Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][CH2:8][NH:9][C:10](=[O:42])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:46]I>CN(C)C=O>[C:1]([O:5][C:6](=[O:43])[CH2:7][CH2:8][N:9]([C:10](=[O:42])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)[CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:15][CH:16]=1)[CH3:46])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCC(=O)OC(C)(C)C)C(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Reaction time: 0.42 h
Yield: 7.9 %

Procedure:
A solution of (±)-3-{4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoylamino}-propionic acid tert-butyl ester (0.0910 g, 0.153 mmol) in dimethylformamide (1.0 mL) at 0° C. was treated with NaH (1 small spatula tip). After 25 min., MeI (0.0240 mL, 0.385 mmol) is added and the reaction is stirred for 1 h. The reaction mixture is quenched with saturated NH4Cl (aq) (2 μL) and extracted with EtOAc (3×10 mL). Combined extracts are washed with brine (1×), dried over MgSO4, filtered, and conc. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 10% EtOAc to 60% EtOAc giving (±)-3-({4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoyl}-methyl-amino)-propionic acid tert-butyl ester (7.4 mg, 8%) as a clear syrup. MS (ES): 554.0 [M+H-(t-Bu)]+.
Reaction SMILES: OC1C(C)=C(O)C=CC=1C=O.[Si](Cl)(C(C)(C)C)(C)C.C(N(CC)C(C)C)(C)C.[Si]([O:36][C:37]1[C:44]([CH3:45])=[C:43]([O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[CH:42]=[CH:41][C:38]=1[CH:39]=[O:40])(C(C)(C)C)(C)C>>[Si:47]([O:46][C:43]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[C:37]([OH:36])[C:44]=1[CH3:45])([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:48])[CH3:49]
Reactant: Cc1c(O[Si](C)(C)C(C)(C)C)ccc(C=O)c1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: Cc1c(O)ccc(C=O)c1O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(O[Si](C)(C)C(C)(C)C)ccc(C=O)c1O

Procedure:
By following Example 2 procedure, 5.0 g of 2,4-Dihydroxy-3-methylbenzaldehyde was reacted with 4.95 g of tert-butyldimethylsilyl chloride and 2.15 g of N,N-diisopropylethylamine to get 7.91 g of crude title product containing 16.5% of 2,4-bis(tert-butyldimethylsilyloxy)-3-methylbenzaldehyde by GC. Crude product was purified by column chromatography to get the title compound as colorless liquid. IR (neat): 3280, 2956, 2932, 2888, 2859, 1646, 1622, 1582, 1493, 1425, 1388, 1360, 1325, 1296, 1249, 1171, 1103, 1021, 1007, 846, 798, 726, 679, 652, and 610 cm−1. 1H-NMR (CDCl3, 400 MHz): δ 11.56 (s, 1H, exch. with D2O, OH), 9.70 (s, 1H, CHO), 7.26 (d, J=8.4 MHz, 1H, aromatic H-6), 6.45 (d, J=8.4 Hz, 1H, aromatic H-5), 2.10 (s, 3H, ArCH3), 1.02 (s, 9H, Si-tert-Bu), 0.27 (s, 6H, SiMe2). 13C NMR (CDCl3, 100 MHz): δ 194.73 (CHO), 162.12 (C-2), 161.44 (C-4), 132.26 (C-6), 116.45 (C-1), 115.39 (C-3), 111.26 (C-5), 25.26 (CMe3), 18.29 (CMe3), 8.15 (ArCH3), 8.19 (SiMe2). Mass (EIMS): 266.26 (M), 265.19 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[C:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])=[CH:4][CH:3]=1.[Cl-:15].[CH3:16][N+:17](=[CH2:19])[CH3:18]>C(#N)C>[ClH:15].[CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[C:7]2[CH2:11][CH2:10][CH:9]([CH2:16][N:17]([CH3:19])[CH3:18])[C:8]2=[O:12])=[CH:4][CH:3]=1
Reactant: C=[N+](C)C
Reactant: [Cl-]
Reactant: Cc1ccc(C=C2CCCC2=O)cc1
Solvent: CC#N
Product: Cc1ccc(C=C2CCC(CN(C)C)C2=O)cc1
Product: Cl
Yield: 75.2 %

Procedure:
5.6 g (0.03 mol) of 2-(4-methylbenzylidene)cyclopentanone was dissolved in 30 mL anhydrous acetonitrile, treated with 8.4 g (0.09 mol) of N,N-dimethyl-methylene ammonium chloride under refluxing, refluxed for 12 h to yield a solid product, then suction filtered and dried, and recrystallized in acetonitrile/chloroform to yield 2-(4-methylbenzylidene)-5-dimethylaminomethyl-cyclopentanone hydrochloride with a yield of 75.2%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Cl)=[N:4][N:3]=1.[OH-].[NH4+:14].O.[NH2:16]N>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:14][NH2:16])=[N:4][N:3]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: NN
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NNc1nnc(Cl)c2ccccc12
Temperature: 60 °C
Yield: 84 %

Procedure:
A mixture of 1,4-dichlorophthalazine 23 (10.2 g, 51.2 mmol) and ammonium hydroxide (4.5 mL) in ethanol (110 mL) was heated to 60° C. Hydrazine hydrate (9 mL, 179 mmol) was added dropwise. After about one-half of the hydrazine hydrate was added, a thick precipitate formed. The mixture was stirred well and the temperature was kept below 74° C. by controlled addition of reagent. After the addition was complete the reaction was heated at reflux for 10 min, then allowed to cool. The reaction was filtered and the solids were washed with water (20 mL) and ethanol (20 mL), then dried at 40° C. in a vacuum oven overnight. The crude material was recrystallized from acetonitrile to afford 8.38 g (84%) of 11 as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[CH3:52][C:53]1(C)C(C)(C)OB(C=C)O1>CCO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH:52]=[CH2:53])=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCO
Product: C=Cc1ccc([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)c(-n2ccc(C)n2)c1
Temperature: 80 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.388 mmol, see Example 1u) in EtOH:H2O (15 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (90 mg, 0.58 mmol), KHCO3 (389 mg, 3.88 mmol), and PdCl2(PPh3)2 (41 mg, 0.058 mmol). The reaction mixture was heated to 80° C. for 1 h, then cooled to RT. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification with a 40 g Isco RediSep silica cartridge (EtOAc:heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])(=[O:3])[NH2:2].[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[NH:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([O:13][C@@H:22]1[CH:23]2[CH2:26][CH2:27][N:20]([CH2:25][CH2:24]2)[CH2:21]1)=[O:12])(=[O:3])[NH2:2]
Reactant: NC(=O)c1sccc1NC(C(=O)O)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1sccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
A mixture of 2-(2-carbamoylthiophen-3-ylamino)-2-phenylacetic acid (I7) (389 mg, 1.41 mmol), (R)-quinuclidin-3-ol (215 mg, 1.69 mmol), DCC (349 mg, 1.69 mmol) and HOBT (259 mg, 1.69 mmol) in dry THF (5 ml) was stirred at room temperature overnight. THF was evaporated, and the crude product was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by preparative HPLC. The fractions with the product are combined and evaporated to dryness. The residue was dissolved in 2M K2CO3 and extracted twice with EtOAc to obtain (R)-quinuclidin-3-yl 2-(2-carbamoylthiophen-3-ylamino)-2-phenylacetate (32 mg, 6% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10](=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH3:17]>CC(C)=O>[CH2:10]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:16][CH3:17]
Reactant: N#Cc1ccccc1O
Reactant: CCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccccc1C#N

Procedure:
75 g (630 ml) of 2-hydroxybenzonitrile are refluxed with 174 g (1.26 mol) of potassium carbonate and 232.2 g (1.89 mol) of ethyl bromide in 11 of acetone overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:19][C:20](=[O:22])[CH3:21])[C:9]([O:11]CC1C=CC=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH2:1]([C@H:8]([CH2:19][C:20](=[O:22])[CH3:21])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)C[C@@H](Cc1ccccc1)C(=O)O
Yield: 87.8 %

Procedure:
A solution or 1.00 g (3.37 mmoles) of benzyl 2(R)-benzyl-4-oxopentanoate (prepared as described in Preparation 19) in 10 ml of ethanol was stirred at room temperature for 3 hours in the presence of 100 mg of 10% w/w palladium-on-charcoal and under about 4 atmospheres of hydrogen. At the end of this time, the catalyst was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The residue was recrystallized from a mixture of hexane and diisopropyl ether, to give 610 mg (yield 88%) of the title compound as white crystals, melting at 71°-73° C.
Reaction SMILES: [CH3:1][CH:2]1[C:11]23[CH2:12][CH:7]([CH:8]([CH3:14])[C:9](=O)[CH2:10]2)[C:6]([CH3:16])([CH3:15])[CH:5]3[CH2:4][CH2:3]1.[C:17](O)(=O)C.[CH:21]([NH2:23])=[NH:22]>C(O)CCC>[CH3:14][CH:8]1[C:9]2=[N:22][CH:21]=[N:23][CH:17]=[C:10]2[C:11]23[CH2:12][CH:7]1[C:6]([CH3:16])([CH3:15])[CH:5]2[CH2:4][CH2:3][CH:2]3[CH3:1]
Reactant: CC1C(=O)CC23CC1C(C)(C)C2CCC3C
Reactant: CC(=O)O
Reactant: N=CN
Solvent: CCCCO
Product: CC1c2ncncc2C23CC1C(C)(C)C2CCC3C
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A 100 mL reaction flask is charged with 3,6,8,8-tetramethyl-hexahydro-3a,7-methano-azulen-5-one (prepared as described in U.S. Pat. No. 3,887,622) (10 g, 0.045 mol), formamidine acetate (21 g, 0.2 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 5,7,7,10-tetramethyl-6,7,7a, 8,9,10-hexahydro-5H-6,10a-methanoazuleno[5,4-d]pyrimidine (˜5 g) is obtained.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]3[O:39][CH2:38]3)[C:32]([O:34]C)=[O:33])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]([OH:39])[CH2:38][S:12][C:10]3[O:11][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:8][N:9]=3)[C:32]([OH:34])=[O:33])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: Sc1nnc(-c2ccccc2)o1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nnc(-c4ccccc4)o3)C(=O)O)cc2)cc1

Procedure:
Example 35 is prepared from 5-phenyl-1,3,4-oxadiazole-2-thiol and 1d using the procedure described for compound 20.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:13])([F:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:13])([F:12])[C:7](=[O:11])[N:8]2[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1Nc2cc(Br)ccc2C1(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C(F)(F)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into the solution of 6-bromo-3,3-difluoroindolin-2-one in DMF (5 mL), was added 1M of NaHMDS solution in THF (1.6 mL), after 30 min., (2-(chloromethoxy)ethyl)trimethylsilane (269 mg) was added. After being stirred at rt for 4 h, the reaction mixture was extracted with ethyl acetate and washed with brine, dried and the solvent was removed, the residue was purified by silica gel chromatography to provide 0.46 g of 6-bromo-3,3-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one 7.35. 1H NMR (400 MHz, Chloroform-d) δ 7.43 (s, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 5.12 (s, 2H), 3.58 (m, 2H), 1.21 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH:19]1(O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:31]=CC=C[CH:27]=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH:26]([CH:19]1[CH2:24][CH2:23][CH:22]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[CH:6]=[CH:5]3)[CH2:21][CH2:20]1)([CH3:31])[CH3:27]
Reactant: OC1CCCCC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Yield: 52 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (2.0 g, 0.0082 mol), cyclohexanol, 4-(1-methylethyl)-(1.3 g, 0.0090 mol), triphenylphosphine (2.6 g, 0.0099 mol), tetrahydrofuran (45 mL, 0.55 mol), and diisopropyl azodicarboxylate (2.0 g, 0.0099 mol) to give 1.6 g of the desired product as a yellow solid (52%). ESI-MS: 368 (M+H)+. 1H NMR (400 MHz, CDCl3) δ=7.81-7.59 (m, 2 H), 7.49-7.30 (m, 1 H), 7.22-7.04 (m, 2 H), 6.88-6.64 (m, 1 H), 4.66 (br. s., 1 H), 4.40 (s, 2 H), 4.34-4.18 (m, 1 H), 2.29-2.07 (m, 2 H), 1.91-1.69 (m, 6 H), 1.64-1.09 (m, 5 H), 0.96-0.69 (m, 6 H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Cl[C:6]1[C:11]2=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[N:13]=[C:14]([CH3:15])[N:10]2[N:9]=[CH:8][N:7]=1.C(=O)(O)[O-].[Na+].COC(C)(C)C>ClCCl>[N:1]1([C:6]2[C:11]3=[C:12]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[N:13]=[C:14]([CH3:15])[N:10]3[N:9]=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: Cc1nc(-c2cnn(C)c2)c2c(Cl)ncnn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: Cc1nc(-c2cnn(C)c2)c2c(N3CCC3)ncnn12
Reaction time: 0.08 h

Procedure:
A solution of azetidine (9.21 g, 161 mmol) in dichloromethane (75 mL) was added to a solution of 4-chloro-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[5,1-f][1,2,4]triazine (38.14 g, 153.4 mmol) in dichloromethane (310 mL). After stirring for 5 minutes, the reaction was treated with aqueous sodium bicarbonate solution (0.89 M, 260 mL, 231 mmol) and vigorously stirred for 2 hours. After the phases separated, a white solid was collected by filtration and mixed with water and dichloromethane; it did not completely dissolve. Filtration provided a second water/dichloromethane mixture, which was combined with the original filtrate. The layers were separated, and the aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (250 mL), then dried over sodium sulfate and filtered. The filtrate was concentrated on a rotary evaporator at 45° C. until solid began to form in the flask. tert-Butyl methyl ether (400 mL) was added with stirring, and the mixture was granulated for 1 hour. Filtration provided the product as a white solid. Yield: 36.07 g, 133.9 mmol, 87%. 1H NMR (400 MHz, CDCl3) δ 2.23-2.31 (m, 2H), 2.65 (s, 3H), 3.97 (s, 3H), 3.98-4.08 (m, 4H), 7.61 (s, 1H), 7.62 (s, 1H), 7.85 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH2:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH:21][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(O)c1cccc(F)c1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Product: O=C(NCCc1ccc(Cl)c(Cl)c1)c1cccc(F)c1

Procedure:
N-[2-(3,4-Dichloro-phenyl)-ethyl]-3-fluoro-benzamide was prepared in analogy to Example 40 from 3-fluoro-benzoic acid and 2-(3,4-dichloro-phenyl)-ethylamine: yellow solid,
Reaction SMILES: [CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[OH:10][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]([N:11]([CH3:12])[C:27](=[O:28])[CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:1]
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C(O)c1ccccc1)N(C)C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A dry 1 L round-bottomed flask equipped with a magnetic stirrer was charged (+)-pseudoephedrine (13.92 g, 84.26 mmol, 1.0 equiv), triethylamine (13.39 mL, 96.06 mmol, 1.14 mmol), and tetrahydrofuran (340 mL). The solution was cooled to 0° C. and phenylacetyl chloride (14.33 g, 92.69 mmol, 1.1 equiv) was added via cannula over a 20 minute interval as a solution in tetrahydrofuran (90 mL). After 30 minutes, the reaction was quenched with saturated sodium bicarbonate. The amide was extracted from brine (1 L) with ethyl acetate (400 mL, 130 mL, 130 mL), and the organic extracts were dried over sodium sulfate. After removal of the solvent under reduced pressure, a solid was obtained. The solid was recrystallized from 2:1:1 ether/dichloromethane/hexanes (500 mL), affording the phenylacetamide (17.90 g, 75% yield) as a white powder: mp 145°-146° C.; 1H NMR (300 MHz, C6D6) δ6.9-7.5 (m, 10H), 4.55 (br, 1H), 4.48 (t, 1H, J=7.1 Hz), 4.11 (m, 1H), 3.95 (m, 1H), 3.83 (m, 1H), 3.78 (s, 2H), 3.31 (d, 2H, J=1.3 Hz), 2.76 (s, 3H), 2.12 (s, 3H), 0.95 (d, 3H, J=7.0 Hz), 0.42 (d, 3H, J=6.7 Hz); 13C NMR (75.5 MHz, CDCl3) δ173.1, 172.2, 142.2, 141.4, 135.5, 134.5, 128.7, 128.64, 128.58, 128.3, 128.1, 127.5, 126.73, 126.68, 126.6, 126.3, 76.2, 75.3, 58.6, 41.8, 41.4, 33.3, 27.0, 15.0, 14.3; FTIR (neat film) cm-1 3393 (br, m), 1618 (s), 1494 (m), 1453 (m), 1402 (m); HRMS (FAB) Calcd for C18H22NO2 (MH+): 284. 1652. Found: 284.1646.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[C:21]1([NH:27][NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C[N:30]1CCOCC1>CO>[C:21]1([NH:27][NH:28][NH:30][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN1CCOCC1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NNc1ccccc1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NNNc3ccccc3)cc2s1
Yield: 25.7 %

Procedure:
the title compound (32 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), phenylhydrazine (66 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 401.4 (M+1, 100%). Yield=26%.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].O1CCCCC1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]3([C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]3)=[CH:20][CH:21]=2)[C:16]([C:30]2[N:35]=[C:34]([O:36][C@H:37]3[CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41][C:38]43[CH2:40][CH2:39]4)[CH:33]=[N:32][CH:31]=2)=[N:15]1>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH2:39]1[C:38]2([CH2:41][CH2:42][NH:43][CH2:44][C@@H:37]2[O:36][C:34]2[N:35]=[C:30]([C:16]3[C:17]4[C:22](=[CH:21][CH:20]=[C:19]([C:23]5([C:26]([F:27])([F:28])[F:29])[CH2:25][CH2:24]5)[CH:18]=4)[NH:14][N:15]=3)[CH:31]=[N:32][CH:33]=2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5(C(F)(F)F)CC5)cc34)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C1(c2ccc3[nH]nc(-c4cncc(O[C@H]5CNCCC56CC6)n4)c3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
TFA (0.5 mL, 6.49 mmol) was added to a solution of (4R)-tert-butyl 4-((6-(1-(tetrahydro-2H-pyran-2-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (25.2 mg, 0.041 mmol) in DCM (0.5 mL) and the resulting solution was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo and the residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% CH3CN/H2O+0.1% TFA, 15 min, 254 nm) to provide 3-(6-((4R)-6-azaspiro[2.5]oct-4-yloxy)-2-pyrazinyl)-5-(1-(trifluoromethyl)cyclopropyl)-1H-indazole tris(2,2,2-trifluoroacetate) (12.0 mg, 0.016 mmol, 38% yield) as a yellow foam: 1H NMR (400 MHz, MeOH-d4) δ ppm 9.04 (1 H, s), 8.42-8.46 (1 H, m), 8.31 (1 H, s), 7.60-7.64 (1 H, m), 7.55-7.59 (1 H, m), 5.07 (1 H, s), 3.89 (1 H, d, J=12.7 Hz), 3.57 (1 H, m, J=13.3, 1.0 Hz), 3.47-3.54 (1 H, m), 3.34-3.39 (1 H, m), 2.72 (1 H, td, J=13.9, 4.5 Hz), 1.45-1.49 (2 H, m), 1.22-1.27 (1 H, m), 1.17-1.22 (2 H, m), 0.99 (1 H, dt, J=8.9, 5.6 Hz), 0.77-0.85 (2 H, m), 0.67-0.73 (1 H, m). 19F NMR (377 MHz, MeOH) δ ppm −71.41 (3 F, s), −77.45 (9 F, br. s.). MS (ESI, pos. ion) m/z: 430.1 (M+1).