Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16](F)=[C:15]([Cl:20])[CH:14]=3)=[CH:11][C:10]([C:21]([O:23]CC)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Br)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2cccc(Cl)c2)n(-c2cccc(Br)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 51A in analogy to the synthesis of the compound of Example 71A. 1.74 g of the title compound are obtained.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[C:11](O)[N:10]3[N:14]=[CH:15][CH:16]=[C:9]3[N:8]=2)[CH2:3][CH2:2]1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:11]1[N:10]2[N:14]=[CH:15][CH:16]=[C:9]2[N:8]=[C:7]([CH:4]2[CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)[CH:12]=1
Reactant: Oc1cc(C2CCSCC2)nc2ccnn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1cc(C2CCSCC2)nc2ccnn12
Temperature: 50 °C

Procedure:
To a mixture of 5-(tetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-ol (Int-1b, 1.50 g, 6.38 mmol) and dimethylaniline (2.0 mL, 15 mml) was added phosphoryl trichloride (20 mL). The mixture was heated at 50° C. for 5 h and concentrated. The residue was diluted with methylene chloride (50 mL) and quenched with saturated NaHCO3 (50 mL). The mixture was separated and the aqueous layer was extracted with methylene chloride (50 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by Biotage (CH2Cl2/EtOAc, 20:1 to 4:1). LC/MS RT=1.92 Min (5 min method). Mass calculated for, M+H 254.04, observed 254.04.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]#[N:13].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].[H-].[Na+]>O1CCCC1>[F:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:12]#[N:13])=[C:2]([NH:1][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])[S:6][C:5]=2[CH:7]=1
Reactant: N#Cc1c(N)sc2cc(F)ccc12
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(Nc2ccccc2[N+](=O)[O-])sc2cc(F)ccc12
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
To a solution of 2-amino-6-fluorobenzo[b]thiophene-3-carbonitrile (15 g), tetrahydrofuran (140 ml) and 2-fluoronitrobenzene (11.3 g) was added portionwise 60% sodium hydride (3.5 g) under ice-cooling and the mixture was stood still at 5° C. for 30 minutes. The precipitated crystals were filtered by suction, washed with isopropyl ether (120 ml) and dried to give 6-fluoro-2-(2-nitroanilino)benzo[b]thiophene-3-carbonitrile (8.0 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH:14]([C:19]2[CH:20]=[CH:21][C:22]3[N:23]([C:25]([C:28]4[CH:37]=[CH:36][C:35]5[C:30](=[CH:31][C:32]([C:38]([OH:40])=O)=[CH:33][CH:34]=5)[N:29]=4)=[N:26][N:27]=3)[CH:24]=2)[C:15]([F:18])([F:17])[F:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=[N:56][C:51]2[CH:52]=CC=N[C:50]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N)C.CCN(C(C)C)C(C)C>CN(C=O)C>[F:18][C:15]([F:17])([F:16])[CH:14]([N:11]1[CH2:12][CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10]1)[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][C:32]([C:38](=[O:40])[NH:56][CH:51]([CH3:52])[CH3:50])=[CH:33][CH:34]=4)[N:29]=3)=[N:26][N:27]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5ccc(C(=O)O)cc5n4)n3c2)C(F)(F)F)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc2ccc(-c3nnc4ccc(C(N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.5 %

Procedure:
To a solution of 2-(6-(1-((S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline-7-carboxylic acid (0.075 g, 0.135 mmol), HATU (0.062 g, 0.16 mmol) and propan-2-amine (0.057 ml, 0.67 mmol) in DMF (1 mL) was added DIEA (0.047 mL, 0.27 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was purified directly by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-90% CH3CN/water gradient; 30 CV)) to give tert-butyl (3S)-1-(2,2,2-trifluoro-1-(3-(7-(isopropylcarbamoyl)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.023 g, 28.6%) as a solid.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1CCCCC1[O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1>C(O)C>[F:48][C:46]([F:47])([F:49])[O:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][O:37][CH:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:29]=[CH:30][C:25]([OH:24])=[CH:26][CH:27]=3)[CH2:32][CH2:33]2)=[CH:44][CH:43]=1
Reactant: FC(F)(F)Oc1ccc(COC2CCN(c3ccc(OC4CCCCO4)cc3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: Oc1ccc(N2CCC(OCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 75 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
Pyridinium p-toluenesulfonate (81 mg) was added to an ethanol solution (3 ml) of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(4-trifluoromethoxybenzyloxy)piperidine (507 mg) and the mixture was stirred at 70 to 80° C. for 24 hours. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the residue, and the result was separated into layers. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. After being concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to afford the title compound as a pale purple solid (305 mg).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[S:13][C:12]=2[CH:21]=1)=[O:7])C>C(O)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]2[S:13][C:12]3[CH:21]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[CH:10][C:11]=3[C:15]=2[CH:16]=1
Reactant: CCOC(=O)c1ccc2c(c1)sc1ccc(C)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2sc3cc(C(=O)O)ccc3c2c1

Procedure:
To a solution of 0.73 g. of potassium hydroxide in 50 ml. of ethanol was added 3.5 g. of 8-methyldibenzothiophene-3-carboxylic acid ethyl ester. The solution was refluxed for 3 hours. The solvent was removed in vacuo on the steam bath, and the crude potassium salt was dissolved in 50 ml. of water. The solution was acidified with dilute hydrochloric acid and the product was filtered off and dried. The yield of 8-methyldibenzothiophene-3-carboxylic acid was 2 g., m.p. 290°-291°.
Reaction SMILES: CS[C:3]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH3:13])=[N:8]1)=[N:4][CH2:5][CH3:6].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH2:24])(=[O:23])=[O:22]>C(#N)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:3]([NH:4][CH2:5][CH3:6])[N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH3:13])=[N:8]1)(=[O:23])=[O:22]
Reactant: CCN=C(SC)N1CCC(CC)=N1
Reactant: NS(=O)(=O)c1ccccc1Cl
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1ccccc1Cl)N1CCC(CC)=N1
Yield: 0.6 %

Procedure:
1.42 g (1 mol equiv.) 3,N-Diethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 1.43 g (1.05 mol equiv.) 2-chlorobenzenesulfonamide were added to 20 mL acetonitrile. The reaction mixture was refluxed overnight and volatiles were removed in vacuo. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue obtained after purification by flash chromatography on silica gel (Et2O) was triturated with diisopropyl ether to afford 2.08 g (81%) 2-chloro-N-[ethylamino-(3-ethyl-4,5-dihydro-pyrazol-1-yl)-methylene]-benzenesulfonamide. 1HNMR (400 MHz, CDCl3) δ 1.15 (t, J=7.3 Hz, 3H), 1.17 (t, J=7.3 Hz, 3H), 2.38 (q, J=7.3 Hz, 2H), 2.80 (t, J=9.8 Hz, 2H), 3.44-3.53 (m, 2H), 4.11 (t, J=9.8 Hz, 2H), 6.73 (br.s., 1H), 7.33 (dt, J=7.6, 2.0 Hz, 1H), 7.38 (dt, J=7.6, 2.0 Hz, 1H), 7.46 (dd, J=7.6, 2.0 Hz, 1H), 8.17 (dd, J=7.6, 2.0 Hz, 1H).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH:31]([CH3:33])[CH3:32])[CH:23]=2)=[O:21])[CH2:11]1)=[O:7])(C)(C)C.[ClH:34].O1[CH2:40][CH2:39][O:38][CH2:37]C1>>[NH2:24][C:25]1[C:26]([Cl:34])=[CH:27][C:40]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH:31]([CH3:33])[CH3:32])[CH:23]=3)=[O:21])[CH2:11]2)=[O:7])=[C:39]([O:38][CH3:37])[CH:30]=1
Reactant: Cl
Reactant: CC(C)n1cc(C(=O)NCCCCN2CC[C@H](CNC(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: C1COCCO1
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCNC(=O)c2cn(C(C)C)c3ccccc23)C1
Reaction time: 1 h

Procedure:
N-(4-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-butyl)-1-isopropyl-1 H-indole-3-carboxamide (1.34 g) was dissolved in 4N hydrochloric acid-dioxane solution (30 ml) and the mixture was stood at room temperature for 60 min. The reaction mixture was concentrated under reduced pressure. Dimethylformamide (30 ml) was added to the residue and the mixture was neutralized with triethylamine (0.81 ml). 4-Amino-5-chloro-2-methoxybenzoic acid (0.59 g) and 1-hydroxybenzotriazole (0.44 g) were added thereto, and the mixture was stirred at 0C for 15 min. Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.62 g) was added, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.62 g of N-(4-((3R)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)butyl)-1-isopropyl-1 H-indole-3-carboxamide.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:24]([NH2:26])=[O:25])[CH:20]=[C:19]1[CH:27]1[CH2:29][CH2:28]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(ON[C@H]1CN[C@@H](C(N)=O)C=C1C)C=C>>[CH2:1]([O:4][NH:5][CH:18]1[CH2:23][NH:22][C@@H:21]([C:24]([NH2:26])=[O:25])[CH:20]=[C:19]1[CH:27]1[CH2:28][CH2:29]1)[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN[C@H](C(N)=O)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON[C@H]1CN[C@@H](C(N)=O)C=C1C
Product: C=CCONC1CN[C@@H](C(N)=O)C=C1C1CC1

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-4-cyclopropyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 269, 0.95 g, 2.25 mmol) following the procedure described for Intermediate 22. The desired product was obtained as a light yellow oil (0.307 g, 57%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[CH:12]=C(C=CC=3)C#N)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].BrC1[N:24]=[C:25]([CH3:28])[S:26]C=1>>[CH3:1][N:2]1[C:7]2=[CH:8][NH:9][C:10]([C:11]3[N:24]=[C:25]([CH3:28])[S:26][CH:12]=3)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Reactant: Cc1nc(Br)cs1
Product: Cc1nc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)cs1

Procedure:
The title compound was prepared by an analogous method to 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Intermediate Ga) by replacing 3-bromobenzonitrile (step 3) with 4-bromo-2-methylthiazole.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:7][Si](C([Si](C)(C)C)C(N)=O)(C)C.ClC(OCC(C)C)=O.C[Si]([O:31][C:32](=[O:36])[C@@H:33]([CH3:35])[NH2:34])(C)C>C(Cl)Cl.CN(C)C=O>[CH2:7]([CH2:35][C@H:33]([NH2:34])[C:32]([OH:31])=[O:36])[CH2:3][C@@H:2]([NH2:1])[C:4]([OH:6])=[O:5].[NH2:1][CH2:2][C:4]([OH:6])=[O:5]
Reactant: C[C@@H](N)C(=O)O[Si](C)(C)C
Reactant: C[C@@H](N)C(=O)O
Reactant: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NCC(=O)O
Product: N[C@H](CCC[C@H](N)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of D-alanine (2.89 g) in a mixture of methylene chloride (30 ml) and dimethylformamide (12 ml) was added bis(trimethylsilyl)acetamide (30 ml) and the mixture was stirred for 15 hours at room temperature to give a clear solution. To a solution of the mixed anhydride of Z-(L)-Boc-(D)-mesoDAP-(D)-NHNHBoc (1) (13.45 g) in methylene chloride (140 ml), prepared by adding N-methylmorphorine (3.03 g) and isobutyl chloroformate (4.10 g) at -15° and stirring the mixture for 40 minutes at the same temperature, was added in one portion the above solution of D-alanine trimethylsilyl ester at -40° C. Then the reaction mixture was allowed to warm up to 0° C. and stirred for 2 hours. The reaction mixture was evaporated and the residue was dissolved in water, acidified with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to give a white powder (12.25 g) of Z-(L)-Boc-(D)-mesoDAP-(D)-NHNHBoc-(L)-D-AlaOH (2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][CH2:18][NH2:19])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][CH2:18][NH:19][C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1ccccc1F
Reactant: NCCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Cc1ccccc1F)NCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluorophenylacetic acid (17 mg, 0.11 mmole) and 4-chlorophenethylamine (15 mg, 0.1 mmole) were dissolved in 5 ml dichloromethane. To this was added catalytic 4-dimethylaminopyridine (DMAP) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 33 mg, 0.11 mmole). The resulting solution was stirred at room temperature overnight. The reaction was then worked up by washing sequentially with 1N HCl, saturated sodium bicarbonate, and saturated sodium chloride. The compound was then purified by flash chromatography on silica gel (40:1 CHCl3/MeOH). 1H NMR (300 Mhz, CDCl3) δ 7.31-6.92 (m, 8H), 5.48 (bs, 1H), 3.51 (s, 2H), 3.42 (m, 2H), 2.70 (m, 2H).
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5](C(F)(F)F)=[CH:4][CH:3]=1.IC1SC2C=C[C:40]([O:43]C)=CC=2N=1>>[CH3:40][O:43][C:4]1[CH:3]=[CH:2][C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Reactant: COc1ccc2sc(I)nc2c1
Product: COc1ccc2sc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)nc2c1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-iodo-5-methoxy-1,3-benzothiazole and conducting the Suzuki coupling at 55° C. for 4 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=8.75 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.06 (s, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.21 (dd, J=2.4, 8.8 Hz, 1H), 4.67 (m, 1H), 3.94 (s, 3H), 3.59-3.62 (m, 2H), 3.25-3.27 (m, 2H), 2.34-2.39 (m, 4H). MS(ES+): m/z=407.13 [MH+]. HPLC: tR=1.12 min (polar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[C:34]([CH3:41])=[C:35]([CH:39]=O)[NH:36][C:37]=2[CH3:38])[CH2:28][CH2:27]1)(=[O:25])[CH3:24]>C(O)C.N1CCCCC1>[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[C:34]([CH3:41])=[C:35](/[CH:39]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:36][C:37]=2[CH3:38])[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCN(Cc2c(C)[nH]c(C=O)c2C)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(=O)N1CCN(Cc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (357 mg, 1 mmol) was condensed with 4-(4-acetyl-piperazin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (263 mg, 1 mmol) in ethanol (3 mL) and piperidine (3 drops) at 95-100° C. for 2 hours to give the titled compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[C:2]#[C:3]C.C([Li])CCC.[CH3:21][O:22][C:23]1[C:32]([CH:33]=[O:34])=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:39])([CH3:38])[O:28]2.CCOCC>C1COCC1.O=[Mn]=O>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([O:5][CH2:1][C:2]#[C:3][C:33]([C:32]2[C:23]([O:22][CH3:21])=[C:24]3[C:29](=[CH:30][C:31]=2[N+:35]([O-:37])=[O:36])[O:28][C:27]([CH3:39])([CH3:38])[CH:26]=[CH:25]3)=[O:34])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1c2c(cc([N+](=O)[O-])c1C=O)OC(C)(C)C=C2
Reactant: CC#CCOc1ccc(OC)c(OC)c1
Agent: O=[Mn]=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(OCC#CC(=O)c2c([N+](=O)[O-])cc3c(c2OC)C=CC(C)(C)O3)cc1OC
Reaction time: 0.5 h

Procedure:
To a solution of 4-but-2-ynyloxy-1,2-dimethoxy-benzene (1.66 g, 8.66 mmol) in THF (75 mL) is added n-butyl lithium (5.54 ml of 1.6 M solution in THF, 8.86 mmol) at −78° C. After 30 min., 5-methoxy-2,2-dimethyl-7-nitro-2H-chromene-6-carbaldehyde (2.17 g, 8.25 mmol) in THF (50 mL) is added. The reaction is stirred for 1 h and then quenched with sat. NH4Cl and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over Na2SO4. The resulting crude material is dissolved in dichloromethane (20 mL) and MnO2 (5.3 g, 61 mmol) is added. After the reaction is stirred overnight at room temperature, ether is added and the suspension is filtered through a pad of celite and silica gel to afford 4-(3,4-dimethoxy-phenyoxy)-1-(5-methoxy-2,2-dimethyl-7-nitro-2H-chromen-6-yl)-but-2-yn-1-one.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:8][C:7]=1[Br:22])(=O)C.O[Li].O>C1COCC1.CO.O>[Br:22][C:7]1[CH:8]=[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: CCOc1ccc(Cc2ccc(COC(C)=O)c(Br)c2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOc1ccc(Cc2ccc(CO)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of 2-bromo-4-(4-ethoxybenzyl)benzyl acetate (0.215 g, 0.59 mmol) in 10 mL of THF/MeOH/H2O (2:3:1) was added LiOH.H2O (0.051 g, 1.21 mmol). After the reaction mixture was stirred at 25° C. for 3 hours, the volatiles were removed using a rotary evaporator. The residue was dissolved in EtOAc, washed once with brine and dried over Na2SO4. The volatiles were removed using a rotary evaporator to yield 0.175 g of the title compound, which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz): δ 7.38-7.36 (m, 2H), 7.13 (d, J=7.6 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.71 (s, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.88 (s, 2H), 1.92 (bs, 1H), 1.40 (t, J=7.2 Hz, 3H); MS ESI (m/z) 320 [M+], calc. 320.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].Cl[CH2:8][CH:9]([OH:15])[CH2:10][S:11]([OH:14])(=[O:13])=[O:12].[Na]>O1CCOCC1.O>[OH:15][CH:9]([CH2:8][NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:10][S:11]([OH:14])(=[O:13])=[O:12]
Reactant: O=S(=O)(O)CC(O)CCl
Reactant: CC(C)CCN
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CCNCC(O)CS(=O)(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a 80° C. solution of isoamylamine (2.0 g, 22.9 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was added via syringe pump (1 h addition) a solution of 3-chloro-2-hydroxy-propane sulfonic acid, sodium salt (3.04 g, 15.3 mmol) in 1,4-dioxane (9.5 mL) and water (0.5 mL). The solution was stirred overnight at 80° C. The solvent was evaporated. The product was passed through an ion exchange column (Dowex 50×8, 100 g, solvent: water). It was recrystallized in absolute EtOH and lyophilized. Yield: 27%. 1H NMR (H2O, 500 MHz) δ ppm 4.24 (m, 1H), 3.22 (m, 1H), 3.02 (m, 5H), 1.49 (m, 3H), 0.79 (d, 3H, J=6.3 Hz). 13C(H2O, 125 MHz) δ ppm 63.54, 54.89, 51.53, 46.48, 34.12, 25.46, 21.56, 21.46. ES-MS 226 (M+1).
Reaction SMILES: C(NCC)C.[C:6]([OH:10])(C)([CH3:8])[CH3:7].[Br:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15](=[O:18])[CH2:16]Br.CC(C)=O>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[C:14]([C:15](=[O:18])[CH2:16][CH2:7][C:6](=[O:10])[CH3:8])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)O
Reactant: O=C(CBr)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCNCC
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CC(=O)CCC(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.6 %

Procedure:
A round bottom flask containing zinc chloride (71.95 mmol, 2.0 eq.) was heated under vacuum until the solid melted (˜300° C.) and the molten solid was kept under vacuum for 5 min. The molten solid was then allowed to cool to room temperature resulting in solidification. The flask was then filled with nitrogen and benzene (36 mL) was added followed by diethylamine (53.97 mmol, 1.5 eq.) and tert-butanol (53.97 mmol, 1.5 eq.). This mixture was stirred until the solid zinc chloride dissolved and then 3-bromophenacylbromide (35.98 mmol, 1.0 eq.) was added followed by acetone (53.97 mmol, 1.5 eq.). The resulting solution was stirred 4 d and quenched by the addition of 0.1N HCl (100 mL) and diluted with brine solution (25 mL) and extracted with ethyl acetate (3×75 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give an orange oil that was purified by column chromatography using 5% acetone/dichloromethane to give the final product as an orange solid (18.93 mmol, 53%). HRMS: calcd for C11H11BrO2+H+, 255.00152; found (ESI, [M+H]+ Obs'd), 255.0020.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:30][C:28]([F:29])([F:31])[O:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][O:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH2:5][C:4]([OH:32])=[O:3])[CH:7]=[CH:8]3)=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cn1ccc2cc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)ccc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2cc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)ccc21

Procedure:
In analogy to the procedure described for example 1 e], {5-[5-(4-trifluoromethoxy-phenyl)-pent-4-ynyloxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as red crystals.