Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)O1.Br[C:21]1[N:25]=[CH:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[CH:28][CH:27]=2)[N:22]=1.C([O-])(O)=O.[Na+].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>[F:39][C:33]([F:38])([O:32][C:29]1[CH:30]=[CH:31][C:26]([N:23]2[CH:24]=[N:25][C:21]([C:9]3[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)=[N:22]2)=[CH:27][CH:28]=1)[C:34]([F:37])([F:36])[F:35]
Reactant: FC(F)(F)C(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A microwave vial was charged with methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (147 mg, 0.561 mmol), 3-bromo-1-(4-(pentafluoroethoxy)phenyl)-1H-1,2,4-triazole (200 mg, 0.559 mmol), NaHCO3 (94 mg, 1.2 mmol), and Pd(PPh3)4 (39 mg, 0.034 mmol). Dioxane (3.8 mL) and water (1.2 mL) were added, the reaction vial was capped, and the reaction was heated at 140° C. for 30 min in a Biotage Initiator® microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to RT, and allowed to stand overnight. A white solid formed, which was filtered and air-dried to give the title compound as a white solid (146 mg, 62%): mp 192-195° C., 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.28 (d, J=9.0 Hz, 2H), 8.19-8.12 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 7.45-7.38 (m, 2H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −85.90, −87.86; ESIMS m/z 414 ([M+H])+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C.Cl[CH2:26][CH2:27][CH2:28][C:29]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1)=[O:30].O>CN(C)C=O>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:26][CH2:27][CH2:28][C:29]([N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32]2)=[O:30])[CH2:12][CH2:11]1
Reactant: O=C(CCCCl)N1CCc2ccccc21
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCN1CCN(c2cccc(Cl)c2Cl)CC1)N1CCc2ccccc21
Temperature: 45 °C
Yield: 113.5 %

Procedure:
A mixture of 1-(2,3-dichlorophenyl)piperazine, hydrochloride (8.0 g) and diisopropylethylamine (10 mL) in dimethyl formamide (50 mL) was heated to 45° C. followed by the addition of 4-chloro-1-(2,3-dihydro-1H-indol-1-yl)butan-1-one (6.7 g). The resulting mixture was heated at 100° C. for 6 h, cooled to room temperature and poured into water. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried (MgSO4), filtered and evaporated in vacuo to give a black oil (14.2 g). The oil was crystallised from acetone, and the formed crystals were recrystallised from ethanol to give a white crystalline material (3.8 g). Mp 134–136° C. 1H NMR (CDCl3): 1.90–2.05 (m, 2H); 2.45–2.60 (m, 4H); 2.65 (s, 4H); 3.00 (s, 4H); 3.20 (t, 2H); 4.10 (t, 2H); 6.90 (d, 1H); 7.00 (t, 1H); 7.05–7–25 (m, 4H); 8.25 (d, 1H). MS m/z: 418 (MH+), 299, 228, 188.
Reaction SMILES: CC([O-])(C)C.[K+].CS(C)=O.[CH2:11]([O:18][CH2:19][C@@H:20]1[CH2:23][C@H:22](C2C=C(C)C=CC=2S([O-])(=O)=O)[CH2:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CCOCC>[CH2:11]([O:18][CH2:19][CH:20]1[CH2:23][CH:22]=[CH:21]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])c([C@H]2C[C@@H](COCc3ccccc3)C2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: C1=CC(COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 250 mL flask with t-BuOK (11.95 g, 0.11 mol) inside, dry DMSO 50 mL was added under argon to give a colorless solution. Then at room temperature, cis-3-(benzyloxymethyl)cyclobutyl-tosylate (12.3 g, 35.5 mmol) was added very slowly to the previous flask. The reaction mixture was left stirring at room temperature for 4 hr, after which time quench the reaction by adding H2O 200 mL slowly, followed by the addition of 100 mL Et2O. The separated water phase was re-extracted with Et2O three times and the combined organic phase was washed with H2O four times. The organic phase was dried over MgSO4 and concentrated to dryness to give a light yellow oil which was purified by silica gel flash chromatography (Hexane:EtOAc=9:1) to give 4.45 g (71.9%, Rf=0.59 ((Hexane: EtOAc=9:1)) the desired product. 1H NMR (CDCl3, 600 MHz): δ 2.19-2.21 (d, J=12, 1H), 2.66-2.69 (dd, J=13.2, 4.2, 1H), 3.11-3.14 (m, 1H), 3.50-3.56 (m, 2H), 4.54 (s, 2H), 6.09-6.11 (m, 2H), 7.27-7.35 (m, 5H). 13C NMR (CDCl3, 150 MHz): δ 34.40, 43.72, 73.32, 74.07, 127.75, 127.89, 128.59, 137.16, 138.59. IR (neat) νmax 3257, 2917, 2849, 1739, 1462, 1376, 1241, 967, 746.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:19])[C:3]=1[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([CH3:31])=[CH2:30])[CH:23]=1)O>CCO.CC(O)=O.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][Si:9]([CH:10]([CH3:12])[CH3:11])([CH:13]([CH3:15])[CH3:14])[CH:16]([CH3:18])[CH3:17])[CH:5]=[C:4]([CH3:19])[C:3]=1[CH2:20][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH:29]([CH3:31])[CH3:30])[CH:23]=1
Reactant: C=C(C)c1cc(C(O)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)ccc1F
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Cc1ccc(F)c(C(C)C)c1

Procedure:
A solution of 1-(2,6-dimethyl-4-triisopropylsilanyloxyphenyl)-1-(4′-fluoro-3′-isopropenylphenyl)methanol (1.2 g, 2.71 mmol) and Pd/C (0.1 g, 10%) in EtOH/HOAc (9:1, 10 mL) was stirred under a H2 atmosphere for 16 h. The reaction mixture was filtrated through a plug of Celite and concentrated to afford the crude 3,5-dimethyl-4-(4′-fluoro-3′-iso-propylbenzyl)triisopropylsilanoxybenzene that was used for the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][N:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.[Cl:18][C:19]1[C:27]2[NH:26][N:25]=[CH:24][C:23]=2[C:22]2[CH2:28][N:29]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:30](=[O:53])[C@@H:31]([CH2:33][C:34](=[O:52])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:32][C:21]=2[CH:20]=1>>[Cl:18][C:19]1[C:27]2[NH:26][N:25]=[CH:24][C:23]=2[C:22]2[CH2:28][N:29]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:30](=[O:53])[C@H:31]([CH2:33][C:34]([N:1]3[CH2:2][CH2:3][CH:4]([C:7]4[C:8](=[O:17])[NH:9][C:10]5[C:15]([CH:16]=4)=[CH:14][N:13]=[CH:12][CH:11]=5)[CH2:5][CH2:6]3)=[O:52])[CH2:32][C:21]=2[CH:20]=1
Reactant: O=c1[nH]c2ccncc2cc1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4cnccc4[nH]c3=O)CC2)C1=O
Yield: 27 %

Procedure:
3-(piperidin-4-yl)-1,6-naphthyridin-2(1H)-one (89 mg, 0.29 mmol) and [4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]acetic acid (95 mg, 0.26 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 27% yield. High resolution MS m/e (M+H)+=575.2538.
Reaction SMILES: C(C1SCCCS1)C.C([Li])CCC.[CH3:14][N:15]1[C:19]([S:20][CH2:21][CH2:22][CH2:23]Cl)=[N:18][N:17]=[N:16]1.[O:25]1C[CH2:28][CH2:27][CH2:26]1>CCCCCC>[CH3:14][N:15]1[C:19]([S:20][CH2:21][CH2:22][CH2:23][C:26](=[O:25])[CH2:27][CH3:28])=[N:18][N:17]=[N:16]1
Reactant: C1CCOC1
Reactant: Cn1nnnc1SCCCCl
Agent: CCC1SCCCS1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCC(=O)CCCSc1nnnn1C
Temperature: -78 °C

Procedure:
2-Ethyl-1,3,-dithian (1,5 g) is dissolved in dried tetrahydrofuran (20 ml) and cooled to -78° C. To the mixture is added dropwise 1.6 N solution of n-butyllithium in n-hexane (6.5 ml) with stirring in argon gas flow. The mixture is stirred at -78° C. for 30 minutes. To the mixture is added dropwise a solution of 1-methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole (1.9 g) in dried tetrahydrofuran (5 ml). After stirring at -78° C. for 1 hour, the mixture is stirred 4 hours while it is heated slowly to 0° C. The reaction mixture is poured into ice-water and extracted with ether. The ether solution is washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. After ether is distilled off, the residue is dissolved in acetonitrile (20 ml). Silver nitrate (7 g) and N-chlorosuccinimide (4.9 g) are dissolved in a mixture of water (40 ml) and acetonitrile (100 ml). To the mixture is added dropwise the dithian solution as above-mentioned with stirring at 0° C. in nitrogen gas flow. After stirring at 0° C. for 30 minutes, the mixture is heated to room temperature and further stirred for 30 minutes. The reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10:1) to give 1-methyl-5-(3-propionylpropyl)thio-1,2,3,4-tetrazole (0.3 g) as colorless liquid, nD25 =1.5042
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]1[CH:29]=[N:30][N:31]2[CH:36]=[CH:35][C:34](=O)[NH:33][C:32]=12.[C:38]([O:42][C:43](=[O:49])[N:44]([CH2:46][CH2:47][NH2:48])[CH3:45])([CH3:41])([CH3:40])[CH3:39].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[C:38]([O:42][C:43](=[O:49])[N:44]([CH3:45])[CH2:46][CH2:47][NH:48][C:34]1[CH:35]=[CH:36][N:31]2[N:30]=[CH:29][C:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)=[C:32]2[N:33]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: O=c1ccn2ncc(-c3cccs3)c2[nH]1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CN(CCNc1ccn2ncc(-c3cccs3)c2n1)C(=O)OC(C)(C)C

Procedure:
1,8-Diazabicycloundec-7-ene (DBU) [6674-22-2] (0.4 mL, 2.5 mmol) was added to an ambient temperature, stirred, turbid solution of 3-thiophen-2-yl-4H-pyrazolo[1,5-a]pyrimidin-5-one (354.3 mg, 1.6 mmol), (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester [121492-06-6] (852.2 mg, 4.9 mmol), and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) [56602-33-6] (937.7 mg, 2.1 mmol) in acetonitrile (16 mL). Upon addition of the DBU the turbidity clears and the solution was permitted to stir for 2 d then partitioned between brine and ethyl acetate. The extract was dried (MgSO4) and flash chromatographed (silica gel, eluted with 10% (v/v) methanol/ethyl acetate). Evaporation of product fractions yielded an oil which was crystallized from heptane to provide methyl-[2-(3-thiophen-2-yl-pyrazolo[1,5-a]pyrimidin-5-ylamino)-ethyl]-carbamic acid tert-butyl ester as 333.6 mg of yellow, fine crystalline powder, mp. 140-141° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotomers present) 1.16-1.28 (m, 5 H) 1.37 (br. s., 3 H) 2.51 (s, 1 H) 2.85 (br. s., 3 H) 3.47 (br. s., 1 H) 3.55 (br. s., 3 H) 6.28 (d, J=6.82 Hz, 1 H) 7.04 (dd, J=5.05, 3.54 Hz, 1 H) 7.30 (dd, J=5.05, 1.01 Hz, 1 H) 7.41 (br. s., 1 H) 7.80 (br. s., 1 H) 8.19 (s, 1 H) 8.48 (d, J=7.07 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 27.81, 27.96, 33.75, 38.41, 46.32, 78.13, 100.28, 100.76, 120.16, 121.75, 126.90, 135.01, 135.20, 140.78, 143.74, 154.91, 155.81. LRMS (ESI) m/z 374.1 [(M+H)]+, calc'd for C18H23N5O2S: 373.48.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])[CH:2]([CH3:4])[CH3:3].O>CO.[BH4-].[K+]>[OH:10][CH:9]1[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](=[O:15])[N:5]1[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)CN1C(=O)c2ccccc2C1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 88.4 %

Procedure:
3-Hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 6.5 g of N-isobutylphthalimide in 60 cm3 of methanol and 1.7 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C., followed by dropwise addition of 50 cm3 of distilled water. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 35° C., and the residue is extracted three times with 60 cm3 of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. to give a pale yellow oil, which is purified by chromatography under argon pressure (60 kPa) on a column of silica gel (particle size 40-63 μm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 5.8 g of 3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white solid melting at 82° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C:12](=[N:13][C:14]([C@@H:24]([NH2:26])[CH3:25])=[C:15]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=3)[CH:16]=2)[CH:11]=[CH:10]1.Cl[C:28]1[C:33]([C:34]#[N:35])=[C:32]([CH3:36])[N:31]=[C:30]([S:37][CH3:38])[N:29]=1.CCN(CC)CC>C1COCC1>[CH3:36][C:32]1[C:33]([C:34]#[N:35])=[C:28]([NH:26][C@H:24]([C:14]2[N:13]=[C:12]3[CH:11]=[CH:10][N:9]([CH3:8])[C:17]3=[CH:16][C:15]=2[C:18]2[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=2)[CH3:25])[N:29]=[C:30]([S:37][CH3:38])[N:31]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc(C)c(C#N)c(N[C@@H](C)c2nc3ccn(C)c3cc2-c2ccnn2C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added (S)-1-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine 2,2,2-trifluoroacetate (364 mg, 0.986 mmol) in THF (6400 μL) along with 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carbonitrile (197 mg, 0.986 mmol) and Et3N (302 μL, 2.168 mmol). The reaction mixture was stirred at room temperature overnight and was subsequently purified on silica, eluting with a gradient of EtOAc/hexanes (2:8 to 9:1) to give the title compound as a clear film (270 mg, 65.5%). ESI-MS m/z [M+H]+ calc'd for C21H22N8S 419.17; found 419.4.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH3:29])([CH3:28])[C:20]2=[O:30])=[O:18])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>Cl.CO.[OH-].[Pd+2].[OH-]>[OH:14][C:11]1([CH2:15][NH:16][C:17]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH3:28])([CH3:29])[C:20]2=[O:30])=[O:18])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC1(C)C(=O)N(C(=O)NCC2(O)CCN(Cc3ccccc3)CC2)c2ccccc21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC1(C)C(=O)N(C(=O)NCC2(O)CCNCC2)c2ccccc21
Reaction time: 20 h
Yield: 33.8 %

Procedure:
A mixture of N-[(1-benzyl-4-hydroxypiperidin-4-yl)methyl]-3,3-dimethyl-2-oxoindoline-1-carboxamide (280 mg, 0.68 mmol, step 1 of Example 12) and palladium hydroxide (80 mg, 20 wt. % Pd on carbon,) in 10% HCl in methanol was stirred under H2 atmosphere for 20 h. The mixture was filtered through a pad of Celite, washed with methanol and the filtrate was concentrated to give pale yellow oil. The residue was chromatographed on silica gel column eluting with CH2Cl2/methanol/NH4OH (10:1:0.2) to give 73 mg (34%) of the title compound as clear yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:3]=[N:4][C:5]([CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:20][CH:19]=1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Reactant: Nc1ccc(Cl)cc1
Product: Cc1c(Cc2ccncc2)nnc(Nc2ccc(Cl)cc2)c1C
Temperature: 25 °C

Procedure:
A solution of 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.153 g para-chioroaniline is heated in a sealed tube for 20h to 130° C. After cooling to RT, the solution is concentrated by evaporation, the residue diluted with 100 ml CH2Cl2 and then extracted with 100 ml sat. aqueous NaHCO3 solution. The organic phase is dried over MgSO4, concentrated by evaporation, and the residue purified by flash chromatography (FC) on silica gel in CH2Cl2/methanol 19/1. The title compound is obtained: m.p. 196-199° C. 1H-NMR (250 MHz, CDCl3): δ=8.45 (s, wide, 2H); 7.55 (d, 2H); 7.25 (d, 2H); 7.10 (d, 2H); 6.20 (s, wide, 1H); 4.25 (s, 2H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 325, 327 (M+H for 35Cl and 37Cl).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.O>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1[nH]cncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cncc(Br)c2=O)cc1
Reaction time: 0.5 h

Procedure:
5-Bromopyrimidin-4(3H)-one (459 mg) was dissolved in N,N-dimethylformamide (13 mL), then with cooling with ice, sodium hydride (55%, 137 mg) was added, followed by stirring at the same temperature for 30 minutes. Then, 1-(chloromethyl)-4-methoxybenzene (392 μL) was added, followed by stirring at room temperature for 15 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 2:1) to obtain 5-bromo-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (382 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]([C:20]([O-:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]([C:20]([OH:22])=[O:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C1CN(Cc2ccccc2)CC1C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C1CN(Cc2ccccc2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 1-Benzyl-4-(2-methylphenyl)pyrrolidine-3-carboxylate (0.685 g, 2.214 mmol) in THF/MeOH/H2O (5 ml) was added 2N NaOH (3.32 ml, 6.64 mmol). The solution was stirred for 12 hours at room temperature and was acidified to pH1-2 with 1N HCl. The crude acid was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:37][C:38]([Cl:42])=[C:39]([NH2:41])[CH:40]=1)(=[O:35])=[O:34])([CH3:31])[CH3:30]>>[Cl:42][C:38]1[S:37][C:36]([S:33](=[O:35])(=[O:34])[NH:32][C:29]([CH3:31])([CH3:30])[CH2:28][OH:27])=[CH:40][C:39]=1[NH:41][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II. Light yellow solid. MS (ISP) 640.1 [ (M+H)+]; mp 223° C.
Reaction SMILES: [CH:1]([N:3]([CH3:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:6][CH:5]=1)=[O:2].[Cl:36][C:37]1[C:38]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:39]=2[S:40][C:41]=1[C:42](Cl)=[O:43]>>[Cl:36][C:37]1[C:38]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:39]=2[S:40][C:41]=1[C:42]([N:19]([CH2:18][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH:1]=[O:2])[CH3:35])=[CH:5][CH:6]=2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17])[CH:20]1[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])[CH2:22][CH2:21]1)=[O:43]
Reactant: COc1ccc(-c2ccc(N(C)C=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2cccc(F)c2c1Cl
Product: COc1ccc(-c2ccc(N(C)C=O)cc2)cc1CN(C(=O)c1sc2cccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 52 (200 mg, 0.42 mmol) is treated with acid chloride 6 (120 mg, 0.49 mmol) using Method D to afford the title compound.
Reaction SMILES: CN(C=O)C.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=1.Cl>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)=[CH:18][CH:17]=1
Reactant: C1=Cc2ccccc2C1
Reactant: Nc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C2C=Cc3ccccc32)cc1

Procedure:
20 ml of DMF, 2.2 g (20 mmol) of indene, 4,4 g (20 mmol) of para-amino-iodo-benzene, 2 ml of triethylamine and 0,134 (0,6 mmol) of Pd(OAc)2 were stirred under reflux for 10 h. The resulting mixture was poured into 200 ml of 15% HCl. Forming precipitate was separated and washed with dichloromethane. The resulting substance was treated with the mixture 50 ml of dichloromethane and 50 ml of 5% KOH in water. Organic layer was separated, washed twice with water, filtered and dried over Na2SO4. Dichloromethane was removed and the residue was recrystallized from 20 ml of EtOH. The yeld of product was 70%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[N:9]=[C:8]2[I:15])=O.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[I:15][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([CH2:3][OH:2])[CH:6]=2)[N:10]([CH3:14])[N:9]=1
Reactant: COC(=O)c1ccc2c(c1)c(I)nn2C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cn1nc(I)c2cc(CO)ccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.4 %

Procedure:
To a solution of 3-iodo-1-methyl-1H-indazole-5-carboxylic acid methyl ester (0.95 g, 3.01 mmol) in CH2Cl2 (30 mL) at 0° C. was slowly added DIBAL-H (1.18 mL, 6.61 mmol). The reaction mixture was stirred at 0° C. for 1.5 h. Carefully quenched with MeOH (1 mL) then diluted with CH2Cl2 (20 mL) and added saturated aqueous Na+K+ tartrate (30 mL). The biphasic mixture was stirred vigorously at room temp for 1 h. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organics were washed with water then dried over MgSO4 and concentrated to afford 810 mg of (3-iodo-1-methyl-1H-indazol-5-yl)methanol as a yellow waxy solid.