine (16 ml, 115 mmol) and bromoacetophenone (22.9 g, 115 mmol) were dissolved in 450 ml of ethyl acetate. The solution was stirred at 50° C. and 4-(bromomethyl)benzoic acid (17.5 g, 155 mmol) was added in seven equal portions over a three hour period. Stirring was continued for an additional 8 hours at 50° C. Precipitated triethylaminehydrobromide was removed by filtration and the ethyl acetate solution was washed with (3×150 ml each) of 10% citric acid, brine saturated sodium bicarbonate and brine. The organic phase was dried with sodium sulfate and concentrated in vacuo. The residue was recrystallized from dichloromethane-petroleum ether to give fine white crystals (10.2 g, 27% yield). 1H NMR (DMSO-d6) δ 7.99 (m, 4H), 7.69-7.54 (m, 5H), 5.74 (s, 2H), 4.77 (s, 2H); 13C NMR (DMSO-d6) δ 193.7, 165.9, 144.6, 134.9, 131.2, 131.0, 130.7, 130.6, 130.2, 129.9, 128.8, 128.6, 68.2, 34.0.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1.[NH2:25][C@H:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:27]([NH2:29])=[O:28].CCN(CC)CC.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:29][C:27](=[O:28])[C@H:26]([NH:25][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=2)[N:3]=1)[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(S(C)(=O)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)cc(N[C@H](CC(C)C)C(N)=O)nc1Nc1cccc(S(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 50.1 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (120.7 mg, 0.330 mmol), (R)-2-amino-4-methylpentanamide (67.1 mg, 0.515 mmol), and Et3N (0.1 mL, 0.717 mmol) in DMF (4 mL) was stirred at 60° C. for 14 h. Saturated aq NaHCO3 (20 mL) was added to the mixture, which was subsequently extracted with EtOAc (2×30 mL). The organic layers were washed with saturated aq NaHCO3 (20 mL), water (20 mL) and brine (20 mL), were dried over anhydrous Na2SO4, and filtered (DM1020). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes/EtOAc=1/2) and then triturated with IPE to give the title compound (76 mg, 50%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.O.NN>C(Cl)Cl>[NH2:3][O:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)OC(=O)N1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(ON)CC1
Reaction time: 3 h
Yield: 62.8 %

Procedure:
Compound 2a (3.31 g, 10 mmol) was dissolved in DCM (21 mL) and treated with hydrazine hydrate (1.52 mL, 31 mmol). After stirring for 3 h, the mixture was chilled in an ice-bath and filtered. The precipitate was washed with a minimal volume of DCM and the resulting filtrate was concentrated under vacuum to afford 1.27 g (63%) of 2b as a colorless oil; LC-MS 203.1 (MH+).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3][CH2:2]1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=3)[C@H:5]2[CH2:9][CH3:11])[CH2:2][CH2:3]1
Reactant: COc1cc(F)ccc1C#N
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(OC)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-ethylpyrrolidin-3-ol 0.5 oxalate (185 mg), 4-fluoro-2-methoxybenzonitrile (290 mg) and lithium carbonate (198 mg), the title compound was obtained as a pale-yellow solid (yield: 144 mg, yield: 55%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: COC(=O)Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccc(C2CCNCC2)cc1

Procedure:
The compound is prepared analogously to Example XI.1 using 4-(4-methoxycarbonylmethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (VIII.2) as educt and TFA in DCM instead of HCl. The crude product is used without further purification in the next reaction step.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1ccc(OCCN2CCOCC2)cc1
Temperature: 110 °C
Reaction time: 17 h
Yield: 144.6 %

Procedure:
To a mixture of 2-(morpholin-4-yl)ethanol (197 mg, 1.5 mmol) in THF (5 mL) was added 4-bromophenol (200 mg, 1.16 mmol), polymeric triphenylphosphine (0.5 g, 1.5 mmol) and DIAD (305 mg, 1.5 mmol). The mixture was degassed with nitrogen for 2 min and stirred at 110° C. for 17 hours. The cooled reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was dissolved with ethyl acetate (50 mL), washed with 2M aqueous NaOH (3×15 mL) and brine (2×20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel to give 4-[2-(4-bromophenoxy)ethyl]morpholine (480 mg, 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, 2H), δ 6.70 (d, 2H), 4.07 (t, 2H), 3.74-3.71 (m, 4H), 2.78 (t, 2H), 2.57-2.55 (m, 4H).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[N:5]([C:13]2[CH:18]=[C:17]([OH:19])[C:16]([Cl:20])=[CH:15][C:14]=2[F:21])[N:6]=[C:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2.Cl[CH:23]([F:25])[F:24].Cl>O.C(O)(C)C>[Cl:3][C:4]1[N:5]([C:13]2[CH:18]=[C:17]([O:19][CH:23]([F:25])[F:24])[C:16]([Cl:20])=[CH:15][C:14]=2[F:21])[N:6]=[C:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2
Reactant: FC(F)Cl
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Fc1cc(Cl)c(OC(F)F)cc1-n1nc2c(c1Cl)CCCC2
Reaction time: 1 h

Procedure:
To a solution of 36 ml of isopropanol, 21 ml of water and 6.0 ml of sodium hydroxide was added 5.28 g of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole II-2, and the resultant mixture was heated at 50° to 60° C. to give a solution. Excessive chlorodifluoromethane gas was introduced, and each 4.5 g of 50% aqueous sodium hydroxide was added 1.5 and 3 hours after starting the gas inlet and further said gas inlet was continued for additional one hour. After cooling, the reaction mixture was neutralized with 2N hydrochloric acid and extracted with dichloromethane. The organic layer was dried and concentrated. The residue was chromatographed on a column of silica gel, eluting with n-hexane-ethyl acetate (4:1 v/v). The eluate was concentrated to give 5.24 g of the titled compound I-2.