Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1.[CH:16]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.[H-].[Na+]>C(O)(=O)C>[CH:16]1([O:21][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OC2CCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To 30 ml of N,N-dimethylformamide, 1.00 g (6.4 mmol) of 6-chloronicotinic acid and 1.72 g (20 mmol) of cyclopentanol were dissolved, followed by adding 0.80 g (20 mmol) of 60% sodium hydride, stirring at room temperature for 1 hour and heating under refluxing for 3 hours. The reaction liquid was then poured in 100 ml of ice water and acetic acid was added to make pH 5. The crystal precipitated was filtered, washed with cold water and hexane, and dried to obtain 1.06 g (yield: 80%) of 6-cyclopentyloxynicotinic acid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:49])[N:32]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[F:48])[C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[O:40])=[CH:35][N:34]=1)([CH3:29])([CH3:28])[CH3:27].[Cl-].[NH4+]>O1CCCC1>[C:26]([O:30][C:31](=[O:49])[N:32]([C:33]1[CH:38]=[CH:37][C:36]([CH:39]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=3)[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:40])=[CH:35][N:34]=1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[F:48])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Cl)cnc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C=O)cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 5 °C
Yield: 41 %

Procedure:
To a solution of 1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (581, 0.420 g, 1.00 mmol) in tetrahydrofuran (15.0 mL) at −40° C. under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.49 mL) was added slowly. The reaction was allowed to warm to 5° C. over 70 minutes, then cooled to −40° C., followed by adding (2-fluoro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 579 in tetrahydrofuran (6.0 mL). The reaction was allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (582, 0.25 g, 41%). MS (ESI) [M+H+]+=623.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=O.[F:21][CH2:22][C:23]1([C:27]#[N:28])[CH2:26][NH:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:21][CH2:22][C:23]1([C:27]#[N:28])[CH2:26][N:25]([C:4](=[O:6])[C@H:3]([N:7]2[C:16](=[O:17])[C:15]3=[CH:18][NH:19][C:13]4[C:14]3=[C:9]([CH:10]=[CH:11][N:12]=4)[CH2:8]2)[CH:2]([CH3:20])[CH3:1])[CH2:24]1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Reactant: N#CC1(CF)CNC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)N1CC(C#N)(CF)C1)N1Cc2ccnc3[nH]cc(c23)C1=O
Yield: 31.9 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (80 mg, 0.293 mmol) under nitrogen. DMF (0.5 mL), 3-(fluoromethyl)azetidine-3-carbonitrile (93 mg, 0.439 mmol), HOBt (67.2 mg, 0.439 mmol), EDC (84 mg, 0.439 mmol) and N,N-dimethylpyridin-4-amine (53.6 mg, 0.439 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (34.5 mg, 25.3%). 1H NMR (400 MHz, DMSO-d6) δ 0.78 (dd, J=6.57, 3.79 Hz, 3 H) 0.97 (dd, J=12.88, 6.32 Hz, 3 H) 2.30-2.41 (m, 1 H) 3.99 (dd, J=9.98, 4.42 Hz, 1 H) 4.22 (d, J=9.35 Hz, 2 H) 4.36 (s, 1 H) 4.62-4.71 (m, 1 H) 4.76-4.88 (m, 2 H) 4.87-5.03 (m, 1 H) 5.02-5.09 (m, 1 H) 7.09 (t, J=4.80 Hz, 1 H) 7.88 (dd, J=5.56, 2.27 Hz, 1 H) 8.27 (t, J=5.31 Hz, 1 H) 12.25 (d, J=8.84 Hz, 1 H). [M+H] calc'd for C19H20FN5O2, 370; found, 370.5.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[S:13](Cl)(=[O:15])=[O:14])(=[O:3])[CH3:2].[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(N(CC)CC)C>O1CCCC1>[CH:17]1([NH:20][S:13]([C:7]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=2[CH2:5][NH:4][C:1](=[O:3])[CH3:2])(=[O:15])=[O:14])[CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: CC(=O)NCc1cc(F)ccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cc(F)ccc1S(=O)(=O)NC1CC1

Procedure:
(Step 1) A solution of 2-[(acetylamino)methyl]-4-fluorobenzenesulfonyl chloride (1.5 g), cyclopropylamine (0.43 ml) and triethylamine (0.87 ml) in tetrahydrofuran (15 ml) was stirred at room temperature for 2 hr. The reaction mixture was quenched with saturated brine, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from methanol-water to give N-[2-(cyclopropylsulfamoyl)-5-fluorobenzyl]acetamide (1.06 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][C:4]=2[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([F:28])[CH:27]=1)[NH2:24].O>CN1C(=O)CCC1>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[N:12]=[CH:13][N:14]=[CH:15][C:10]=3[C:9]3[CH:8]=[CH:7][C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][C:4]=3[N:3]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c1ncncc12
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(Nc1cc(F)cc(F)c1)c1ncncc12
Temperature: 120 °C

Procedure:
methyl 5-chloropyrimido[4,5-c]quinoline-8-carboxylate (10 mg) was mixed with 3,5-difluoroaniline (100 mg) in NMP (0.1 ml). The mixture was heated under microwaves at 120° C. for 10 minutes. Water was added and the material extracted with CH2Cl2. The solvent was removed. Trituration in a mixture of ethylacetate and hexanes and filtration provided methyl 5-(3,5-difluorophenylamino)pyrimido[4,5-c]quinoline-8-carboxylate. This material was suspended in a 1:1 mixture of THF and MeOH (2 ml) and a 5N aqueous solution of Lithium Hydroxide was added. The mixture was vigorously stirred at room temperature for 5 hours. Water and 6N hydrochloric acid were added to induce precipitation of the expected material. The solid was filtered, washed with water, dried and suspended in MeOH. Filtration and drying gave 5-(3,5-difluorophenylamino)pyrimido[4,5-c]quinoline-8-carboxylic acid as a yellow solid (4 mg, 31% yield). LCMS (ES): 95% pure, m/z 353 [M+1]+. 1H NMR (DMSO-d6, 400 MHz) δ 6.90 (br t, J=9.6, 1H), 8.02 (dd, J=1.6, J=8.0, 1H), 8.18 (br d, J=10.8, 2H), 8.34 (d, J=1.6, 1H), 8.86 (d, J=8.4, 1H), 9.65 (s, 1H), 10.40 (s, 1H), 10.44 (s, 1H) ppm.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=1)[CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:20]1([N:19]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=[C:11]2[C@@H:8]([NH2:7])[CH2:9][CH3:10])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)c1nc2cccnc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.4 %

Procedure:
To a solution of [(S)-1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)propyl]carbamic acid tert-butyl ester (1.27 g, 3.60 mmol) in DCM (25 mL) was added TFA (10 mL) and the mixture stirred at RT for 15 min. The volatiles were removed in vacuo and the resulting residue dissolved in DCM and washed with a saturated solution of NaHCO3. The aqueous phase was extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) to afford the title compound as a brown oil (440 mg, 40% over 3 steps). 1H NMR (CDCl3, 400 MHz): δ 8.34 (1H, d, J=4.82 Hz), 8.08 (1H, d, J=8.00 Hz), 7.67-7.52 (3H, m), 7.45 (2H, d, J=7.60 Hz), 7.30-7.22 (1H, m), 3.99 (1H, t, J=6.70 Hz), 2.02-1.87 (1H, m), 1.83-1.69 (3H, m), 0.89 (3H, t, J=7.40 Hz).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].[Cl:17][S:18](O)(=[O:20])=[O:19].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[P+]=O>C(Cl)Cl>[C:13]([NH:12][C:10]1[S:11][C:7]([C:6]2[CH:5]=[C:4]([S:18]([Cl:17])(=[O:20])=[O:19])[S:3][C:2]=2[Br:1])=[C:8]([CH3:16])[N:9]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1nc(C)c(-c2ccsc2Br)s1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=[P+]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of N-[5-(2-bromo-thiophen-3-yl)-4-methyl-thiazol-2-yl]-acetamide obtained in Step II, as describe above (1100 mg; 3.47 mmol; 1 eq), in DCM (60 ml) is cooled to 0° C. with an ice bath. The reaction is degassed with nitrogen and chlorosulfonic acid (1.16 ml; 17.3 mmol; 5 eq) dissolved in DCM (30 ml) is added dropwise. The reaction mixture is stirred at 0° C. for 15 minutes. Phosphorus pentachloride (1444 mg; 6.94 mmol; 2 eq) is added followed directly by phosphorus oxide chloride (1.3 ml; 13.9 mmol; 4 eq). The reaction is stirred for an additional 2 hours at room temperature. Then the reaction mixture is poured into a beaker with crushed ice and directly transferred in a separated funnel. It is extracted with 2 portions EtOAc. The organic layer is dried over MgSO4, affording the title compound (1440 mg; quantitative yield).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Cl.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>C(#N)C>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:21]1[NH:20][CH:24]=[CH:23][N:22]=1
Reactant: CN(C)C(=O)C(Cl)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CN(C)C(=O)C(c1ccccc1)(c1ccccc1)c1ncc[nH]1

Procedure:
18.1 g diphenyl-chloroacetic acid dimethylamide (m.p. 128°C, prepared by analogy with Example 19) are heated with 15.6 g imidazole in 120 ml acetonitrile at boiling temperature for 18 hours. The solvent is distilled off in a vacuum. After the addition of 70 ml of water, the mixture is extracted with methylene chloride. After drying, the solvent is distilled off in a vacuum and the solid residue is recrystallized from methanol. The diphenyl-imidazolyl-acetic acid dimethyl amide of m.p. 202°C is thus obtained in the form of colourless crystals.
Reaction SMILES: [CH:1]1[C:6](C(O)=O)=[CH:5][C:4]2[C:10]3([O:26][C:27](=[O:28])[C:3]=2[CH:2]=1)[C:19]1[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[C:14]([OH:25])[CH:13]=[CH:12][C:11]3=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:6]1[CH:1]=[CH:2][C:3]([C:27]([OH:28])=[O:26])=[C:4]([C:10]2[C:11]3[CH:12]=[CH:13][C:14]([OH:25])=[CH:15][C:16]=3[O:17][C:18]3[C:19]=2[CH:20]=[CH:21][C:22]([CH:23]=3)=[O:24])[CH:5]=1
Reactant: O=C(O)c1ccc2c(c1)C1(OC2=O)c2ccc(O)cc2Oc2cc(O)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
5(6)-carboxy fluorescein is dissolved in NMP to a concentration of 0.2 M. Activation is performed with 0.9 eq. HATU and 1 eq. DIPEA for 2 min before coupling for at least 2×20 min or until the Kaiser test is negative.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])[C:7](=[O:21])[CH:6]=2.[C:22]1([CH2:28][C:29]#[CH:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.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:21]=[C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:30]#[C:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:3]=[CH:4]2)=[CH:9][N:8]1[CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]
Reactant: C#CCc1ccccc1
Reactant: N#Cc1cccc(Cn2cc3cc(Br)ncc3cc2=O)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cn2cc3cc(C#CCc4ccccc4)ncc3cc2=O)c1

Procedure:
The coupling of 3-(7-bromo-3-oxo-2H-6-azaisoquinolin-2-ylmethyl)benzonitrile (0.85 g, 2.51 mmol) with 3-phenyl-1-propyne (0.78 mL, 6.3 mmol) using triethylamine (0.70 mL, 5.0 mmol), CuI (0.034 g, 0.18 mmol), and Pd(Ph3P)4 (0.20 g, 0. 17 mmol) in dimethylformamide is carried out as described in Example 1, Step (2). Purification is carried out on a silica gel column eluted with hexanes/ethyl acetate 3:1 to give the desired product.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:36]1[CH:40]=[CH:39][N:38]=[C:37]1[CH:41]=[O:42].[Li]N1C(C)(C)CCCC1(C)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:40]2[S:36][C:37]([CH2:41][OH:42])=[N:38][CH:39]=2)[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1nccs1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Agent: [Li]N1C(C)(C)CCCC1(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(-c3cnc(CO)s3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42), 1,3-thiazole-2-carbaldehyde and lithium 2,2,6,6-tetramethylpiperidide.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH:41]2[CH:39]([O:40]2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:38][C@@H:39]([OH:40])[C@H:41]([N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)[S:21][C:20]2=[O:22])[CH2:42]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
3-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-(trans)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione (from Example 1) and 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester following a similar procedure as described for Example 270.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][CH:11]=[C:10]([Cl:17])[CH:9]=2)=[O:5])[CH3:2].CC(=CC)C.[O-:23]Cl=O.[Na+]>CC(O)(C)C>[CH3:2][CH2:1][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([OH:23])=[O:16])=[CH:12][CH:11]=[C:10]([Cl:17])[CH:9]=2)=[O:5]
Reactant: [O-][Cl+][O-]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
To a solution of commercially available 6-chloro-3-formyl-1H-indole-2-carboxylic acid ethyl ester in t-BuOH and 2-methyl-2-butene (50 eq) was added 9.2 eq NaClO2 (9 eq) and aq. NaH2PO4 (7 eq) and stirred 12 h at room temperature. After concentration the mixture was dissolved in H2O and adjusted to pH7 and then extracted with EtOAc; partial concentration of the organic phase precipitated the product in 52% yield.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[C:15]1([S:21]([N:24]2[C:28]3=[N:29][CH:30]=[C:31]([NH:40][C:41](=[O:48])[CH2:42][CH:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)[C:32]([NH:33][CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[C:27]3[CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([S:21]([N:24]2[C:28]3=[N:29][CH:30]=[C:31]([NH:40][C:41](=[O:48])[CH2:42][CH:43]4[CH2:44][CH2:45][CH2:46][CH2:47]4)[C:32]([NH:33][CH:34]4[CH2:35][CH2:36][N:37]([S:11]([CH3:10])(=[O:13])=[O:12])[CH2:38][CH2:39]4)=[C:27]3[CH:26]=[CH:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CC1CCCC1)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Nc2c(NC(=O)CC3CCCC3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisopropylethylamine (0.166 ml, 0.954 mmol) and methanesulfonyl chloride (0.027 ml, 0.350 mmol), were added sequentially to a solution of crude N-[1-benzenesulfonyl-4-(piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-cyclopentyl-acetamide (hydrochloride salt) (0.382 mmol, obtained in preceding step) in CH2Cl2 (10 ml) at 25° C. The reaction mixture was stirred for 30 min at 25° C., then was partitioned between half-saturated NaHCO3 (75 ml) and CH2Cl2 (100 ml). The organic layer was dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to afford N-[1-benzenesulfonyl-4-(1-methanesulfonyl-piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-cyclopentyl-acetamide as a white foam. LCMS (Method G, ESI): RT=0.93 min, m+H=560.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][NH:58][CH2:59][C:60]1[CH:75]=[CH:74][C:63]([CH2:64][N:65]2[CH2:69][CH2:68][CH:67]([NH:70][C:71](=[O:73])[CH3:72])[CH2:66]2)=[CH:62][CH:61]=1>C(Cl)Cl>[C:71]([NH:70][CH:67]1[CH2:68][CH2:69][N:65]([CH2:64][C:63]2[CH:62]=[CH:61][C:60]([CH2:59][N:58]([CH3:57])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:75][CH:74]=2)[CH2:66]1)(=[O:73])[CH3:72]
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(NC(C)=O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(NC(C)=O)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (80 mg, 0.22 mmol), EDCI (61 mg, 0.32 mmol), HOBt (45 mg, 0.34 mmol), DIPEA (0.08 mL, 0.45 mmol), N-(1-{4-[(methylamino)methyl]benzyl}pyrrolidin-3-yl)acetamide dihydrochloride (36 mg, 0.13 mmol) and DCM (20 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([NH:32][CH3:33])=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([NH:32][CH3:33])=[O:31])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2cccc3c2OCC3)CC1
Reactant: CNC(=O)CCl
Product: CNC(=O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N-methyl-acetamide gave the title compound.
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:19])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[I-].[Na+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[F:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][N:39]([CH2:2][CH:3]([CH3:19])[CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:38][CH2:37]2)=[CH:34][CH:35]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(CCl)CN1c2cccc3cccc(c23)S1(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(CN1CCN(c2ccc(F)cc2)CC1)CN1c2cccc3cccc(c23)S1(=O)=O
Temperature: 20 °C
Yield: 20.1 %

Procedure:
The experiment is carried out as in Example 56, starting with 2-(3-chloro-2-methylpropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (10.4 g), triethylamine (5.1 cc), sodium iodide (5.4 g) and 4-(4-fluorophenyl)piperazine (6.5 g) in toluene (130 cc). The mixture is heated at boiling point for 16 hours, then cooled to a temperature of about 20° C. After purification by flash chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane and then ethyl acetate as eluants, and recrystallization from boiling acetonitrile (20 cc), 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-methylpropyl}naptho[1,8-cd]isothiazole 1,1-dioxide (3.1 g) is obtained m.p. 133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[C:10]=1[O:11][CH3:12])[C:5]([Cl:27])=[O:6]
Reactant: COc1c(Cl)cc(C(=O)O)cc1OC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(C(=O)Cl)cc1OC(F)(F)F
Temperature: 60 °C
Reaction time: 13 h

Procedure:
To 3-chloro-4-methoxy-5-trifluoromethoxybenzoic acid (401 mg), toluene (4 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.13 mL) were added, and then the mixture was stirred at 60° C. for 13 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (436 mg) as a brown oily substance.