Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[N:34]1[CH:39]=[CH:38][N:37]=[C:36]2[NH:40][CH:41]=[CH:42][C:35]=12.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[N:34]1[CH:39]=[CH:38][N:37]=[C:36]2[N:40]([CH2:6][C@H:7]3[CH2:12][N:11]([S:13]([C:16]4[S:17][CH:18]=[CH:19][CH:20]=4)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]3[C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=3)[CH:41]=[CH:42][C:35]=12
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: c1cnc2[nH]ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cn2ccc3nccnc32)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a 50-mL round-bottomed flask was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (50 mg, 0.095 mmol, Intermediate B), 5H-pyrrolo[2,3-b]pyrazine (17 mg, 0.142 mmol, ARK Pharm., Libertyville, Ill.) and cesium carbonate (62 mg, 0.19 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 80° C. for 18 h. The mixture was allowed to cool to room temperature. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an off-white glass. The crude product was purified by silica gel chromatography, eluting with 100% EtOAc to give 2-(4-((S)-2-((5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (38 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.[CH3:21][S:22]([CH2:25][C:26](=O)[CH3:27])(=[O:24])=[O:23]>CC(O)C.O.O.[Na+].Cl[Au-](Cl)(Cl)Cl>[CH3:21][S:22]([C:25]1[C:26]([CH3:27])=[N:1][C:2]2[C:3]([C:13]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:4][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=2)(=[O:24])=[O:23]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccccc1
Agent: Cl[Au-](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2ccccc2)c1S(C)(=O)=O
Yield: 40.4 %

Procedure:
(2-Amino-5-trifluoromethoxy-phenyl)-phenyl-methanone (0.3 g, 1 mmol), methylsulfonylacetone (0.22 g, 2 mmol) and sodium tetrachloroaurate (III) dihydrate (13 mg, 0.036 mmol) were mixed in 2-propanol (3 mL) and heated at reflux under nitrogen for 5 days. 2-propanol was evaporated and the residue was purified by flash chromatography on silica gel in heptane/ethyl acetate 2:1. One obtained 154 mg (34%) of a white solid. MS: m/z=382 (M+H).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O1CCOCC1.C([O-])([O-])=O.[K+].[K+].[Br-:26].Cl[CH2:28][CH2:29][CH2:30][P+:31]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35]>C(O)C>[Br-:26].[CH2:1]([NH:13][CH:40]([P+:31]([CH2:30][CH2:29][CH3:28])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:41][CH2:42][CH3:43])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCC[P+](CCCC)(CCCC)CCCCl
Reactant: CCCCCCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCCCCCCCCCNC(CCC)[P+](CCC)(CCCC)CCCC
Temperature: 25 °C

Procedure:
In a 100 ml of reaction flask, 9.30g of n-dodecylamine (about 0.05 mol) (Tianjin Kelong Chemical Agent Factory, CP Grade) was added, and dissolved by adding 25 ml of dioxane under stirring, then 25 ml of anhydrous ethanol and 7.0 g anhydrous K2CO3 (ground) were added, heated to reflux, and 30 ml of an ethanol solution of 13 g (about 0.035 mol) of γ-chloropropyl tributyl phosphonium bromide (13 g of γ-chloropropyl tributyl phosphonium bromide was dissolved previously in 30 ml ethanol) was then added dropwise within 6 hrs under stirring and reflux, then again reacted for 2hrs under stirring and reflux, when the reaction was ended, the inorganic salt was filtered out while the solution was hot, and the solvent was distilled off from the filtrate, then the residue was cooled to room temperature, then 100 ml of diethyl ether was added to separate a large quantity of white solid, and filtered, the crude product was then obtained. The crude product was recrystallized from the mixed solvent of tetrahydrofuran and diethyl ether (volume ratio 1:1) for purification, the γ n-dodecylamino-propyl tributyl phosphonium bromide having the structural formula was then obtained: n-C12H25NH(CH2)3P+(C4H9)3 Br−.
Reaction SMILES: [CH:1]([N:4]([CH2:17][CH2:18][NH:19][CH3:20])[CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([CH3:3])[CH3:2].[CH3:21][Si:22]([CH2:25]Cl)([CH3:24])[CH3:23].[OH-].[Na+]>CO>[CH:1]([N:4]([CH2:17][CH2:18][N:19]([CH3:20])[CH2:25][Si:22]([CH3:23])([CH3:24])[CH3:21])[CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([CH3:2])[CH3:3]
Reactant: CNCCN(CCNC(=O)CN1CCCC1=O)C(C)C
Reactant: C[Si](C)(C)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(CCNC(=O)CN1CCCC1=O)CCN(C)C[Si](C)(C)C
Reaction time: 30 h
Yield: 28.1 %

Procedure:
A mixture of 8.71 g (30.7 mmol) of N-[2-[(isopropyl)[2-(methylamino)ethyl]amino]ethyl]-2-oxo-1-pyrrolidineacetamide and 3.76 g (30.7 mmol) of trimethylsilylmethyl chloride was stirred at 80°-90° C. for 30 hours. The reaction mixture was neutralized with methanol solution of NaOH and concentrated in vacuo. The residue was chromatographed on alumina column and distilled in vacuo to afford 3.20 g (Yield: 28.1%) of the desired compound.
Reaction SMILES: C(O)(=O)C.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C@H:15]([NH:17][CH2:18][C@H:19]([CH3:22])[CH2:20][F:21])[CH3:16])=[CH:6]1.[F:23][C:24]1[CH:25]=[C:26](/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])[CH:27]=[C:28]([F:32])[C:29]=1[CH:30]=O>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:25]=[C:26](/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])[CH:27]=[C:28]([F:32])[C:29]=1[C@@H:30]1[C:6]2[NH:5][C:13]3[C:8]([C:7]=2[CH2:14][C@@H:15]([CH3:16])[N:17]1[CH2:18][C@H:19]([CH3:22])[CH2:20][F:21])=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Reactant: C[C@H](CF)CN[C@H](C)Cc1c[nH]c2ccccc12
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2C[C@H](C)CF)c(F)c1
Temperature: 95 °C
Yield: 61.8 %

Procedure:
Acetic acid (2.0 ml) was added to a solution of (S)—N—((R)-1-(1H-indol-3-yl)propan-2-yl)-3-fluoro-2-methylpropan-1-amine (273 mg, 1.10 mmol) and (E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (obtained as described in Example 1, preparation of starting materials) (226 mg, 1 mmol) in toluene (8.0 ml). The reaction was warmed to 95° C. for 2.5 h. The volatiles were removed under vacuum, then the residue was passed through an SCX-2 column. The column was then eluted with 7M NH3/methanol to liberate the product. The filtrate was concentrated and the crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM. Pure fractious were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-((S)-3-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (282 mg, 61.8%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, 30° C.) δ 0.82 (3H, d), 1.12 (3H, d), 1.81-1.99 (1H, m), 2.24 (1H, ddd), 2.64 (1H, ddd), 2.71 (1H, dd), 2.93-3.01 (1H, ddd), 3.42 (1H, dq), 3.81 (3H, s), 4.25-4.39 (1H, m), 4.38-4.53 (1H, m), 5.20 (1H, s), 6.39 (1H, d), 6.99 (2H, m), 7.06-7.16 (2H, m), 7.21-7.25 (1H, m), 7.52 (3H, m). m/z: ES+ [M+H]+ 457.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][C:6]1([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CCN(CC)CC.N1C=CC=CC=1.CCOC(C)=O>CS(C)=O>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][C:6]1([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COc1cccc(CC2(CO)CCCCCC2)c1OC
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(CC2(C=O)CCCCCC2)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
The alcohol from Step C above (25 g, 89 mmol) was dissolved in 500 mL of anhydrous DMSO. To this solution was added Et3N (50 mL, 358 mmol). Then SO3.Pyridine (57 g, 358 mmol), was dissolved in 400 mL of DMSO, and this solution was added to the reaction vessel. The solution was then stirred at room temperature for two hours. The reaction solution was then poured over ice and the resulting mixture was warmed to room temperature and extracted with CH2Cl2. The organic layer was washed with 1M HCl, water, and brine, then the organic layer was dried over MgSO4, filtered and evaporated. The crude product was chromatographed on silica gel, eluting with 10:1 hexane:EtOAc to give the title product as a colorless oil (20 g, 81% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH3:11])[N:8]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1nc2cc(Br)cnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2cc(Br)cnc2n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To 5.06 g of 5-bromo-2,3-diaminopyridine 46 (Ryabukhin et al (2006) Synthesis 21:3715-3726; Oguchi et al (2000) J. Med. Chem. 43(16):3052-3066; Seki et al (1995) J. Hetero. Chem. 32(3):1071-73; Fray et al (1995) J. Med. Chem. 38(18):3524-35) was added 50 mL acetic acid under N2 and the reaction was heated to reflux overnight. Complete reaction was confirmed by LCMS. The solution was concentrated in vacuo and purified by flash chromatography (DCM/MeOH) to give 4.68 g of 6-bromo-2-methyl-3H-imidazo[4,5-b]pyridine 51 (82% yield), which may also be prepared by the methods of Cee et al (2007) J. Med. Chem. 50(4):627-40; Itoh et al (1982) J. Hetero. Chem. 19(3):513-17. 6-Bromo-2-methyl-3H-imidazo[4,5-b]pyridine (4.68 g) in 150 mL THF was added to 0.63 g (1.1 eq) NaH in 10 mL THF under N2 at −78° C. The reaction was stirred at −78° C. for 30 minutes followed by the addition of 3.86 g of SEM-Cl(1.05 eq) and allowed to warm up to room temperature. The reaction was stirred at room temperature 4.5 hours and complete reaction was confirmed by LCMS. The reaction was quenched with water followed by the addition of NaCl (not saturated) and the two products extracted with EtOAc and concentrated in vacuo. The two regioisomers were separated by flash chromatography (EtOAc/Hexanes) to give 2.84 g 6-bromo-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 52 and 1.94 g 6-bromo-2-methyl-1-((2-trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine 53 (63% overall yield). 6-Bromo-2-methyl-34(2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 52 (2.08 g) was dissolved in 50 mL toluene followed by the addition of 2.32 g (1.5 eq) of bis(pinacolato)diboron, 0.24 g (0.05 eq) of PdCl2(dppf), and 1.79 g (3.0 eq) of KOAc. The reaction mixture was heated to 95° C. under N2 and let stir overnight. Complete reaction confirmed by LCMS. The mixture was cooled to room temperature, rotovapped and purified by flash chromatography (EtOAc/Hexanes) to give 1.83 g of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 54 (77% yield). MS (Q1) 390.2 (M)+
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[S:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=2)[N:12]=1)C(OCC)=O)C.[BH4-].[Na+]>CCO>[OH:3][CH2:4][CH2:5][C:11]1[N:12]=[C:13]2[C:18]([C:17]([NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=3[S:29][C:30]3[CH:31]=[CH:32][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:34][CH:35]=3)=[CH:16][CH:15]=[N:14]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(CCO)ccc23)cc1

Procedure:
The product from Example 23b (56 mg, 0.10 mmol) was reacted with NaBH4 (40 mg, 1.00 mmol) in 5 mL EtOH for 24 h. Quenched with aqueous NH4Cl and adjusted to pH 7 with dilute HCl. Extracted with EtOAc and dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound which was purified by HPLC with TFA giving the trifluoroacetic acid salt (15 mg, 25%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.04 (s, 3 H) 2.35 (s, 3 H) 3.16 (t, J=6.43 Hz, 2 H) 3.91 (t, J=6.25 Hz, 2 H) 6.31 (d, J=6.99 Hz, 1 H) 7.14 (d, J=8.09 Hz, 1 H) 7.22-7.33 (m, 4 H) 7.51 (d, J=8.82 Hz, 2 H) 7.83 (d, J=8.82 Hz, 1 H) 8.42 (d, J=6.99 Hz, 1 H) 8.94-9.05 (m, 1 H) 10.04 (s, 1 H) 11.03 (s, 1 H) 14.40 (s, 1 H); MS (ESI+) m/z 445 (M+H−TFA)+.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C)C=O>C(O)(C)(C)C>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: Sc1ccccc1
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: N=C(N)N1CCC(CCC(=O)OSc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 35 %

Procedure:
A mixture of 2.4 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 1.1 g of thiophenol, 2.1 g of dicyclohexylcarbodiimide and 15 ml of dry dimethylformamide was stirred at room temperature for 17 hours. After removal of any insoluble materials, the solvent was removed. The residue was washed with ether and then with t-butanol to obtain 1.2 g (yield: 36.4%) of phenylthio 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 168° to 170° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([F:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:5]1[C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])=[CH:3][CH:4]=1
Reactant: OB(O)c1ccccc1F
Reactant: O=C(O)c1nc(Br)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1nc(-c2ccccc2F)ccc1F
Yield: 81 %

Procedure:
Method 1 was followed using 6-bromo-3-fluoropicolinic acid (1.0 equiv.) and 2-fluorophenylboronic acid (1.5 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 3-fluoro-6-(2-fluorophenyl)picolinic acid in 81% yield. LC/MS=236.1 (M+H), Rt=0.72 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH2:16]([O:18][C:19](=O)[O:20]CC)[CH3:17].[H-].[Na+]>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([C:3]1[CH:4]=[C:5]([F:9])[CH:6]=[C:7]([F:8])[C:2]=1[F:1])[C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH3:15]
Reactant: CCOC(=O)OCC
Reactant: CCOC(=O)Cc1cc(F)cc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1cc(F)cc(F)c1F
Temperature: 0 °C
Yield: 82.9 %

Procedure:
Ethyl 2-(2,3,5-trifluorophenyl)-acetate (29 g) was slowly added to a mixture of diethylcarbonate (63 g) and sodium hydride (9.5 g) in toluene (350 ml). After being refluxed for 3 hours, the reaction mixture was cooled, treated with ice-water and washed with water. The organic layer was separated, dried and filtered. The filtrate was concentrated in vacuo to yield 32 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[N:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[OH:17][C:7]1([C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)[CH2:16][CH2:15][C:10](=[O:11])[CH2:9][CH2:8]1
Reactant: Cc1cnc(C2(O)CCC3(CC2)OCCO3)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(C2(O)CCC(=O)CC2)s1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A solution of 8-(5-methyl-1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (1.0 g, 4.14 mmol) in 20 mL of THF/3 N HCl (1:1) was stirred for 1 h at 50° C. After cooling to room temperature, the mixture was treated with Na2CO3 to pH 8 and extracted with EtOAc three times. The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated to give 0.82 g (99%) of the desired product. MS (M+H)+=212.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][C:7]=2[CH:8]=1.C(N(CC)CC)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:38][C:28]1[CH:33]=[CH:32][C:31]([S:34]([O:1][CH2:2][CH2:3][C:4]2[O:5][C:6]3[CH:12]=[CH:11][C:10]([C:13]4[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=4)=[CH:9][C:7]=3[CH:8]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(-c2ccc3oc(CCO)cc3c2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCc2cc3cc(-c4ccc(C#N)cc4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
The product from Example 1B (2.03 kg, 7.71 mol) in acetonitrile (31.8 kg) was treated in succession with triethylamine (1.86 kg, 18.34 mol), 4-(dimethylamino)pyridine 0.10 kg, 0.87 mol), and p-toluenesulfonyl chloride (3.50 kg, 17.99 mol). After stirring at room temperature for about 5 hours, the reaction mixture was distilled to a minimum volume and treated with isopropyl alcohol (24.1 kg). The suspension was heated at about 30° C. for 1 hour, then cooled to about 5° C., filtered, and the filter cake was washed with isopropyl alcohol (5.20 kg). The solid was dried at 50° C. to provide 2.59 kg (80% yield) of the title compound. MS-DCI (M+NH4)+ m/z at 435; 1H NMR (CDCl3 at 400 MHz) δ 2.38 (s, 3H), 3.15 (t, 2H), 4.38 (t, 2H), 6.50 (s, 1H) 7.18-7.24 (m, 2H), 7.37-7.46 (m, 2H), 7.67-7.74 (m, 7H); 13C NMR (CDCl3 at 100 MHz) δ 21.9, 28.9, 67.2, 104.4, 110.3, 111.2, 118.7, 119.2, 123.0,127.5, 127.6, 129.0, 129.4, 132.2, 132.4, 133.9, 144.4, 145.7, 154.1, 154.5.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[C:13]([C:20]3[NH:28][C:27]4[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=4[CH:21]=3)[CH:14]=[CH:15][CH:16]=2)[N:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([C:20]4[NH:28][C:27]5[CH2:26][CH2:25][NH:24][C:23](=[O:29])[C:22]=5[CH:21]=4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: Nc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5ccc(Cl)cc5)nc34)cc21
Reaction time: 3 h
Yield: 17.5 %

Procedure:
To 4-chloroaniline (Alfa Aesar, Ward Hill, Mass.; 0.225 g, 1.763 mmol) and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added LHMDS (1.0 M solution in THF; 1.763 ml, 1.763 mmol). After 3 h, the reaction mixture was partitioned between saturated aq. NH4Cl and DCM. The aq. layer was extracted with DCM (3×), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. EtOAc was added, the layers were separated, and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The solid was suspended in MeOH and filtered, rinsing 1× MeOH to give 2-(2-((4-chlorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.017 g, 0.044 mmol, 17% yield) as a dull-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.96 (1H, br. s), 9.62 (1H, s), 8.12 (1H, d, J=9.0 Hz), 7.89 (1H, dt, J=7.2, 0.8 Hz), 7.72-7.81 (2H, m), 7.61 (1H, dt, J=7.8, 0.9 Hz), 7.36-7.46 (2H, m), 7.31 (1H, t, J=7.6 Hz), 7.08 (1H, d, J=9.0 Hz), 6.88-7.00 (2H, m), 3.37-3.52 (2H, m), 2.70 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 389.0 (M+H)+.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.O[CH:15]([C:33]1[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:46])[CH:34]=1)[CH2:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH3:32]>ClCCl>[F:11][CH:15]([C:33]1[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:46])[CH:34]=1)[CH2:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH3:32]
Reactant: CCOC(=O)COc1ccc(C(O)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(F)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
To a solution of bis-(2-methoxyethyl)aminosulfur trifluoride (0.031 g) in anhydrous dichloromethane (0.05 ml) at −78° C. under nitrogen was added a solution of ethyl [4-(1-hydroxy-2-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}ethyl)-2-methylphenoxy]acetate (intermediate 16, 0.061 g) in anhydrous dichloromethane (1 ml). After two hours at −78° C. the reaction was quenched with saturated sodium bicarbonate solution (2.5 ml) and the product extracted into dichloromethane. The organic extract was separated by hydrophobic frit and evaporated to yield a yellow oil. Purification by flash column chromatography using neat cyclohexane and ethyl acetate:cyclohexane (1:9) as eluents to give the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N+:13]=[N-:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[C:15]([N:12]=[N+:13]=[N-:14])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COc1ccc(C=O)cc1Br
Reactant: COC(=O)CN=[N+]=[N-]
Product: COC(=O)C(=Cc1ccc(OC)c(Br)c1)N=[N+]=[N-]

Procedure:
Following the general procedure of PREPARATION 61 and making non-critical variations but starting with 3-bromo-4-methoxybenzaldehyde (5.0 g) and methyl azidoacetate (10.7 g), the title compound is obtained, NMR (300 MHz, CDCl3) 8.10, 7.73, 6.89, 6.79, 3.94 and 3.90 δ.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]2[O:12]C(OCC)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:13]=1[OH:12])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc2c1OC(OCC)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCOc1cccc(O)c1O

Procedure:
A solution of 38 (3.3 g, 15 mmol) and p-toluenesulfonic acid monohydrate (0.17 g, 0.9 mmol) in aqueous MeOH (21 mL, MeOH: H2O 20:1) was stirred at rt for 16 h, then neutralised by the addition of saturated NaHCO3 aq. and the methanol was removed in vacuo. The residue was extracted with t-BuOMe (3×) and the organic phase was dried (Na2SO4) and evaporated to dryness to give 39 compound (2.4 g, 95%) which was used as such in the next step: