Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([S:20](O)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH2:25][CH3:26])[C:5]1=[O:27])[CH2:2][CH3:3].S(Cl)(Cl)=O.[CH3:32][N:33]([CH2:35][CH2:36][NH2:37])[CH3:34]>CN(C)C=O>[CH3:32][N:33]([CH3:34])[CH2:35][CH2:36][NH:37][S:20]([C:17]1[CH:18]=[CH:19][C:14]([C:9]2[NH:10][C:11]3[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:27])[N:6]([CH2:24][CH2:25][CH3:26])[C:7]=3[N:8]=2)=[CH:15][CH:16]=1)(=[O:21])=[O:22]
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CCC)c1=O
Reactant: CN(C)CCN
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)NCCN(C)C)cc3)nc2n(CCC)c1=O
Temperature: 0 °C
Yield: 13 %

Procedure:
A mixture of 4-(1,3-dipropyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid (3.93 g, 0.01 moles) and N,N-dimethylformamide (100 ml) is prepared, cooled to 0° C., treated with thionyl chloride (2.4 g, 0.02 moles), and permitted to warm to ambient temperature with vigorous stirring. The resulting slurry is cooled to 0° C., treated with a solution of unsym dimethylethylenediamine (8.8 g, 0.10 mole) in N,N-dimethylformamide (11 ml) added in one portion, and allowed to warm to ambient temperature. The resulting solution is concentrated on a rotary evaporator. The residue is suspended in water, filtered, recrystallized from ethanol, and dried at 78° to yield 0.60 grams of N-[2-(dimethylamino)ethyl]-4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)benzenesulfonamide, mp, 270°-272° C.(d).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:15])=O>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 78 °C

Procedure:
4-Nitrobenzoic acid, thionyl chloride and DMF were placed in a 3-liter 4-necked glass flask and heated for 2 hours at 78° C. under reflux. The end of the reaction was monitored by the clarity of the reaction mixture. There was a clear solution at the end of the reaction. Thionyl chloride was removed under reduced pressure. Dichloroethane (1 liter) was added, and evaporation was carried out to yield 4-nitrobenzoyl chloride in the form of a solid. The solid was dissolved in dichloroethane (1 liter). Dichloroethane (10 liters) was introduced into a 20-liter glass flask and cooled to 0° C. Aluminium chloride was added at 0-5° C. The 4-nitrobenzoyl chloride prepared above, dissolved in dichloroethane, was then added dropwise at 0-5° C. Phenoxypropionic acid was added in portions to the reaction composition at 0.5° C., and stirring was carried out overnight at 25° C. The TLC was checked and the reaction composition was quenched in a mixture of hexane (8 liters) and ice-water (15 liters). The composition was stirred and the solids were filtered off. The product was washed with hexane and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[CH3:37][O:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1>>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[C:7]([C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=3[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2cccc(CN(C(=O)c3cc(C(=O)O)c(C(=O)O)cc3C(=O)O)[C@H]3CCCc4ccccc43)c2)c1

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 3-methoxyphenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[N:8]=[CH:7]2)([O-])=O>C(O)(=O)C.CCOC(C)=O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[N:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Yield: 75.8 %

Procedure:
5-nitro-1-N-(3-fluorobenzyl)indazole (7.9 g, 29.1 mmol, 1 equiv) and iron (8.13 g, 145.6 mmol, 5 equiv) were mixed in 200 mL acetic acid and 50 mL EtOAc, and were stirred at rt for 36 h. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated in vacuo to 10 mL volume. The contents were diluted with water (10 mL) and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc (3×500 mL), the combined organic layers dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude material was purified by column chromatography eluting with hexanes/EtOAC (4:1 to 3:1) to give 5-amino-1-N-(3-fluorobenzyl)indazole (5.32 g, 76%) as a light brown solid. 1H-NMR (DMSO-d6) δ 7.72 (s, 1H), 7.22-7.36 (m, 2H), 6.87-7.05 (m, 3H), 6.70-6.77 (m, 2H), 5.48 (s, 2H), 4.78 (br s, 2H); LCMS RT=1.66 min; [M+H]+=242.2.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][CH:12]([C:18]1[CH:19]=C(O)[CH:21]=[C:22]([CH:24]=1)[OH:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH3:11][CH:12]([C:18]1[CH:24]=[C:22]([OH:23])[C:21]2[C:2]3[CH2:6][CH2:5][S:4][C:3]=3[C:7](=[O:8])[O:9][C:10]=2[CH:19]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)C1SCCC1=O
Reactant: CCCCCC(C)c1cc(O)cc(O)c1
Product: CCCCCC(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-(2-heptyl)resorcinol to give 1,2-dihydro-7-(2-heptyl)-9-hydroxy-4-oxo-4H-thieno[2,3-c][1]benzopyran.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:15])=[C:9]2[CH:16]=O)[CH2:2][CH2:3][CH3:4].C(OC1C=C2C(=CC=1)NC(C)=C2/C=[CH:32]/[C:33]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)=[O:34])C>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:15])=[C:9]2/[CH:16]=[CH:32]/[C:33]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2[nH]c(C)c(C=O)c2c1
Reactant: CCOc1ccc2[nH]c(C)c(/C=C/C(=O)c3ccncc3)c2c1
Product: CCCCOc1ccc2[nH]c(C)c(/C=C/C(=O)c3ccncc3)c2c1
Yield: 57 %

Procedure:
5-Butoxy-2-methylindole-3-carboxaldehyde 409d (250 mg, 1.08 mmol) was reacted in a similar manner to that for 402a to yield a bright yellow powder (206 mg, 57%): mp 227-228° C. TLC Rf 0.33 (80% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 11.39 (s, 1H), 8.81-8.80 (m, 2H), 8.08-8.06 (d, 1H, J=15.3 Hz), 7.93-7.92 (m, 2H), 7.41 (d, 1H, J=12.3 Hz), 7.34-7.31 (d, 1H, J=15.24 Hz), 7.30-7.28 (d, 1H, J=8.64 Hz), 6.84-6.82 (dd, 1H, J1=8.64 Hz, J2=2.34 Hz), 4.08-4.06 (t, 2H, J=6.48 Hz), 2.57 (s, 3H), 1.76-1.71 (m, 2H), 1.52-1.45 (m, 2H), 0.97-0.94 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, d6-DMSO) δ 188.2, 154.6, 150.6, 145.74, 145.19, 139.6, 131.0, 126.6, 121.4, 112.90, 112.25, 111.44, 109.3, 104.3, 64.8, 31.0, 18.9, 13.8, 12.2. Elemental analysis calculated for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38. Found: C, 75.39; H, 6.55; N, 8.37.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[F:20])[C:13](OC)=[O:14]>C1COCC1>[NH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[F:20])[C:13]([NH:8][CH2:7][CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14]
Reactant: CC(C)(C)OCCN
Reactant: COC(=O)c1ccc(F)c(N)c1
Solvent: C1CCOC1
Product: CC(C)(C)OCCNC(=O)c1ccc(F)c(N)c1
Temperature: 90 °C

Procedure:
A mixture comprising 2-tert-butoxyethanamine (1.2 g, 5.12 mmol, 50% w/w) and methyl 3-amino-4-fluorobenzoate (0.866 g, 5.12 mmol) in THF (10 ml) was treated with TBD (0.713 g, 5.12 mmol) and heated at 90° C. for 16 hrs. After cooling to RT, the solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic portion was separated and washed with 10% aq citric acid (×2), NaHCO3 (sat. aq), brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the title compound as a clear oil;
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:4]=[N:3]1.[CH3:16][CH2:17][Mg+].[Br-].CCOCC>C(Cl)Cl>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]([NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH2:16][CH3:17])[CH:4]=[N:3]1
Reactant: CC[Mg+]
Reactant: Cc1c(/C=N/S(=O)C(C)(C)C)cnn1C
Agent: [Br-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(NS(=O)C(C)(C)C)c1cnn(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of (E)-N-((1,5-dimethyl-1H-pyrazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (Step A5A) (600 mg, 2.64 mmol) in CH2Cl2 (15 ml) was added a 3.0 M solution of EtMgBr in ether (1.76 ml, 5.28 mmol) at −48° C. under nitrogen. After being stirred for 120 min, the reaction mixture was allowed to warm to rt slowly over 2 h and further stirred for 15 h at rt. The reaction was quenched by addition of sat. NH4Cl aq., diluted with water, and the aqueous layer was extracted with CH2Cl2 3 times. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (CH2Cl2: MeOH=50:1 to 20:1) to give the desired product as a pale yellow oil (650 mg, >96% yield). 1H NMR (270 MHz, CDCl3) δ 0.87 (3H, t, J=5.4 Hz), 1.17 (9H, s), 1.77-1.85 (2H, m), 2.25 (3H, s), 3.78 (3H, s), 3.31 (1H, brs), 4.16-4.22 (1H, m), 7.31 (1H, s).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added tert-butyl (aminooxy)acetate 88 (0.13 g, 0.86 mmol, Organic Letters, 2002, 4(6) 869-872), 1-hydroxybenzotriazole (0.15 g, 1.11 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.10 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl [({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetate 89 (0.23 g, 79%) as a white solid.
Reaction SMILES: O[CH2:2][C:3]#[N:4].[CH:5]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:7])[CH3:6]>O.C(O)C>[CH:9]1([N:8]([CH2:2][C:3]#[N:4])[CH:5]([CH3:7])[CH3:6])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#CCO
Reactant: CC(C)NC1CCCC1
Solvent: CCO
Solvent: O
Product: CC(C)N(CC#N)C1CCCC1

Procedure:
Hydroxyacetonitrile (8.2 ml of a 70% w/w solution in water, 0.1 mol) was added to a solution of N-isopropylcyclopentanamine (11.43 g, 0.09 mol) (Preparation 47) in ethanol (60 ml). The reaction mixture was heated under reflux for 3 hours, allowed to cool and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to give the title compound (14.1 g) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[NH2:14][CH2:15][CH:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[OH:17].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:17][CH:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:15][NH:14][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: NCC(O)c1cccnc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(O)c1cccnc1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 296 mg, 1.51 mmol) and 2-amino-1-pyridin-3-ylethanol (Preparation 98, 214 mg, 1.55 mmol) in DMF (10 mL) was added HOBt (225 mg, 1.47 mmol), DIPEA (0.55 mL, 3.16 mmol) and EDCI (340 mg, 1.77 mmol). After stirring at rt for 12 h the solvent was removed in vacuo and the residue then taken up in THF (150 mL) and washed with diluted sodium hydroxide solution (1M, 50 mL) and brine (2×50 mL). The solution was dried (MgSO4) and concentrated to an oil that was further purified by flash chromatography on silica gel (eluent: DCM/methanol: 90/10+0.5% triethylamine) to give the title compound as off-white solid. δH (d6 DMSO): 3.53 (2H, m), 4.85 (1H, m), 5.75 (1H, d), 7.15 (1H, s), 7.37 (1H, dd), 7.75 (2H, m), 8.47 (1H, m), 8.57 (1H, s), 8.89 (1H, appt), 12.24 (1H, s); m/z (ES+)=317.17 [M+H]+; RT=2.71 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[N:34]=[N:35][N:36]([CH2:38][C:39](O)=[O:40])[CH:37]=1>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][N:36]3[CH:37]=[C:33]([C:32]([F:42])([F:31])[F:43])[N:34]=[N:35]3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: O=C(O)Cn1cc(C(F)(F)F)nn1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(NC(=O)Cn3cc(C(F)(F)F)nn3)ccn2)c2cnccc21

Procedure:
Prepared according to the method described for Method M (Example 206) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 27) and [4-(Trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetic acid (Preparation 90). The residue was purified using alumina eluting with 3% MeOH in DCM to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cncnc1N
Product: CCOC(=O)c1cncnc1NC(C)=O
Yield: 59 %

Procedure:
Compound 21 (0.72 g, 4.3 mmol) was mixed with 8 mL of acetic anhydride and the reaction mixture was stirred under reflux for 2 h until no starting material was observed by TLC (4:1 EtOAc/hexanes). The reaction mixture was concentrated in vacuo and the product was purified by flash chromatography (CH2Cl21EtOAc) to yield 0.53 g of compound 22 in 59% yield.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:32][CH2:31][CH2:30][O:29][CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: COCCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: COCCNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), 2-methoxyethanamine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 335 (M+, 1), 290 (18), 88 (bp), 70 (8), 58 (8), 56 (12).
Reaction SMILES: [Br:1][C:2]1[C:3]([SH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([S:8][CH:14]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)C1
Reactant: Sc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ncccc2Br)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-bromopyridine-2-thiol (0.30 g, 1.6 mmol), tert-butyl 3-bromopyrrolidine-1-carboxylate (0.79 g, 3.2 mmol) and K2CO3 (438 mg, 3.20 mmol) in DMF (12 mL) was stirred at rt for 4 h. The reaction mixture was concentrated to dryness and the residue subjected to FCC purification to give partially purified title compound (1.05 g, 63% purity).
Reaction SMILES: FC(F)C1C([C:8](Cl)=[O:9])=CN(C)N=1.[NH:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][OH:19].C(N(CC)CC)C>ClCCl>[OH:19][CH2:18][C@@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[CH:8]=[O:9]
Reactant: OC[C@@H]1CCCN1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CN1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (1.9 g, 10.0 mol) in dichloromethane (40 ml) was added dropwise to a stirred solution of (S)-pyrrolidin-2-yl-methanol (1.0 g, 10.0 mmol) and triethylamine (2.8 ml, 20.0 mmol) in dichloromethane 60 ml. The reaction mixture was stirred for 10 minutes at ambient temperature and then allowed to stand for 3 h at ambient temperature. The reaction mixture was washed with 1M NaOH (30 ml) and 2M HCl (30 ml) and then dried over Na2SO4. After removal of the solvent, the residue (1.76 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:dichloromethane/methanol 9:1). 1.28 g (49% of theory) of (3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-((S)-(2-hydroxymethyl-pyrrolidin-1-yl)-methanone was obtained in form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:14].[CH:16]([N:19]1[C:23]([Sn](CCCC)(CCCC)CCCC)=[CH:22][CH:21]=[N:20]1)([CH3:18])[CH3:17]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:23]2[N:19]([CH:16]([CH3:18])[CH3:17])[N:20]=[CH:21][CH:22]=2)[C:7]([CH:11]([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(I)c(C(C)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C(C)C)c(C(C)F)cc1N
Temperature: 90 °C
Reaction time: 24 h
Yield: 16.5 %

Procedure:
To a solution of 2-amino-4-(1-fluoro-ethyl)-5-iodo-benzoic acid methyl ester (0.561 g, 1.74 mmol) in dioxane (5 mL) were added 1-isopropyl-5-tributylstannanyl-1H-pyrazole (0.84 g, 2.08 mmol) and Pd(PPh3)2Cl2 (142 mg, 0.174 mmol) and the resulting mixture was stirred at 90° C. for 24 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:10 to 3:7)) to give 2-amino-4-(1-fluoro-ethyl)-5-(2-isopropyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (90 mg, 0.287 mmol, 16%) ES-MS: m/z 306 [M+H]+, rt 6.47 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=1)[NH:7][C:6]([C:19]1[S:20][CH2:21][C@@H:22]([CH2:24][CH2:25]O)[N:23]=1)=[CH:5]2.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH2:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH:10]=1)[NH:7][C:6]([C:19]1[S:20][CH2:21][C@H:22]([CH2:24][CH2:25][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:23]=1)=[CH:5]2
Reactant: Cc1cc(NCC2CCOCC2)c2[nH]c(C3=N[C@H](CCO)CS3)cc2c1
Reactant: C1COCCN1
Product: Cc1cc(NCC2CCOCC2)c2[nH]c(C3=N[C@@H](CCN4CCOCC4)CS3)cc2c1

Procedure:
2-((R)-2-{5-methyl-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-ethanol prepared in Step B and morpholine were reacted according to the same procedure as Example 156 to give the title compound.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:4]([CH2:15][CH3:16])[C:3]=1[C:17](=[O:20])[CH2:18][CH3:19].C(O)C.[NH2:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]([CH2:15][CH3:16])[C:3]([C:17](=[O:20])[CH2:18][CH3:19])=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([S:25]([NH2:24])(=[O:27])=[O:26])=[CH:29][CH:30]=3)[C:6]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: CCC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1CC
Reactant: NS(=O)(=O)c1ccc(B(O)O)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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1CC
Temperature: 25 °C
Yield: 32.9 %

Procedure:
To the solution of 1-(3-bromo-5-(4-chlorophenyl)-1-ethyl-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 51c, 0.5 g, 1.41 mmol) in a mixture of toluene: ethanol (3:12 ml) was added 4-aminosulfonylbenzene boronic acid (0.34 g, 1.69 mmol) and potassium carbonate (0.48 g, 3.52 mmol) at a temperature of about 25° C. in a sealed tube and a nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.16 g, 0.14 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 90° C. to 95° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane (2×20 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silicagel (100-200 mesh) using 30-35% ethyl acetate in hexanes as an eluent to obtain the title compound (0.2 g, 32.9%).