Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Zn]CC)C.CCCCCC.C(O)(C(F)(F)F)=O.C(I)I.C(OC([N:29]1[CH2:34][CH2:33][N:32]2[C:35]([CH3:40])=[N:36][C:37]([CH:38]=[CH2:39])=[C:31]2[CH:30]1[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:38]1([C:37]2[N:36]=[C:35]([CH3:40])[N:32]3[CH2:33][CH2:34][NH:29][CH:30]([CH2:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([C:49]([F:50])([F:52])[F:51])=[CH:45][CH:44]=4)[C:31]=23)[CH2:39][CH2:1]1
Reactant: C=Cc1nc(C)n2c1C(CCc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)CC2
Reactant: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Product: Cc1nc(C2CC2)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of 1M diethylzinc in hexane (37.0 ml; 37.000 mmol) in anhydrous DCM (40 ml) was added dropwise a solution of TFA (2.82 ml; 36.924 mmol) in anhydrous DCM (20 ml). After 30 min., a solution of methylene iodide (2.97 ml; 36.924 mmol) in anhydrous DCM (20 ml) was added dropwise to the reaction mixture, and stirring at 0° C. was continued for 10 min. A solution of 3-methyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-1-vinyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (0.536 g; 1.231 mmol) in anhydrous DCM (5 ml) was then added dropwise, and the resulting mixture was further stirred at 0° C. for 1 h, and finally at rt for 6 h. The reaction mixture was then treated dropwise with TEA (7 ml), and with an aq. sat. solution of NaHCO3 (50 ml). The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH/25% aq. NH4OH, 200/10/1) afforded the target compound 1-cyclopropyl-3-methyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine as a yellow solid (0.186 g; 34%). LC-MS: tR=0.68 min.; [M+H]+=350.42 g/mol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:34]2[S:38][C:37]([C:39]3([O:43]COC)[CH2:42][CH2:41][CH2:40]3)=[N:36][CH:35]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.Cl>CO.O1CCCC1>[Cl:1][C:2]1[C:3]([C:34]2[S:38][C:37]([C:39]3([OH:43])[CH2:42][CH2:41][CH2:40]3)=[N:36][CH:35]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:25])=[O:26])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(C3=CCN(C(=O)OC(C)(C)C)CC3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCNCC3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 65 °C

Procedure:
A mixture of tert-butyl 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Example 89A) (0.1 g, 0.146 mmol) in methanol (0.7 mL) and tetrahydrofuran (0.25 mL) was treated with 10% aqueous HCl solution (0.165 mL), and the reaction was heated at 65° C. for 5 hours. The reaction was cooled to ambient temperature and concentrated to dryness. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by flash chromatography on a silica gel column, eluting with a gradient of 0% to 5% methanol in dichloromethane, to provide the title compound. MS ESI(+) m/z 541.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:5]2[CH:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.C1(O)C=CC=CC=1>C(Cl)Cl>[N:23]1([C:2]2[N:3]=[C:4]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:5]3[CH:10]=[C:9]([CH3:11])[S:8][C:6]=3[N:7]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1
Yield: 184.9 %

Procedure:
A solution of 2-chloro-6-methyl-4-(3,4-methylene dioxybenzylamino)-thieno-[2,3-d]-pyrimidine (1.67 g), imidazole (1.02 g) and phenol (2 g) are heated 5 hours at 150° C. After cooling, the residue is dissolved in CH2Cl2. The solvent is removed, and the usual workup yields 2-(imidazol-1-yl)-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine (3.38 g) Mp. 162° C.
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].I.[NH:20]=[C:21]1[N:25]([CH3:26])[CH2:24][CH2:23][S:22]1>C(Cl)Cl.C(N(CC)CC)C>[CH3:26][N:25]1[CH2:24][CH2:23][S:22][C:21]1=[N:20][C:16](=[O:18])[CH2:15][NH:14][C:12]([O:11][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:13]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CN1CCSC1=N
Agent: CCOC(=O)Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCSC1=NC(=O)CNC(=O)OC(C)(C)C
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Ethyl chloroformate (0.25 ml.) at -5° C. was added to a solution of 350 mg. of t-butoxycarbonylaminoacetic acid and 0.4 ml. of triethylamine in 10 ml. of methylene chloride at -5° C. After stirring 5 minutes at -5° C. there was added a solution of 610 mg. of 2-imino-3-methylthiazolidine hydrogen iodide and 1.0 ml. of triethylamine in 10 ml. of methylene chloride also at -5° C. Stirring was continued at -5° C. for 15 minutes and one hour at room temperature. The reaction mixture was washed with 40 ml. of 20% (w/v) citric acid solution, sodium bicarbonate solution, and water, dried and concentrated to dryness. The residue was triturated with ether, petroleum ether and ether and finally collected to give pure N-(3-methylthiazolidin-2-ylidene)-t-butoxycarbonylaminoacetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:26]3[CH2:27][CH2:28][CH2:29][C@H:25]3[CH2:24][N:20]3[CH2:21][CH2:22][CH2:23][C@H:19]3[CH3:18])=[O:15])=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: COc1cccc(-c2ccc(C(=O)O)cc2)n1
Product: COc1cccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCC[C@H]3C)cc2)n1
Yield: 76 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure B′ using 4-(6-Methoxy-pyridin-2-yl)-benzoic acid (573 mg, 2.5 mmol) and 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine (337 mg, 2.0 mmol) to give 580 mg (76% yield). MS (ES+) 380.2 (M+H)+
Reaction SMILES: Br.[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13])[CH3:3].C(N1CCOCC1)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>O1CCCC1>[CH2:2]([NH:4][C:5](=[O:16])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:15])[C@H:12]([CH3:14])[NH:13][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:3]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Reactant: CCOC(=O)Cl
Agent: Br
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
2 g (0.0066 mol) of L-alanyl-L-proline ethylamide hydrobromide were suspended in 20 ml of dry tetrahydrofuran, 1.84 ml (0.0145 mol) of N-ethylmorpholine and 0.76 ml (0.0079 mol) of ethyl chloroformate were added and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated off and the residue dissolved in 100 ml of chloroform and washed successively with 2-N hydrochloric acid in brine, brine, saturated sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to an oil which soon crystallised. Recrystallisation from chloroform/petrol yielded 0.88 g (47%) of N-ethoxycarbonyl-L-alanyl-L-proline ethylamide of melting point 126°-128° C.; [α]D20 =-117.6° (c=1.02% in methanol).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][OH:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccccc2)C1

Procedure:
(2S,4R)-1-Benzyloxycarbonyl-2-hydroxymethyl-4-t-butyldimethylsilyloxypyrrolidine (111 g) was dissolved in dry dichloromethane (1100 ml), and triethylamine (36.87 g) was added thereto. After addition of methanesulfonyl chloride (41.81 g) under nitrogen stream while ice-cooling, the resultant mixture was stirred at the same temperature for 30 minutes. The reaction mixture was washed with water, aqueous sodium chloride solution, water, aqueous sodium bicarbonate solution and water in order and dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-1-benzyloxycarbonyl-2-methylsulfonyloxymethyl-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=1)[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]([C:36]1[O:40][N:39]=[C:38]([NH2:41])[CH:37]=1)([CH3:35])[CH3:34].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:41][C:38]2[CH:37]=[C:36]([C:33]([CH3:35])([CH3:34])[C:32]([F:42])([F:31])[F:43])[O:40][N:39]=2)=[O:29])=[C:22]([F:30])[CH:21]=1)[CH3:2]
Reactant: CC(C)(c1cc(N)no1)C(F)(F)F
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)O)c(F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)on2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (55.1 g, 134 mmol) and 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (26 g, 134 mmol) in pyridine (500 mL) was added T3P® (137.5 mL, 134 mmol) dropwise and stirred at 25° C. for 1 h. After TLC analysis showed the starting material was consumed completely, the mixture was poured into stirring cold water (1 L). The mixture was stirred for 0.5 h and then let stand for 10 h. The solid was filtered, washed with H2O (200 mL×3) and TBME (200 mL×2) and dried in vacuo to give an off-white solid of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (65 g, 100 mmol, 74% yield): 1H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.40-7.32 (m, 3H), 7.26 (d, J=9.6 Hz, 2H), 6.90 (d, J=8.8 Hz, 3H), 6.43 (s, 1H), 5.26 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 3.81 (s, 2H), 3.78 (s, 3H), 1.56 (s, 6H), 1.35 (t, J=7.2 Hz, 3H); ES-LCMS m/z: 588 (M+H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=2)[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7]1.[C:20](Cl)(=[O:22])[CH3:21].O>C(Cl)Cl>[CH3:16][C:12]1[C:13]([C:20](=[O:22])[CH3:21])=[CH:14][C:15]2[C:6]([CH3:19])([CH3:5])[CH2:7][CH2:8][C:9]([CH3:18])([CH3:17])[C:10]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reaction time: 0.5 h

Procedure:
To a suspension of AlCl3 (2.88 g; 21.6 mmol) in methylene chloride (5 ml) was added over 15 minutes a solution of 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydro-naphthalene (4.0 g; 20 mmol) and acetyl chloride (1.6 ml; 21.6 mmol) in methylene chloride (20 ml) at 0° C. The reaction mixture was stirred for 30 minutes and ice cooled water (50 ml) was added. The organic phase was separated and the water phase was further extracted with methylene chloride (3×30 ml). The combined organic phases were first washed with brine then dried before evaporated. The residue was purified by column chromatography using hexane:methylene chloride (1:1) to give the title compound in 4.9 g (100%) yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[C:14](=[O:15])[C:13]3([CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:11]2)=[CH:7][CH:6]=1)=[O:4].Cl>O1CCOCC1>[O:15]=[C:14]1[C:13]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:11][N:10]1[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:35][CH:34]=1
Reactant: COC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To tert-butyl 3-(4-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.31 g, 0.65 mmol) was added 4M solution of HCl in dioxane (3 mL). After stirring at room temperature for 90 minutes, the reaction mixture was concentrated in vacuo to obtain methyl 4-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18]([OH:20])[CH3:19])=[CH:15][C:14]([F:21])=[CH:13][C:12]=3[N:11]3[CH2:22][CH2:23][CH:24]([CH2:25][C:26]([OH:28])=[O:27])[C:10]=23)=[CH:4][CH:3]=1.[CH3:29]COCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18]([OH:20])[CH3:19])=[CH:15][C:14]([F:21])=[CH:13][C:12]=3[N:11]3[CH2:22][CH2:23][CH:24]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:10]=23)=[CH:4][CH:3]=1
Reactant: CC(O)c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Reactant: CCOCC
Product: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(C)O)cc(F)cc12

Procedure:
(+/−)-[9-[(4-Chlorophenyl)sulfanyl]-6-fluoro-8-(1-hydroxyethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (Example 14, 100 mg) was esterified in Et2O by addition of an excess of CH2N2. After removal of the solvents, the title ester was obtained quantitatively as a pale yellow solid and used as such.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O.N1CCCCC1>C(O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=[C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][C:5]1=[O:11]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: O=Cc1cc2ccccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cccc2c1C(=Cc1cc3ccccc3[nH]1)C(=O)N2
Temperature: 95 °C

Procedure:
A mixture of 4-methyl-2-oxindole (147 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was heated in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 3-(1H-indol-2-ylmethylene)-4-methyl-1,3-dihydro-indol-2-one.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[C:14]1(=[O:34])[N:18]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[C:17](=[O:29])[C:16]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:15]12.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:24]([OH:25])[C:23]2[CH:27]=[CH:28][C:20]([CH2:19][N:18]3[C:17](=[O:29])[C:16]4=[CH:30][CH:31]=[CH:32][CH:33]=[C:15]4[C:14]3=[O:34])=[CH:21][CH:22]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)N1C(=O)C(=C(O)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2ccccc21

Procedure:
Prepared analogously to Example 10(a) from 1-acetyl-2-indolinone and 4-phthalimidomethyl-benzoic acid (melting point: 260-262° C.) in dry DMF in the presence of TBTU, HOBT and Hrinig's base (20° C., 4 hours), stirring in dilute hydrochloric acid, extracting with CH2Cl2, evaporating the dried organic extract in vacuo, triturating the evaporation residue with EtOac and drying the solid substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.[OH-].[Ba+2].[OH-].COCCOC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:5]1[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: Nc1ncc(Br)cn1
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(-c2cccs2)cn1

Procedure:
A mixture of 2-amino-5-bromopyrimidine (0.299 g, 1.72 mmol), 2-thienylboronic acid (1.56 g, 12.79 mmol), barium hydroxide (0.813 mg, 2.58 mmol), DME (8 mL) and water (1.5 mL) is purged with dry argon. Tetrakis(triphenyl-phosphine) palladium(0) (99.0 mg, 0.086 mmol) is added, and the resultant solution is stirred at 80° C. for 4 hours. The solvents are evaporated in vacuo, and the residue is partitioned between EtOAc and water. The aqueous extract is separated, and extracted with EtOAc. The organic extracts are combined, washed with sat. aq. NaHCO3 and 5% aq. Na2S2O3, dried, (Na2SO4) and the solvent is evaporated in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10](F)[CH:9]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1.Cl>CS(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([C:26](=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[OH:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(=C(O)c1ccc(F)cc1)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
Potassium carbonate (3.3 g, 24 mmol) was added to a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (2.45 g, 11 mmol) and ethyl 3-(4-fluorophenyl)-3-oxopropanoate (2.7 g, 13 mmol) in DMSO (11 mL). The yellow solution turned purple and the reaction was stirred at r.t. After 8 h, the reaction was neutralized with 25 mL of 1 N HCl and extracted with EtOAc. The organic phase was washed with water (×3) and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography on a Biotage 40+M column (gradient elution 5% to 25% EtOAc/hexanes over 10 column volumes, fraction collection at λ=254 nm) to afford the title compound as a viscous amber oil, 4.8 g (105% yield, contains ˜10 weight % EtOAc by 1H NMR). 1H NMR (˜0.6:1 ratio of keto:enol tautomers, 500 MHz, CDCl3) δ ppm 13.47 (s, 1H) 7.94-8.05 (m, 2H) 7.86 (d, J=8.55 Hz, 1H) 7.62-7.72 (m, 1.2H) 7.51 (dd, J=8.55, 2.14 Hz, 1H) 7.29-7.35 (m, 2H) 7.15-7.21 (m, 1.2H) 7.12 (d, J=2.14 Hz, 1H) 6.94 (t, J=8.55 Hz, 2H) 6.35 (s, 0.6H) 4.20-4.34 (m, 2H) 4.04-4.11 (m, 1.2H) 1.23-1.27 (m, 2H) 1.18 (t, J=7.17 Hz, 3H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18.5 μm 4.6×50 mm; 2 peaks elute with HPLC Rt=1.69 and 1.83 min (˜1:2 ratio), (ES−) m/z (M−) for both=408, 410 (1:1 ratio).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:24])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[CH:13][C:12]=2[O:19][CH2:20][CH:21]([F:23])[F:22])[CH2:5][CH2:4]1.[Cl:27][C:28]1[C:41]([N:42]=[C:43]=S)=[C:40]([Cl:45])[CH:39]=[CH:38][C:29]=1[CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].CC(C)N=C=NC(C)C>>[F:1][C:2]([F:25])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([O:19][CH2:20][CH:21]([F:22])[F:23])=[CH:13][C:14]3[NH:18][C:43]([NH:42][C:41]4[C:40]([Cl:45])=[CH:39][CH:38]=[C:29]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:35])[CH3:36])[C:28]=4[Cl:27])=[N:17][C:15]=3[CH:16]=2)=[O:24])[CH2:5][CH2:4]1
Reactant: Nc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OCC(F)F)cc3[nH]2)c1Cl

Procedure:
The title compound is prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-(2,2-difluoro-ethoxy)-4,5-diamino-benzoic acid amide and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide with DIC in analogy to example 1 g.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: COc1cccc(CBr)c1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: COc1cccc(Cn2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)c1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 3-methoxy-benzyl bromide (67 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(3-methoxy-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (65 mg, 42%) as a light yellow oil. APCI-MS (M+H) 327.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([N:12]([CH2:16][C:17]#[N:18])[CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].O>O1CCCC1>[CH:7]1([N:12]([CH:13]([CH3:15])[CH3:14])[CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)N(CC#N)C1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(CCN)C1CCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 9.2 %

Procedure:
Lithium aluminium hydride (66 ml of a 1 molar solution in tetrahydrofuran, 0.066 mol) was added to a stirred solution of [cyclopentyl(isopropyl)amino]acetonitrile (10 g, 0.66 mol) (Preparation 24) in tetrahydrofuran (100 ml) at 0° C. The reaction mixture was stirred at 0° C. for 20 minutes and then heated under reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and left to stand overnight. The reaction mixture was cooled in an icebath and treated dropwise with 4.8 ml of a 7.5% w/w aqueous sodium hydroxide solution followed by 7.4 ml of water. The solvent was removed under reduced pressure and the residue slurried with diethyl ether (200 ml) for 30 minutes and then filtered. The filtrate was evaporated under reduced pressure to give the title compound as a colourless oil (10.30 g).