Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:4]([C:5](Cl)=[O:6])[C:3]1([CH3:9])[CH3:8].Cl.[O:12]([NH2:14])[CH3:13].C(N(CC)CC)C>ClCCl>[CH3:13][O:12][NH:14][C:5]([CH:4]1[C:2]([CH3:10])([CH3:1])[C:3]1([CH3:9])[CH3:8])=[O:6]
Reactant: CON
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)C1C(C)(C)C1(C)C
Yield: 75 %

Procedure:
Tetramethylcyclopropanecarbonyl chloride (TMC-Cl) (4 g; 25 mmol) dissolved in 20 ml of dry dichloromethane was slowly added to a stirred and dry dichloromethane solution of methoxylamine hydrochloride (2.5 g; 30 mmol) and triethylamine (6.3 g; 50 mmol). After the addition, the reaction mixture was stirred for 2 hr at room temperature. Dichloromethane was evaporated under vacuum, 10 ml of water was added and the products were extracted using 30 ml of ethyl acetate. The organic fraction was dried over MgSO4, filtered and evaporated under vacuum. The product was crystallized using 20 ml ethyl acetate and 30 ml petroleum ether to afford 3 g (75% yield) and its chemical structure was identified by elemental analysis and spectroscopic methods.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.[P:18](Cl)([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[S:19].C(N(CC)CC)C.O>O1CCCC1>[CH2:21]([O:20][P:18]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)([O:23][CH2:24][CH3:25])=[S:19])[CH3:22]
Reactant: N#CC(=C1C=CC(=NO)C=C1)c1ccccc1
Reactant: CCOP(=S)(Cl)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOP(=S)(OCC)ON=C1C=CC(=C(C#N)c2ccccc2)C=C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8 g (36 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-phenyl-acetonitrile, prepared as described in example 1.1, are dissolved in 90 ml of tetrahydrofuran (THF) and cooled in an ice bath. After adding 7.5 g (39 mmol) of diethyl chlorothiophosphate to the solution, 5.4 g (54 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. The reaction mixture is gradually warmed to room temperature, and stirred overnight. The reaction mixture is poured into 100 ml of water, and extracted with ethyl acetate. The organic phase is washed with 0.1N hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by flash chromatography on silica gel with ethyl acetate—hexane (1:3) as eluent. The product is a yellow solid, with mp 66-82° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3); δ [ppm]: 1.32-1.42 (m, 6H), 4.21-4.37 (m, 4H), 6.87(Z)/6.98(E) (dd, 1H), 7.17(Z)/-7.19(E) (dd, 1H), 7.26(E)17.37(Z) (dd, 1H), 7.43-7.54 (m, 6H). 1H-NMR reveals that the product is a 56:44 mixture of Z and E isomers. The signals are tentatively assigned to Z and E isomers.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15](=[O:27])[C:16]([S:19][C:20]1[S:21][CH:22]=[C:23]([CH2:25][NH2:26])[N:24]=1)([CH3:18])[CH3:17])([CH3:13])([CH3:12])[CH3:11].Cl[C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=1>>[C:10]([O:14][C:15](=[O:27])[C:16]([S:19][C:20]1[S:21][CH:22]=[C:23]([CH2:25][NH:26][C:29]2[N:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][N:30]=2)[N:24]=1)([CH3:18])[CH3:17])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CN)cs1
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(NCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
N,N-Diisopropylethylamine (2.24 g) was added to 2-{[4-(aminomethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (5.0 g) synthesized in Example 13 and 2-chloro-5-ethylpyrimidine (2.47 g), and the mixture was stirred at 130° C. for 8 hr. The reaction mixture was directly purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (5.0 g) as a slightly yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:19])[CH2:5][CH2:6][CH3:7].C[C:22]1[C:23]([CH3:38])=[C:24](C)[C:25]([CH3:36])=[C:26]2[C:30]=1[N:29]([CH3:31])[C:28](C)=[C:27]2[CH2:33]NI.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:33][C:27]2[C:26]3[C:30](=[CH:22][C:23]([CH3:38])=[CH:24][C:25]=3[CH3:36])[N:29]([CH3:31])[CH:28]=2)[C:9]1=[O:19])[CH2:5][CH2:6][CH3:7]
Reactant: CCC[C@H](C(=O)OC)n1c(=O)[nH]c2ccccc2c1=O
Reactant: Cc1c(C)c(C)c2c(c1C)c(CNI)c(C)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC[C@H](C(=O)OC)n1c(=O)c2ccccc2n(Cc2cn(C)c3cc(C)cc(C)c23)c1=O
Temperature: 100 °C
Yield: 80.7 %

Procedure:
To a solution of (R)-2-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-yl)-pentanoic acid methyl ester (50 mg, 0.18 mmol) (prepared according to example 1, steps 1-3) in DMF (10 mL) are added trimethyl-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-amino iodide (97 mg, 0.27 mmol) and K2CO3 (50 mg, 0.36 mmol) at room temperature. The solution is heated to 100° C. for 4 hours. The solution is cooled and is extracted with water and EtOAc. The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography with 20% EtOAc in Hexane as the eluent to afford (R)-2-[2,4-dioxo-1-(1,4,6-trimethyl-1H-indol-3-ylmethyl)-1,4-dihydro-2H-quinazolin-3-yl]-pentanoic acid methyl ester (65 mg, 80%) as a white foam.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][CH:27]=[N:28]2)=[CH:23][CH:22]=1>>[N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[C:21]([NH:20][C:15]([CH:12]3[CH2:11][CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:19])[F:18])[N:8]=4)[CH2:14][CH2:13]3)=[O:17])[CH:30]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(O)C1CCN(c2cccc(C(F)(F)F)n2)CC1
Product: O=C(Nc1ccc2cccnc2c1)C1CCN(c2cccc(C(F)(F)F)n2)CC1

Procedure:
Using the procedure outlined in Example 107, the title compound was prepared from 1-(6-trifluoromethylpyrid-2-yl)-piperidine-4-carboxylic acid (D102) (100 mg, 0.36 mmol) and 7-aminoquinoline (D55) (27 mg, 0.19 mmol) as an off white solid. MS(ES): MH+ 401, M-H+ 399.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19]C(OC(C)(C)C)=O)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.C(OC(=O)[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36](C=O)C=1)(C)(C)C.C1(NC(C2CCNCC2)=O)CCCC1>>[CH:34]1([NH:33][C:4]([CH:6]2[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=3)[CH2:10][CH2:11]2)=[O:5])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)OC(C)(C)C)c2)CC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C=O)c1
Agent: O=C(NC1CCCC1)C1CCNCC1
Product: Nc1cccc(CN2CCC(C(=O)NC3CCCC3)CC2)c1

Procedure:
The title compound is prepared according to the reactions 1.001a and 1.001d described above using (3-formyl-phenyl)-carbamic acid tert-butyl ester and piperidine-4-carboxylic acid cyclopentylamide: LC-MS A: tR=0.45 min; [M+H]+=302.40.
Reaction SMILES: ClC1C=[C:6]([O:8][CH3:9])[CH:5]=CN=1.Cl[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.Cl.CC[O:20]CC>ClCCl>[CH2:6]([O:8][C:9]([C@:13]1([NH2:12])[CH2:14][C@@H:15]1[CH:16]=[CH2:11])=[O:20])[CH3:5]
Reactant: Clc1ccccn1
Reactant: CCOCC
Reactant: COc1ccnc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: C=C[C@H]1C[C@@]1(N)C(=O)OCC

Procedure:
Compound 8 was prepared by the same procedure as that described for the preparation of Compound 7, except 2-chloro-4-methoxypyridine (259 mg, 1.80 mmol) was used in Step 1 in place of the 2-chloropyridine, and 2.0M HCl in ether was added to the concentrated Step 1 product in dichloromethane to give the hydrochloride salt in Step 2. The scale of Steps 2 and 3 were also adjusted based on the yields of the previous steps. Compound 8 (0.0290 g, 11.6% yield) was obtained as an off-white powder bis-TFA salt from reverse phase preparative HPLC. This compound was a single isomer. 1H NMR (500 MHz, MeOD) δ ppm 1.00 (d, J=6.71 Hz, 3H) 1.11 (d, J=6.71 Hz, 3H) 1.16 (dd, J=7.63, 2.75 Hz, 2H) 1.22-1.42 (m, 4H) 1.48 (dd, J=9.61, 5.34 Hz, 1H) 1.93-1.97 (m, 1H) 2.32 (q, J=8.85 Hz, 1H) 2.36-2.50 (m, 2H) 2.67 (dd, J=13.43, 7.02 Hz, 1H) 2.89 (s, 1H) 3.01 (ddd, J=12.82, 8.09, 4.73 Hz, 1H) 3.17-3.27 (m, 1H) 3.84 (s, 3H) 3.95 (s, 3H) 3.98-4.08 (m, 1H) 4.20 (dd, 1H) 4.26-4.33 (m, 2H) 4.70 (dd, J=10.38, 7.02 Hz, 1H) 5.17 (dd, J=10.53, 1.37 Hz, 1H) 5.36 (dd, J=17.09, 1.22 Hz, 1H) 5.77-5.87 (m, J=17.17, 9.58, 9.58 Hz, 1H) 5.97 (t, J=3.36 Hz, 1H) 6.32 (d, J=2.44 Hz, 1H) 6.55 (dd, J=7.32, 2.14 Hz, 1H) 7.14 (dd, J=9.16, 2.44 Hz, 1H) 7.22 (d, J=2.44 Hz, 1H) 7.30 (d, J=5.80 Hz, 1H) 7.72 (d, J=7.32 Hz, 1H) 7.93 (d, J=5.80 Hz, 1H) 8.01 (d, J=9.16 Hz, 1H); LC-MS, MS m/z 707 (M++H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[C:33]([O:34][CH3:35])=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:27][CH3:26])=[C:33]([O:34][CH3:35])[CH:32]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
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: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cnc1OC
Yield: 54.3 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.2 mmol) in 1,2-dimethoxyethane (2 mL) was added 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (63 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.01 mmol), and 2 M sodium carbonate (0.20 mL, 0.4 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (51 mg, 55%). ESI-MS m/z calc. 469.44. found 470.5 (M+1)+. Retention time 2.03 minutes.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].Br[CH2:26][C:27](=[O:41])[CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:16]([N:15]1[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=[C:6]1[CH:2]([NH:1][CH2:26][C:27](=[O:41])[CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40])[CH:3]([CH3:5])[CH3:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)C(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(NCC(=O)CCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A suspension of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (1.0 g, 2.93 mmol), 2-(4-bromo-3-oxo-butyl)-isoindole-1,3-dione (867 mg., 2.93 mmol, prepared as described in WO 89/10360), and potassium carbonate (405 mg, 2.93 mmol) in DMF (14 mL) was stirred at room temperature for 80 minutes. The reaction was diluted with water and the resulting white solid (1.6 g) was used in the subsequent step without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[CH2:15]([NH:18][C:19]([NH2:21])=[S:20])[CH2:16][CH3:17].C(O)C>C(OC(C)C)(C)C>[BrH:1].[CH2:15]([NH:18][C:19]1[S:20][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=2)[N:21]=1)[CH2:16][CH3:17]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: CCCNC(N)=S
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: Br
Product: CCCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A mixture of 2-bromo-1-[4-(trifluoromethyl)phenyl]ethanone (5.34 g), N-propylthiourea (2.60 g) and ethanol (50 mL) was stirred for 1 hr while heating under reflux. The reaction mixture was cooled and diluted with isopropyl ether. The precipitated solid was collected by filtration, washed with isopropyl ether and dried to give the title compound (5.11 g, yield 70%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:13]([CH2:19]Cl)[CH2:14][Si:15]([Cl:18])([Cl:17])[Cl:16]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:19]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:13][CH2:14][Si:15]([Cl:18])([Cl:17])[Cl:16]
Reactant: Fc1ccccc1
Reactant: ClCC(Cl)C[Si](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Fc1ccccc1C(CC[Si](Cl)(Cl)Cl)c1ccccc1F
Reaction time: 1 h
Yield: 40.7 %

Procedure:
In the same apparatus and procedures as EXAMPLE 2 above, 18.8 ml (200 mmol) of fluorobenzene and 0.31 g (2.3 mmol) of aluminum chloride were alkylated with 5.61 g (22.8 mmol) of (2,3-dichloropropyl)trichlorosilane for 10 min at 70° C. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane (50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and fluorobenzene were distilled, the reaction products were vacuum distilled to give 3.39 g of [3,3-bis(fluorophenyl)propyl]trichlorosilane (bp; 121-122° C./0.5 torr, yield; 41%) as a mixutre of isomers.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([CH3:47])([CH3:46])[CH:44]=O)[CH2:39][CH2:38]1.N1CCCC1.C(Cl)Cl>C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:47][C:43]([N:40]4[CH2:41][CH2:42][CH:37]([OH:36])[CH2:38][CH2:39]4)([CH3:44])[CH3:46])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Reactant: CC(C)(C=O)N1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.5 %

Procedure:
A mixture of (R)-3-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3-oxopropanenitrile (150 mg, 0.31 mmol), 2-(4-hydroxy-1-piperidyl)-2-methyl-propanal (167 mg, 0.98 mmol), pyrrolidine (0.03 mL, 0.31 mmol) and DCM (10 mL) was stirred at room temp for 2 days and then diluted with aq. NaHCO3 (40 mL) and extracted with DCM. The organic was dried (MgSO4), filtered and concentrated to an oil. The crude material was purified at Isolera (25 g column: 30% iPrOH/DCM) to obtain the product which was isolated by lyophilization to provide 61 mg (32% yield) of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-hydroxypiperidin-1-yl)-4-methylpent-2-enenitrile as a powder. MS (pos. ion) m/z: 625 (M+1).
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH3:11])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[N:20]2[CH2:23][C:22](=[CH:24][S:25]([CH2:28][C:29]3[CH:30]=[C:31]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:32]=[CH:33][CH:34]=3)(=[O:27])=[O:26])[CH2:21]2)=[CH:15][CH:14]=1>C(OCC)(=O)C.O>[CH3:11][O:10][C:8]([N:38]1[CH2:39][CH2:40][N:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][S:25]([CH:24]=[C:22]3[CH2:21][N:20]([CH:19]([C:16]4[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=4)[C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=4)[CH2:23]3)(=[O:26])=[O:27])[CH:30]=2)[CH2:36][CH2:37]1)=[O:9]
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Reactant: COC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 6 h
Yield: 103.2 %

Procedure:
2 cm3 of pyridine and then 10.4 mg of methyl chloroformate are successively added, at a temperature close to 20° C., to 54.25 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 6 hours at a temperature close to 20° C., the reaction medium is concentrated to dryness under reduced pressure (5 kPa) at a temperature close to 30° C. The residue obtained is taken up in 5 cm3 of ethyl acetate and 5 cm3 of water. After separating after settling out, the organic phase is washed with 2 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 62 mg of 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid methyl ester are thus obtained in the form of a beige lacquer [1H NMR spectrum (400 MHz, CDCl3), δ in ppm): 2.75 (s, 3H), 3.15 (broad t, J=5.5 Hz, 4H), 3.62 (mt, 4H), 3.74 (s, 3H), 3.80 (mt, 2H), 4.32 (mt, 2H), 4.49 (s, 1H), 6.81 (d, J=8 Hz, 1H), 6.90 (dd, J=8 and 2.5 Hz, 1H), 6.99 (broad s, 1H), from 7.20 to 7.40 (mt, 9H)].
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.ClC1C=[C:27]([C:31]2[C:35](COC3C=CC(C(O)=O)=CN=3)=C(C)O[N:32]=2)C=CC=1.C(N)(C)C>>[CH:31]([NH:32][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:35])[CH3:27]
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Solvent: CC(C)N
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 73 %

Procedure:
As described for example 98b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (19 mg, 0.06 mmol) was converted, instead of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (16 mg, 73%) which was obtained as a white solid. MS: m/e=354.3 [M+H]+.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[C:19]([NH2:20])=[CH:18][C:17]([C:21]2[C:22]([CH3:27])=[N:23][O:24][C:25]=2[CH3:26])=[CH:16][C:15]=1[C:28]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[OH:29]>C1COCC1.O.C(OCC)(=O)C>[CH3:27][C:22]1[C:21]([C:17]2[CH:16]=[C:15]([C:28]([OH:29])([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:14]3[NH:13][C:6](=[O:7])[NH:20][C:19]=3[CH:18]=2)=[C:25]([CH3:26])[O:24][N:23]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1noc(C)c1-c1cc(N)c(N)c(C(O)(c2ccccn2)c2ccccn2)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccccn2)c2ccccn2)c2[nH]c(=O)[nH]c2c1
Reaction time: 72 h

Procedure:
CDI (1.1 g, 6 mmol) was added to a solution of (2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)phenyl)di(pyridin-2-yl)methanol (1.43 g, 3.7 mmol) in THF (10 mL) and the reaction mixture was stirred for 3 days. The reaction mixture was diluted with 100 mL water and 100 mL ethyl acetate and sonicated and filtered to yield the desired product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Br:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: OB(O)c1ccc(F)cc1Br
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4Br)nccc3c2)cc1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.053 g, 0.119 mmol) was added (2-bromo-4-fluorophenyl)boronic acid (Combi-Blocks, San Diego, Calif.) (0.042 g, 0.190 mmol), potassium carbonate (0.082 g, 0.594 mmol), dioxane (0.594 ml) and water (0.198 ml). The mixture was purged with argon prior to the addition of Pd(PPh3)4 (0.014 g, 0.012 mmol). The vessel was sealed and irradiated at 100° C. for 30 mins affording fairly clean conversion to desired product. The organic phase was decanted, the aqueous rinsed with EtOAc and the EtOAc decanted. The combined organics were dried under reduced pressure and purified with a 25 g HP silicycle column ramping EtOAc in heptane (0-45%, then isocratic at 45%) to provide product as an off-white foam 1-(2-bromo-4-fluorophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate KKK) (54 mg, 0.092 mmol, 78% yield) with minor impurities according to LC/MS and NMR (˜20% impurity). m/z (ESI) 582.2/584.2 (M+H)+.