Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([OH:10])=[O:9])([CH3:5])([CH3:4])[CH3:3].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].C(N(CC)C(C)C)(C)C.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:2]([N:6]([C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=1)[CH2:7][C:8]([OH:10])=[O:9])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)NCC(=O)O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N(CC(=O)O)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
tert-Butyl glycine hydrochloride (6.6 g, 50 mmol) was suspended in methylene chloride and meta-trifluoromethyl benzoic acid (9.5 g, 50 mmol) was added, followed by N,N-diisopropylethylamine (17.5 mL, 100 mmol), EDC (10.2 g, 53 mmol), and DMAP (300 mg, 2.5 mmol). The reaction was stirred for 12 hrs at RT and partitioned between EtOAc and 1 N HCl. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The material was purified via flash chromatography to give tert-Butyl (3-trifluoromethylbenzoyl)glycine as a clear and colorless oil (12 g), which was dissolved in methylene chloride (40 mL), cooled to 0° C., and treated with trifluoroacetic acid (20 mL). The reaction was stirred for 3.5 hrs at RT and concentrated in vacuo. The material was redissolved in methylene chloride and concentrated again; this procedure was repeated three more times to give the desired carboxylic acid 1.2 (Z=—C(O)—, R2=3-trifluoromethylphenyl, all other R=H; 8.9 g). 1H-NMR (300 MHz): δ 8.03 (s, 1H), 7.94 (d, 1H, J=7.7 Hz), 7.66 (d, 1H, J=7.7 Hz), 7.48 (t, 1H, J=7.9 Hz), 4.08 (s, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=O.O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)(=O)C([Cl:39])=O>O1CCOCC1.O.CN(C=O)C>[C:10]1([C:7]2[NH:6][C:5]([C:3]([Cl:39])=[O:2])=[CH:9][CH:8]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(-c2cccc3ccccc23)[nH]1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(Cl)c1ccc(-c2cccc3ccccc23)[nH]1

Procedure:
5-Naphthalen-1-yl-1H-pyrrole-2-carboxylic acid methyl ester was diluted with 1:1 dioxane-water (30 ml), and treated with lithium hydroxide hydrate (24.4 mmol, 1.02 g), then heated to reflux for 15 min. The solution was acidified with 20% aqueous citric acid (30 ml), then extracted with ethyl acetate (75 ml). The organics were washed with brine (2×20 ml), then concentrated under reduced pressure. The residue was diluted with CH2Cl2, (30 ml), and treated with oxalyl chloride (24.0 mmol, 2.10 ml), and DMF (one drop), then heated to reflux for 30 min. The solution was concentrated under reduced pressure to provide 1.95 g of 5-naphthalen-1-yl-1H-pyrrole-2-carboxylic acid chloride.
Reaction SMILES: [Br:1][C:2]1[C:11]([Br:12])=[CH:10][C:5]2[N:6]=[C:7]([OH:9])[NH:8][C:4]=2[CH:3]=1.[N+:13]([O-])([O-:15])=[O:14].[K+]>OS(O)(=O)=O>[N+:13]([C:10]1[C:5]2[NH:6][C:7]([OH:9])=[N:8][C:4]=2[CH:3]=[C:2]([Br:1])[C:11]=1[Br:12])([O-:15])=[O:14]
Reactant: Oc1nc2cc(Br)c(Br)cc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1c(Br)c(Br)cc2nc(O)[nH]c12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The procedure of Cheesman, G. W. H., J. Chem. Soc. 1170 (1962), was adapted. To a stirred suspension of 5,6-dibromo-2-hydroxybenzimidazole (140 mg, 0.48 mmol) in concentrated H2SO4 (1 mL) at 0° C. was added KNO3 (58.5 mg, 0.56 mmol, Baker) in one portion. The mixture was stirred at 0° C. for 3 h then at room temperature for one day. The mixture became a blue solution. Then it was poured into ice (30 g) resulting in the separation of a bright yellow precipitate which was collected by filtration and washed with distilled water (2×1 mL) followed by ethanol (2×1 mL) to give 150 mg of crude title compound (90%) (contains minor impurities by NMR). Crystallization from DMSO/H2O gave pure title compound as bright yellow microcrystals, mp 305°-308° C. (dec.). IR (KBr, cm-1): 3412, 3143, 1712, 1537. 1H NMR (DMSO-d6): δ 7.430 (s, 1H), 11.455 (s, 1H), 11.715 (s, 1H). HRMS: calcd for C7H3N3O3Br2 (M+) m/z: 334.8538; found 334.8540. Potency relative to DCK: inactive.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=1[Cl:44])[CH3:36]>CN(C=O)C.[Cu]I>[Cl:44][C:38]1[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=1/[C:35](/[CH3:36])=[CH:34]\[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=2[C:13]2[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1=2
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC(=CBr)c1ccc(Cl)cc1Cl
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (214 mg, 1 mmol) was dissolved in DMF. Copper (I) iodide (19 mg, 0.1 mmol), L-proline (23 mg, 0.2 mmol) and K3PO4 (424 mg, 2 mmol) were added and the reaction mixture was stirred for 10 min at RT. 1-(1-Bromoprop-1-en-2-yl)-2,4-dichlorobenzene (318 mg, 1.2 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh) eluting with 0-5% methanol-dichloromethane. The product was further purified by reverse phase HPLC. Yield: 30 mg. 1HNMR (CDCl3, TFA salt) δ (ppm): 7.50 (s, 1H), 7.38 (s, 2H), 7.28 (d, 1H), 7.18 (d, 1H), 7.05 (d, 1H), 6.56 (s, 1H), 3.90 (m, 2H), 3.40 (m, 1H), 3.22 (m, 5H), 3.0 (s, 3H), 2.42 (s, 3H), 1.82 (s, 3H)
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH3:13])=[CH:7][NH:8]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH3:13])=[CH:7][N:8]2[S:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])=[O:21]
Reactant: Cc1c[nH]c2cccc(Br)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2cccc(Br)c12
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Aq. 4M NaOH (3 mL) was added to a stirring mixture of 4-bromo-3-methyl-1H-indole (456 mg, 2.17 mmol; Intermediate 28), benzenesulfonyl chloride (306 μg, 2.39 mmol) and tetrabutylammonium hydrogen sulfate (74 mg, 0.22 mmol) in DCM (30 mL). The reaction mixture was stirred 1 h, combined with an earlier batch of this intermediate (followed this experimental and starting with 4-bromo-3-methyl-1H-indole, 100 mg, 0.48 mmol; Intermediate 28), washed twice with water, dried and concentrated. The crude product was purified by flash column chromatography (DCM/hexane 1:3). The product (650 mg, 70%) was obtained as a white solid. MS (ESI+) for C15H12BrNO2S m/z 350 (Monoisotop+H)+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]([OH:14])=O)=[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.O[NH:28][C:29]([C:31]1[S:32][C:33]([S:36](=[O:39])(=[O:38])[NH2:37])=[CH:34][CH:35]=1)=[NH:30]>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]3[O:14][N:30]=[C:29]([C:31]4[S:32][C:33]([S:36]([NH2:37])(=[O:39])=[O:38])=[CH:34][CH:35]=4)[N:28]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: O=C(O)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3ncn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)s1

Procedure:
The title compound was prepared from 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carboxylic acid (example C.30) (188 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/ethyl acetate) as a yellow solid (199 mg, 71%). MS (ISN) 559.1 [(M−H)−]; mp 295° C.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[N:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([S:38](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH:31]=[N:30][N:29]=1>C1COCC1.[Cl-].[NH4+]>[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([S:38]([N:7]([C:5]3[S:6][C:2]([F:1])=[CH:3][N:4]=3)[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH:31]=[N:30][N:29]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nncc2c1
Reactant: COc1ccc(CNc2ncc(F)s2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncc(F)s2)S(=O)(=O)c2ccc3c(Cl)nncc3c2)cc1
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
A round-bottom flask was charged with 5-fluoro-N-(4-methoxybenzyl)thiazol-2-amine (Intermediate MMM) (184 mg, 0.774 mmol) and THF (1 mL) to give a clear, light-orange solution. The flask was cooled in a dry ice-acetone bath for 5 min to give a suspension. Lithium bis(trimethylsilyl)amide (1M in THF) (774 μl, 0.774 mmol) was added drop wise to give a clay-colored suspension. The mixture was stirred for 15 min, after which time it was a solution. A solution of perfluorophenyl 1-chlorophthalazine-6-sulfonate (from Intermediate AAAA, Step 2; 265 mg, 0.645 mmol) in THF (1 mL with a 0.25 mL syringe/vial wash) was added drop wise. After 45 min, the mixture was diluted with saturated aq ammonium chloride and extracted with EtOAc. The organic extract was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g column, 20 to 70% EtOAc/Heptane) to give 1-chloro-N-(5-fluorothiazol-2-yl)-N-(4-methoxybenzyl)phthalazine-6-sulfonamide (129 mg, 0.277 mmol, 43.0% yield) as a cream-colored solid: m/z (ESI) 465.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[Br:1][C:2]1[C:3]([CH2:9][N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:36]([NH:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:37])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(CNCc2nc(F)ccc2Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(Cc2nc(F)ccc2Br)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
To a solution of (3-bromo-6-fluoro-pyridin-2-ylmethyl)-(4-methoxy-benzyl)-amine (637 mg, 2.0 mmol, 1.0 equiv) and N,N-diisopropylethylamine (700 μL, 4.0 mmol, 2.0 equiv) in dichloromethane (10 mL) was added phenyl isocyanate (260 μL, 2.4 mmol, 1.2 equiv) and the reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was diluted with dichloromethane, washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, eluted with petrol—EtOAc 0-60%) to afford (1-(3-bromo-6-fluoro-pyridin-2-ylmethyl)-1-(4-methoxy-benzyl)-3-phenyl-urea (760 mg). MS: [M+H]+=445.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([C:9]2[O:13][C:12]([C:14](=[O:27])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:11][CH:10]=2)[CH:6]=[C:5]([O:28]C)[N:4]=1>CCOC(C)=O>[C:21]1([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([C:12]2[O:13][C:9]([C:7]3[NH:8][C:3](=[O:2])[NH:4][C:5](=[O:28])[CH:6]=3)=[CH:10][N:11]=2)=[O:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)nc(OC)n1
Solvent: CCOC(C)=O
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2cc(=O)[nH]c(=O)[nH]2)o1
Yield: 85.4 %

Procedure:
The title compound was prepared from 1-(5-(2,6-dimethoxypyrimidin-4-yl)oxazol-2-yl)-7-phenylheptan-1-one (20 mg, 0.051 mmol) following General Procedure H. Flash chromatography (EtOAc) yielded the title compound as a white solid (16 mg, 90%): 1H NMR (CDCl3/CD3OD, 500 MHz) δ 7.92 (s, 1H), 7.28-7.24 (m, 2H), 7.18-7.15 (m, 3H), 6.19 (s, 1H), 3.06 (t, 2H, J=7.4 Hz), 2.58 (t, 2H, J=7.7 Hz), 1.73 (quintet, 2H, J=7.3 Hz), 1.61 (quintet, 2H, J=7.4 Hz), 1.38-1.36 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 188.3, 163.8, 158.0, 151.7, 144.9, 142.5, 139.1, 129.8, 128.3, 128.1, 125.5, 98.8, 39.2, 35.7, 31.1, 28.81, 28.78, 23.5; MALDI-FTMS m/z 368.1595 (M+H+, C20H22N3O4, requires 368.1605).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>C1COCC1>[CH2:13]([NH:17][S:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)(=[O:11])=[O:10])[CH2:14][CH2:15][CH3:16]
Reactant: O=S(=O)(Cl)Cc1cccc(Cl)c1
Reactant: CCCCN
Solvent: C1CCOC1
Product: CCCCNS(=O)(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
A solution of (3-chlorophenyl)methanesulfonyl chloride (3.00 g, 13.33 mmol) in dry THF (50 mL) was added dropwise to a solution of butylamine (2.63 mL, 26.65 mmol) in dry THF (50 mL) at 0° C. and under an atmosphere of nitrogen. After the addition was completed the ice-bath was removed and the mixture was stirred at rt for 1.5 h. It was evaporated and the residue was partitioned between DCM and HCl (1M). The combined organic layers were washed with water, dried with MgSO4 and evaporated to dryness to give the title compound (2.89 g, 83%) as a white powder; 1H NMR (500 MHz, CDCl3): δ 7.29-7.42 (m, 4H), 4.22 (s, 2H), 4.16 (bs, 1H), 2.99-3.05 (m, 2H), 1.46-1.53 (m, 2H), 1.29-1.38 (m, 2H), 0.92 (t, 3H); 13C NMR (125 MHz, CDCl3): δ 132.2, 129.0, 128.3, 127.7, 126.6, 126.4, 55.9, 41.2, 30.0, 17.3, 11.21; Mass Spectrum: M−H+ 260.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12](=[NH:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:3])[CH3:2].C([Li])CCC.Cl[P:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12](=[N:20][P:27]([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=N)Nc2c(C)cccc2C(C)C)cc1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]CCCC
Product: Cc1ccc(C(=NP(C(C)C)C(C)C)Nc2c(C)cccc2C(C)C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.33 g of N1-(2-isopropyl-6-methylphenyl)-4-methylbenzamidine (Amidine V, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.80 mL chlorodiisopropylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, a yellow semi-solid was isolated (1.86 g, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][C:13](=O)[C:6]3=[CH:5][C:4]=2[CH:3]=1.[C:15]([O:19][C:20]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][C:13](=[CH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCn2c1cc1cc(Br)ccc12
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=C1CCn2c1cc1cc(Br)ccc12
Temperature: 65 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 7-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (0.50 g, 1.999 mmol) in THF (10 mL) was added (tert-butoxycarbonylmethylene)triphenylphosphorane (1.881 g, 5.00 mmol). The mixture was stirred at 65° C. for 16 h and concentrated. The residue was purified by silica gel flash chromatography to provide the title compound (0.50 g). LCMS m/z=348 [M+H]+.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][S:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2>CO>[CH3:3][S:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([O-:18])=[O:17])[CH:9]=[CH:8]2.[Na+:2]
Reactant: CSc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc2cc(C(C)C(=O)[O-])ccc2c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a mixture of 4 g. of sodium hydroxide and 500 ml. of methanol are added 24.6 g. of 6-methylthio-2-naphthyl-α-methylacetic acid. The mixture is stirred for 18 hours at 50° C. The cooled mixture is then evaporated to give sodium 6-methylthio-2-naphthyl-α-methylacetate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[O:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[N:9][C:8]=2[CH:18]=1)([O-])=O.CCO.[C:22](Cl)(Cl)=[S:23].C(=O)([O-])[O-].[Ca+2]>C(Cl)(Cl)Cl.[Pd].O>[CH3:17][C:14]1[O:13][C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([N:1]=[C:22]=[S:23])=[CH:18][C:8]=3[N:9]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)o1
Reactant: S=C(Cl)Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc3cc(N=C=S)ccc3o2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 420.2 %

Procedure:
3.32 g (0.0013 mole) of 5-nitro-2-(5-methyl-2-furyl)benzoxazole and 0.65 g of 10% Pd are suspended in 100 ml of abs. EtOH and hydrogenated at 65 psi over a period of 4 hr. The catalyst is removed and the EtOH evaporated under vacuum yielding a dark brown residue. The residue is dissolved in 150 ml of CHCl3 and added dropwise to the following cold suspension: 1.5 g (0.013 mole) of thiophosgene, 1.3 g (0.013 mole) of calcium carbonate, 150 ml of CHCl3 and 30 ml of water. After the addition is complete the mixture is warmed to room temperature and allowed to stir overnight. The CHCl3 layer is then separated and evaporated to dryness yielding 1.4 g of a light brown solid (43%) mp 110°-121°. This material is then extracted with petroleum ether and the extracts then evaporated yielding a tan solid. This material is recrystallized from petroleum ether yielding 0.540 g of white powder, mp 130°-132° (16%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[CH3:33][O:34][CH2:35][C:36](N(OC)C)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1)=[O:37]
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: COCC(=O)N(C)OC
Product: COCC(=O)c1c[nH]c2ncc(-c3cc(OC)c(OC)c(OC)c3)nc12

Procedure:
2-Methoxy-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-ethanone was prepared starting from 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine and 2,N-dimethoxy-N-methyl-acetamide (Journal of Medicinal Chemistry, 47(10), 2405-2408; 2004) following general procedures as described in these Examples, to afford a pale yellow solid. MP 229-230° C., M+H=358.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Cl:10][SiH:11]([Cl:13])[Cl:12]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]1([CH3:1])[CH:9]=[CH:8][C:5]([CH:6]([Si:11]([Cl:13])([Cl:12])[Cl:10])[CH3:7])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(C)cc1
Reactant: Cl[SiH](Cl)Cl
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(C(C)[Si](Cl)(Cl)Cl)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
Into a 3 liter round-bottom flask fitted with a reflux condenser, addition funnel and magnetic stir bar, was charged 4-methylstyrene (900 g, 7.6 mols) and Bis(triphenylphosphine)palladium (II) dichloride (1.8 g, 0.2% wt). The reaction mixture was heated to 70° C. and then trichlorosilane (1031 g, 7.6 mols) was added dropwise to the reaction mixture. During the addition, the reaction mixture was maintained between 80 to 100° C. After the addition was finished, the reaction mixture was kept at 70° C. for additional two hours. After distillation, pure (1-p-tolyl-ethyl)trichlorosilane (1400 g, 5.53 mols) was obtained (collected at 75° C./1 mmHg). The product structure was characterized by GC-MS and 13C NMR (δ˜14 ppm, CDCl3, Cl3Si—CH (CH3)-Ph; δ˜35 ppm, CDCl3, Cl3Si—CH(CH3)-Ph).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH3:21][C@H:22]1[CH2:27][O:26][CH2:25][CH2:24][NH:23]1>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][C@@H:22]2[CH3:21])[CH:5]=[C:4]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[N:3]=1
Reactant: CS(=O)(=O)Cc1cc(Cl)nc(Cl)n1
Reactant: C[C@H]1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(Cl)n1
Temperature: -5 °C

Procedure:
2,4-Dichloro-6-(methylsulfonylmethyl)pyrimidine (30 g, 0.13 mol) was dissolved in dichloromethane and stirred (under nitrogen) at −5° C. Triethylamine (17.4 mL, 0.13 mol) was added to give a clear brown solution. (3S)-3-Methylmorpholine was dissolved in dichloromethane and added dropwise keeping the reaction below −5° C. The cooling bath was then removed and the mixture stirred for 1 hour. The reaction mixture was heated at reflux for 2 hours, then the reaction mixture was washed with water, dried then evaporated. The crude material was purified by preparative HPLC to give the desired material as a solid (19.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:44]=[CH:45][C:46]=1[CH3:47])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH:41]3[CH3:43])=[O:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([NH:23][C:24]2[CH:25]=[C:26]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]5[CH2:42][CH:41]5[CH3:43])=[O:39])[N:36]=4)[N:33]=3)[CH:44]=[CH:45][C:46]=2[CH3:47])=[O:10])[N:5]([CH3:11])[N:4]=1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4C)cn3n2)cc1N
Reactant: COc1cc(C(=O)O)n(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5C)cn4n3)ccc2C)n(C)n1
Yield: 68.8 %

Procedure:
Using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (194 mg, 1.24 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (109 μL, 1.22 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide (300 mg, 0.89 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 249, the title compound (291 mg, 69%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4](C(OC(C)(C)C)=O)[N:3]=1.[O:14]=[S:15]1(=[O:42])[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:28]=[C:29]([CH:33]=[C:34]([O:36][C@@H:37]([CH3:41])[CH2:38][O:39][CH3:40])[CH:35]=3)[C:30](O)=[O:31])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17][CH2:16]1>>[O:42]=[S:15]1(=[O:14])[C:21]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:28]=[C:29]([CH:33]=[C:34]([O:36][C@@H:37]([CH3:41])[CH2:38][O:39][CH3:40])[CH:35]=3)[C:30]([NH:1][C:2]3[CH:6]=[CH:5][NH:4][N:3]=3)=[O:31])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCCS3(=O)=O)cc(C(=O)O)c1
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCCCS3(=O)=O)cc(C(=O)Nc2cc[nH]n2)c1

Procedure:
The preparation of 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate was described earlier. The preparation of 3-[(5,5-dioxido-3,4-dihydro-2H-1,5-benzoxathiepin-8-yl)oxy]-5-{[(s)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid is described below.