Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C@H:17]([CH2:18][F:19])[CH2:16][O:15][C:14]3=[O:20])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:21][N:22](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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:19][CH2:18][C@@H:17]1[CH2:16][O:15][C:14](=[O:20])[N:13]1[C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C1OC[C@@H](CF)N1c1nc(-c2ccc(Br)cc2)cs1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2csc(N3C(=O)OC[C@H]3CF)n2)cc1
Temperature: 120 °C
Yield: 81 %

Procedure:
(4S)-3-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-4-(fluoromethyl)-1,3-oxazolidin-2-one (0.21 g, 0.59 mmol), prepared in Example 73, and zinc cyanide (41 mg, 0.35 mmol) were dissolved in 8 mL of dimethylformamide. The mixture was purged with nitrogen for 15 min, tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.029 mmol) was added and the mixture was heated to 120° C. for 2 h. The mixture was cooled and diluted with ethyl acetate, and washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (100% CH2Cl2) afforded the title compound (146 mg, 81%) as a white solid. mp 195-196° C. HRMS: calcd for C14H10FN3O2S+H+, 304.05505; found (ESI, [M+H]+), 304.0555. Analytical HPLC: retention time 8.8 min, 210-370 nm the Xterra® RP18 column, 3.5%, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>C(C(C)=O)C>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(COc2ccc(C=O)cc2)cc1
Yield: 52.8 %

Procedure:
18.3 g of p-hydroxybenzaldehyde is dissolved in 200 ml of methyl ethyl ketone, and then 22.8 g of potassium carbonate and 23.2 g of α-chloro-p-xylene are added thereto. The resulting mixture is refluxed for 10 hours in a stream of nitrogen. Insoluble substances produced are removed by filtration, and then the solvent is distilled away. The resulting residue is distilled under reduced pressure to obtain 17.9 g of 4-(4-methylbenzyloxy)benzaldehyde in the form of white crystal.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22]([OH:24])=O.C(Cl)(=O)C([Cl:28])=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22]([Cl:28])=[O:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1ccc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc1
Solvent: C1CCOC1
Product: CSc1ccc(/C=C2/C(C)=C(CC(=O)Cl)c3cc(F)ccc32)cc1

Procedure:
(Z)-5-fluoro-2-methyl-1-(4-methythiobenzylidene)-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 35 ml) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]2[CH:6]([C:16]3[C:17]([S:23][CH3:24])=[N:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[Cl:27][C:28]1[CH:33]=[C:32](Cl)[N:31]=[CH:30][N:29]=1>>[Cl:27][C:28]1[N:29]=[CH:30][N:31]=[C:32]([N:20]2[CH:21]=[C:16]([CH:6]3[C:7]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=4[CH:9]=[CH:10][C:4]4[CH:3]=[C:2]([CH3:1])[CH:26]=[CH:25][C:5]3=4)[C:17]([S:23][CH3:24])=[N:18][C:19]2=[O:22])[CH:33]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CSc1nc(=O)[nH]cc1C1c2ccc(C)cc2C=Cc2cc(C)ccc21
Product: CSc1nc(=O)n(-c2cc(Cl)ncn2)cc1C1c2ccc(C)cc2C=Cc2cc(C)ccc21

Procedure:
The subtitle compound was prepared from the product of step (ii) (0.33 g) and 4,6-dichloropyrimidine (0.149 g) by the method of example 16 step (i). Purification was by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.23 g. 1H NMR: δ (DMSO) 8.98(d,1H), 8.24(d,1H), 7.61(d,1H), 7.53(d,2H), 7.24(d,2H), 7.23(s,2H), 6.95(s,2H), 5.41(s,1H), 2.42(s,3H), 2.30(s,6H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[CH3:44])[C:38](O)=[O:39].Cl.CN(C)CCCN=C=NCC>CC#N>[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[CH3:44])[C:38]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])=[O:39]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1ccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1Cl
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-chloro-4-methyl-benzoic acid (0.4 g, 2.4 mmol) were added. To the reaction mixture, was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, and the residue was stirred in H2O (50 mL). A suspension formed and after filtration the solid was reslurried in acetone (20 mL). The suspension was filtered to afford 3-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-methyl-benzamide as a white solid (0.75 g, 79%): mp, 249-251° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.8 min. (97%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.39 (s, 3H), 2.53-2.64 (m, 2H), 2.85-2.96 (m, 1H), 4.94 (d, J=5.8 Hz, 2H), 5.15-5.20 (dd, J=5, 12 Hz, 1H), 7.47-7.97 (m, 6H), 7.82-7.89 (m, 3H), 9.22 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 19.55, 21.97, 30.92, 38.36, 48.86, 121.89, 126.07, 127.15, 127.60, 131.22, 131.52, 133.11, 133.33, 134.80, 139.06, 139.10, 165.13, 166.94, 167.50, 169.81, 172.74. Anal Calcd for C22H18ClN3O5: C, 60.08; H, 4.12; N, 9.55; Cl, 8.06. Found: C, 59.69; H, 4.15; N, 9.60; Cl, 8.08.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19]1[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[C:21](O)[C:20]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH3:17]>N1C=CC=CC=1>[CH2:16]([O:18][C:19]1[CH:24]=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[C:21]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C:20]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc(O)c(-c2ccc(F)cc2)c(OCC)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(OCC)c(-c2ccc(F)cc2)c(OS(=O)(=O)C(F)(F)F)c1

Procedure:
Trifluoromethanesulfonic anhydride (8.66 mL) was added at 0° C. to a mixture of ethyl 2-ethoxy-4′-fluoro-6-hydroxybiphenyl-4-carboxylate (13.0 g) and pyridine (80 mL), and the resultant mixture was stirred at the same temperature as above for 20 minutes. The reaction mixture was passed through a short silica gel (NH) column, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (15.6 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([NH:18]C(=O)OC(C)(C)C)[CH:12]=[CH:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([NH2:18])[CH:12]=[CH:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(CN3CCCCC3)ccc2c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2cc(CN3CCCCC3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
The tert-butyl 6-(1-piperidinylmethyl)-2-naphtylcarbamate (710 mg, 2.09 mmol) obtained in Reference Example 3 was dissolved in trifluoroacetic acid (10 ml), and the solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, ethyl acetate (50 ml) was added to the residue, the mixture was washed with an aqueous potassium carbonate solution (50 ml) and an aqueous saturated sodium chloride solution (50 ml), and concentrated under reduced pressure to obtain the titled compound (420 mg, 1.75 mmol) as pale orange crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:19]([Cl:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[Cl:21])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:24]=1[C:25]([N:27]=[C:28]=[O:29])=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[C:14]([Cl:21])=[CH:15][C:16]([NH:17][C:28]([NH:27][C:25](=[O:26])[C:24]3[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:23]=3[F:22])=[O:29])=[CH:18][C:19]=2[Cl:20])=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(Oc2ccc(Cl)c3ccccc23)c(Cl)c1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 53.7 %

Procedure:
A solution containing 2.25 g (6.6 m moles) of 4-(4-chloro-1-naphthoxy)-3,5-dichloroaniline in 45 ml of toluene was placed under a nitrogen atmosphere and heated to 70° C. via an addition funnel was then added 1.82 g (9.9 m moles) of 2,6-difluorobenzoylisocyanate in 5 ml of toluene. The resulting mixture was then stirred at 70° C. for 45 min. and then cooled to room temperature. It was then cooled below 0° C. and filtered. The collected white white solid was dried under vacuum to afford 1.86 g of the desired product, m.p. 237°-239° C. NMR: (DMSO-d6): δ6.47 (d, J=8 Hz, 1H)- 7.0-8.6 (m, 10H), 10.40 (broad s, 1H), 11.60 (broad s, 1H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40].C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:45]5[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 60 °C
Yield: 34.5 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) in DMF (3 mL) was added 1-methane sulfonyl piperazine (181 mg, 1.104 mmol) followed by diisopropyl ethylamine (0.192 mL, 1.104 mmol) and tetrabutyl ammonium iodide (136.2 mg, 0.368 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-(methylsulfonyl)piperazin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea (85 mg, 35%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.55-7.20 (m, 5H), 6.50 (s, 1H), 4.25 (m, 1H), 3.95 (s, 3H), 3.15 (m, 4H), 2.55 (m, 6H), 2.00 (m, 2H), 1.30 (s, 9H); LC-MS (ESI) m/z 670 (M+H)+.
Reaction SMILES: CN([CH:4]=[C:5]1[C:13](=O)[C:12]2[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]=2[CH2:7][CH2:6]1)C.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[CH:32][C:33]([O:40][C:41]([F:44])([F:43])[F:42])=[C:34]([NH:36][C:37]([NH2:39])=[NH:38])[CH:35]=2)[CH2:26][CH2:25]1.O>CN(C=O)C>[OH:17][CH2:16][CH2:15][N:11]1[C:12]2[C:13]3[N:39]=[C:37]([NH:36][C:34]4[CH:35]=[C:30]([N:27]5[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]5)[CH:31]=[CH:32][C:33]=4[O:40][C:41]([F:44])([F:42])[F:43])[N:38]=[CH:4][C:5]=3[CH2:6][CH2:7][C:8]=2[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]1
Reactant: CCOC(=O)c1nn(CCO)c2c1CCC(=CN(C)C)C2=O
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(NC(=N)N)c2)CC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(CCO)c2c1CCc1cnc(Nc3cc(N4CCN(C)CC4)ccc3OC(F)(F)F)nc1-2
Temperature: 110 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a solution of 2.66 g (8.34 mmol) of ethyl 6-[(dimethylamino)methylene]-7-oxo-1-(2-hydroxy-ethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate in 15 mL of DMF, 2.64 g (8.34 mmol) of N-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenyl]-guanidine was added. The mixture was stirred for 4 h at 110° C. After cooling the mixture was poured into water (100 mL) and stirred for 30 minutes. The precipitate was filtered, washed with water and dried to yield 2.86 g of title compound (61%).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[C:7]1([C:13]2[CH:14]=[C:15]3[N:20]([CH:21]=2)[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.C1COCC1>[O:3]=[C:2]([C:21]1[N:20]2[C:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:14][C:13]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:1]([Cl:6])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc(-c2cc3n(c2)CCCC3)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
Oxalyl chloride (17.2 mL, 0.19 mol) was added to an ice-cold solution of 2-phenyl-5,6,7,8-tetrahydro-indolizine (32 g, 0.16 mol) in a mixture of toluene (20 mL) and THF (30 mL). The reaction mixture was allowed to warm to room temperature and stirred for 30 min. then concentrated under vacuum. The residue was triturated with petrol (5×300 mL) to afford oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (42 g, 89%) as a dark yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.CC(C)([O-])C.[K+].CN(C=O)C>C(OCC)(=O)C>[N:31]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)(=[O:23])=[O:24])=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: c1c[nH]cn1
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3F)nccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3-n3ccnc3)nccc2c1
Temperature: 150 °C

Procedure:
A microwave vial was charged with 1-(2-fluoro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.090 g, 0.198 mmol), imidazole (0.054 g, 0.794 mmol), and potassium tert-butoxide (0.111 g, 0.992 mmol). DMF (0.992 ml) was added and the reaction was heated in a microwave reactor at 150° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, then acidified with concentrated HCl solution and extracted twice with ethyl acetate. The aqueous layer was passed through an SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The ammonia/methanol filtrate was combined with the previously isolated organic layers. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 10% MeOH:DCM) to afford 1-(2-(1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.90 (br. s., 1H), 8.66 (d, J=5.7 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H), 8.13 (d, J=5.4 Hz, 1H), 8.08 (s, 1H), 8.03 (dd, J=1.2, 8.1 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.79-7.73 (m, 1H), 7.70-7.63 (m, 1H), 7.48 (t, J=1.0 Hz, 1H), 7.26 (d, J=4.6 Hz, 1H), 6.89-6.81 (m, 2H), 6.62 (t, J=1.1 Hz, 1H). m/z (ESI) 502.2 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=3)[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)C)(C)(C)C.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[F:29][C:27]1[CH:28]=[C:23]([C:21]2[CH:20]=[CH:19][C:18]([O:30][CH3:31])=[C:17]([CH:22]=2)[CH2:16][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([NH:7][CH3:6])[CH2:14][CH2:13]2)[C:39]([C:38]2[S:37][C:36]3[C:42]([F:47])=[CH:43][CH:44]=[C:45]([F:46])[C:35]=3[C:34]=2[Cl:33])=[O:40])[CH:24]=[N:25][CH:26]=1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2cncc(F)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CNC1CCC(N(Cc2cc(-c3cncc(F)c3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1

Procedure:
Following the synthetic protocol described in Method D′; 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carboxylic acid [5-(5-fluoro-pyridin-3-yl)-2-methoxy-benzyl]-(4-methylamino-cyclohexyl)-amide is prepared starting from {4-[5-(5-Fluoro-pyridin-3-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester and 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carbonyl chloride. The desired product is isolated in 46%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([S:33](Cl)(=[O:35])=[O:34])[CH:31]=2)[C:26]([Cl:37])=[CH:25][N:24]=1>C(Cl)Cl>[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([S:33]([NH:1][C@@H:2]3[CH2:3][CH2:4][C@H:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)(=[O:35])=[O:34])[CH:31]=2)[C:26]([Cl:37])=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H]1CC[C@@H](NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of t-butyl cis-4-aminocyclohexanecarboxylate (282 mg, 1.20 mmol), NEt3 (0.33 mL, 2.37 mmol) and 1,4-dichloro-7-isoquinolinesulphonyl chloride (296 mg, 1.00 mmol) in CH2Cl2 (10 mL) was stirred at 0° C. for 1 h. The mixture was diluted with CH2Cl2 (150 mL), was washed with dilute HCl (30 mL, 1 M), water, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (100:0 to 75:25) to give t-butyl cis-4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}cyclohexanecarboxylate (360 mg, 0.78 mmol) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:6][C@H:5]1B(O)O.[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[C:12]=1[C:13]#[N:14]>>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:5]2[CH2:6][C@H:4]2[CH2:3][O:2][CH3:1])[C:12]=1[C:13]#[N:14]
Reactant: COC[C@@H]1C[C@H]1B(O)O
Reactant: N#Cc1c(N)cccc1Br
Product: COC[C@@H]1C[C@H]1c1cccc(N)c1C#N
Yield: 64 %

Procedure:
Prepared as in Example 270a from (±)-trans-2-(methoxymethyl)cyclopropylboronic acid (example 271b) and 2-amino-6-bromobenzonitrile in 64% yield as a yellowish brown waxy solid. 1H NMR (400 MHz, DMSO-d6) δ 0.932 (m, 2H), 1.341 (m, 1H), 1.879 (m, 1H), 2.324 (s, 3H), 3.351 (d, J=6 Hz, 2H), 5.896 (br. s, 2H), 6.148 (d, J=8 Hz, 1H), 6.550 (d, J=8 Hz, 1H), 7.130 (t, J=8 Hz, 1H).
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.[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22]O)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:22][CH:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN1CCC(CO)CC1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Product: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-7-hydroxy-6-methoxy-quinazoline and (1-Methyl-piperidin-4-yl)-methanol. LC/ESI-MS: m/z=322 [M+H].
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O>CN(C)C=O>[F:31][C:30]([F:33])([F:32])[CH2:29][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccc(C(F)(F)F)cc1)CC(F)(F)F
Yield: 44 %

Procedure:
Using 1.0 g of (4-(trifluoromethyl)benzyl)malononitrile, 8 ml of N,N-dimethylformamide, 0.73 g of cesium carbonate, and 1.0 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 0.58 g of 2-(2,2,2-trifluoroethyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (72)).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].FC(F)(F)C(O)=O.[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:23][S:24][C:25]1[N:30]=[C:29]([NH:31][S:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH:28]=[C:27]([O:41][CH3:42])[N:26]=1>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3]([N:38]1[CH2:39][CH2:40][N:35]([S:32]([NH:31][C:29]2[CH:28]=[C:27]([O:41][CH3:42])[N:26]=[C:25]([S:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=3[F:15])[N:30]=2)(=[O:33])=[O:34])[CH2:36][CH2:37]1)(=[O:5])=[O:4]
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CCN(S(=O)(=O)N(C)C)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared by adding dimethyl sulfamoyl chloride to a solution of N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, trifluoroacetate salt (the product from example 36) (0.25 g) in DCM (5 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) then titurated with Toluene, DCM followed by Et2O to give the title compound as a white solid. Yield: 0.11 g