Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[N:3]=1
Reactant: NC(=O)c1ccc(Cl)nc1OC1CCCC1
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Cl)nc1OC1CCCC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
To a solution of 6-chloro-2-cyclopentyloxy-nicotinamide (1.56 g, 6.48 mmol) and pyridine (3.14 mL, 38.88 mmol) in acetonitrile (30 mL), phosphorus oxychloride (1.77 mL, 19.44 mmol) was added over a period of 5 min. The reaction was stirred at 55° C. for 1 h. Acetonitrile was evaporated in vacuo and the resulting residue was then neutralized with 1N NaOH at 0° C. until pH reached to 7. The reaction mixture was extracted with EtOAc (100 mL). The organic layer was collected and the aqueous was further extracted with EtOAc (3×50 mL). All organics were combined washed with brine (2×25 mL), dried over anhyd. Na2SO4, filtered, and concentrated to give the title compound (1.63 g, 94%) as yellow oil, which was carried forward without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=7.8 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 5.49-5.42 (m, 1H), 2.25-1.78 (m, 2H), 1.80-1.64 (m, 4H), 1.60 (t, J=6.8 Hz, 2H).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:9]#[N:10]>O.Cl>[OH:2][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:9]#[N:10]
Reactant: Cc1ccc(C#N)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C#N)cc1O
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
A solution of 49.2 g (0.72 mol) of NaNO2 in 217 ml of water was added dropwise over the course of 30 min to 85 g (0.72 mol) of 3-amino-4-methylbenzonitrile in 1.8 l of 6N HCl at 0-5° C. The mixture was then stirred at 0-5° C. for a further 30 min and then at the boiling point for 1 h. After the solution had cooled it was possible to extract the product with ethyl acetate and, from this, the phenolate with ice-cold 5N NaOH. The aqueous phase was then acidified to pH 3 with 6N HCl and the product was extracted with ethyl acetate. 41 g (43%) of the phenol were obtained. 1H-NMR (DMSO-d6; δ in ppm): 10.3 (s, OH); 7.25 (dd, 1H); 7.15 (d, 1H); 7.1 (dd, 1H); 2.20 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6]C(C(NC(CC2C=CC=CC=2)=O)C(O)=O)[NH:4][CH:3]1[C:21]([OH:23])=[O:22].COC1C=CC=C(N)C=1.C1(C)C=CC=CC=1.C(O)(=O)C>O>[NH2:4][C@@H:3]([C:21]([OH:23])=[O:22])[C:2]([SH:6])([CH3:24])[CH3:1]
Reactant: CC1(C)SC(C(NC(=O)Cc2ccccc2)C(=O)O)NC1C(=O)O
Agent: COc1cccc(N)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(S)[C@@H](N)C(=O)O
Reaction time: 4 h

Procedure:
3.52 g (0.01 mole) of benzylpenicilloic acid, 3.70 g (0.03 mole) of m-anisidine and 20 ml of toluene were added to a solution of 3.60 g (0.06mole) of acetic acid in 30 ml of water. The mixture was heated under reflux, with stirring, for 4 hours in a nitrogen atmosphere. The reaction mixture was then treated as described in Example 9 to give D-penicillamine as colorless crystals: yield 1.07 g (71.8%), m.p. 201°-202° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:20]([O:27][C:28]1[CH:29]=[C:30]([CH:59]=[CH:60][C:61]=1[F:62])[C:31]([NH:33][NH:34][C:35](=[O:58])[C@H:36]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[C:50](Cl)[C:49]=1C)[C@@H:37]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[CH3:38])=O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].[CH2:63]([Cl:65])Cl>>[Si:40]([O:39][C@@H:37]([CH3:38])[C@@H:36]([NH:47][C:48]1[CH:49]=[CH:50][C:51]([C:54]#[N:55])=[C:63]([Cl:65])[C:53]=1[CH3:52])[C:35]1[O:58][C:31]([C:30]2[CH:59]=[CH:60][C:61]([F:62])=[C:28]([O:27][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH:29]=2)=[N:33][N:34]=1)([C:43]([CH3:46])([CH3:44])[CH3:45])([CH3:42])[CH3:41]
Reactant: ClCCl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)c(O[Si](C)(C)C(C)(C)C)c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
Triphenylphosphine (331 mg, 1.26 mmol) was dissolved in 25 mL of DCM followed by addition of 12 (321 mg, 1.26 mmol) and TEA (256 mg, 2.53 mmol) at 0° C. 3-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-fluorobenzohydrazide (410 mg, 0.631 mmol) in 15 mL DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to rise to room temperature and stirred for additional 10 min. The reaction was quenched with 50 mL saturated sodium thiosulfate and extracted with EtOAc. The crude mixture was chromatographed to give the product (400 mg). 1H NMR (500 MHz, CDCl3, δ in ppm): 7.69 (m, 3H), 7.54 (d, J=9 Hz, 1H), 7.35 (t, J=9 Hz, 1H), 6.65 (d, J=9 Hz, 1H), 5.56 (d, J=9 Hz, 1H), 4.99 (m, 1H), 4.74 (m, 1H), 2.37 (s, 3H), 1.62 (d, J=6 Hz, 3H), 1.20 (s, 9H), 1.06 (s, 9H), 0.40 (s, 6H), 0.27 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1.C(Br)(Br)(Br)[Br:26].[CH2:30]([NH:42][C:43](=[O:63])[C:44]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:47]([O:58][CH2:59][CH2:60]O)=[C:46]([Br:62])[CH:45]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CCOC(C)=O>[CH2:30]([NH:42][C:43](=[O:63])[C:44]1[CH:49]=[C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:47]([O:58][CH2:59][CH2:60][Br:26])=[C:46]([Br:62])[CH:45]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2cccc(OC)c2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(OC)c2)c1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a flamed dried flask was added triphenylphosphine (98 mg, 0.373 mmol) and 1.5 mL anhydrous THF. This was stirred until all the triphenylphosphine had dissolved. Then CBr4 (123 mg, 0.373 mmol) was added. The reaction mixture was stirred for one-half hour at room temperature then it was cooled to ° C. before N-dodecyl-3-bromo-4-(2-hydroxyethoxy)-5-(3-methoxyphenyl)benzamide (200 mg, 0.373 mmol) was added. The cooling bath was removed after the addition was complete. After the reaction mixture had warmed up to room temperature, 0.2 eq each of triphenylphosphine (19.6 mg, 0.075 mmol) and CBr4 (24.8 mg, 0.075 mmol) were added. The reaction was stirred for one-half hour then the solvent was removed under vacuum to give a yellow semisolid. This material was subjected to flash chromatography (25% EtOAc:75;% Hexanes) to yield 150 mg, 67% of a yellow oil. 1H NMR (CDCl3) δ1.25 (t, J=8.13 Hz, 3H); 1.22-1.40 (m, 18H); 1.52-1.63 (m, 2H); 3.35 (t, J=8.18 Hz, 2H); 3.40 (q, J=6.54 Hz, 2H); 3.84-3.90 (m, 5H); 6.00 (m, 1H); 6.93 (dd, J=8.18 Hz, 2.45 Hz, 1H); 7.07-7.11 (m, 2H); 7.35 (t, J=8.18 Hz, 1H); 7.65 (d, J=2.45 Hz, 1H); 7.9 (d, J=2.45 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]3=[N:10][C:9]=2[C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[C:24]([NH:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[O:25])[CH:5]=[CH:4][N:3]=1.[N:38]1([CH:44]2[CH2:49][CH2:48][N:47]([C:50]3[CH:56]=[CH:55][C:53]([NH2:54])=[C:52]([O:57][CH3:58])[CH:51]=3)[CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[N:38]1([CH:44]2[CH2:49][CH2:48][N:47]([C:50]3[CH:56]=[CH:55][C:53]([NH:54][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][C:15]([C:17]([F:19])([F:20])[F:18])=[CH:16][C:11]6=[N:10][C:9]=5[C:21]5[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=5)[C:24]([NH:26][C:27]5[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=5[F:33])=[O:25])[CH:5]=[CH:4][N:3]=4)=[C:52]([O:57][CH3:58])[CH:51]=3)[CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3cc(C(F)(F)F)ccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: COc1cc(N2CCC(N3CCCCC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3cc(C(F)(F)F)ccn23)n1
Temperature: 145 °C
Yield: 63.2 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Example 189, step A) (110 mg, 0.21 mmol) and 4-(1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline (Example 22, step C) (54 mg, 0.19 mmol) in 2,2,2-trifluoroethanol (2 mL) was added p-toluenesulfonic acid monohydrate (95 mg, 0.50 mmol). The mixture was stirred and heated on a microwave at 145° C. for 40 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow solid. The solid was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (95 mg, 0.12 mmol, 65%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.46 (br s, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 8.23-8.28 (m, 2H), 8.08 (d, 1H, J=7.88 Hz), 7.84 (d, 1H, J=7.70 Hz), 7.64 (t, 1H, J=7.70 Hz), 7.18-7.45 (m, 5H), 6.70 (d, 1H, J=2.20 Hz), 6.47-6.53 (m, 2H), 3.74-3.81 (m, 5H), 2.61-2.68 (m, 2H), 2.42-2.48 (m, 4H), 2.28-2.37 (m, 1H), 1.75-1.82 (m, 2H), 1.34-1.59 (m, 8H). MS (ESI): 782 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:4]1[C@:21]2(O)[C@:16]([CH3:24])([CH2:17][CH2:18][C:19](=[O:23])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3].C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC[C@]5(O)[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[K+].[Br-]>CC(C)=O.C(OCC)(=O)C>[CH2:1]([C@H:4]1[C:21]2[C@:16]([CH3:24])([CH2:17][CH2:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3]
Reactant: C#CC[C@@H]1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C[C@]12O
Agent: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)CCCC[C@]34C)[C@@H]1CC13OCCOC12OCCO3
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
6β-Propargyl-5α-hydroxyandrostane-3,17-dione (10). The 6β-propargyl bisketal 8 (0.6 mmol) was dissolved in acetone (30 ml) and p-TSOH (5 mg) was added. The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate, washed (5% NaHCO3, brine, water) and dried. The ethyl acetate was removed in vacuo and the product was purified by column chromatography to yield the dione 90% yield; m.p. 145°-146° C.; IR (KBr) 3475 (C C--H), 3300 (OH), 2100, 1735 and 1715 (C=O) cm-1 ; 1H-NMR (CDCl3) δ 0.91 (s, 3H, 18-CH3), 1.21 (s, 3H 19-CH3), 3.0 (d, 1H, 4β-H).
Reaction SMILES: C(OC(=O)CCCOC1C=CC=C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)C=1CCC(OCC)=O)C.[CH2:49]([O:51][C:52](=[O:93])[CH2:53][CH2:54][CH2:55][O:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]2[CH:75]=[C:74]([C:76]([N:78]3[CH2:82][CH2:81][C:80]([F:84])([F:83])[CH2:79]3)=[O:77])[CH:73]=[C:72](Br)[CH:71]=2)[C:58]=1[CH2:86][CH2:87][C:88]([O:90][CH2:91][CH3:92])=[O:89])[CH3:50].[CH2:94]1[O:102][C:101]2[CH:100]=[CH:99][C:98](B(O)O)=[CH:97][C:96]=2[O:95]1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.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]>[CH2:49]([O:51][C:52](=[O:93])[CH2:53][CH2:54][CH2:55][O:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]2[CH:75]=[C:74]([C:76]([N:78]3[CH2:82][CH2:81][C:80]([F:84])([F:83])[CH2:79]3)=[O:77])[CH:73]=[C:72]([C:99]3[CH:98]=[CH:97][C:96]4[O:95][CH2:94][O:102][C:101]=4[CH:100]=3)[CH:71]=2)[C:58]=1[CH2:86][CH2:87][C:88]([O:90][CH2:91][CH3:92])=[O:89])[CH3:50]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N3CCC(F)(F)C3)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCC(F)(F)C3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Yield: 80.1 %

Procedure:
The title compound was prepared by the same method as 4-{3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester starting from 4-[3-{6-[3-bromo-5-(3,3-difluoro-pyrrolidine-1-carbonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (150 mg, 0.215 mmol), 3,4-methylenedioxyphenylboronic acid (73.56 mg, 0.43 mmol), PdCl2(dppf) (23.6 mg, 0.03 mmol) and cesium carbonate (141.5 mg, 0.43 mmol) in 1,2-dimethoxyethane (5.0 mL) to obtain 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(3,3-difluoro-pyrrolidine-1-carbonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (127 mg, 80%) as a colorless oil
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=[O:15]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cccc(F)c1
Product: COC(=O)c1nc(C)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.91 min; [M+H]+=252.1.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([N:43]=[C:44]=[O:45])[CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:44]([NH:43][C:35]4[CH:34]=[C:33]([O:32][CH3:31])[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=4)=[O:45])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)Nc2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 44.7 mg (0.21 mmol) of 3,4,5-trimethoxyphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 11 mg (17.4% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH2:17][CH2:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:18]1[N:22]=[CH:21][N:20]([C:23](N2C=NC=C2)=[O:24])[CH:19]=1>C(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[CH2:17][CH2:16][C:11]3[N:12]=[C:13]([NH:15][C:23]([N:20]4[CH:19]=[CH:18][N:22]=[CH:21]4)=[O:24])[S:14][C:10]=3[C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)c1nc2c(s1)CCc1nc(N)sc1-2
Solvent: ClCCl
Product: CC(C)(C)c1nc2c(s1)CCc1nc(NC(=O)n3ccnc3)sc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-tert-Butyl-4,5-dihydro-benzo[1,2-d;3,4-d′]bisthiazol-2-ylamine (Stage T.1, 175 mg, 0.659 mmol) was dissolved in DCM (10 mL), CDI (297 mg, 1.648 mmol) was then added, and the RM was stirred at rt for 2 h. The title compound was isolated by filtration, washed with DCM and dried under HV.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:14]([CH2:17][C:18]([F:19])([F:21])[F:20])[CH2:15][O:16][C:30]3=[O:32])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCC(CC(F)(F)F)Nc1nc(-c2ccc(Br)cc2)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCC(CC(F)(F)F)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 83.2 %

Procedure:
2-{[4-(4-Bromophenyl)-1,3-thiazol-2-yl]amino}-4,4,4-trifluorobutan-1-ol (0.700 g, 1.83 mmol), prepared in the previous step, was dissolved in 20 mL of methylene chloride. Triethylamine (2.65 mL, 18.3 mmol) was added and the solution was cooled to 0° C. Triphosgene (1.36 g, 4.6 mmol) was added in two portions and the mixture was stirred at 0° C. for 45 min and then at 25° C. for 2 h. The mixture was diluted with methylene chloride and poured into 250 mL of saturated aqueous sodium bicarbonate and the layers were separated. The organics were washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (5% acetone/hexane) afforded the title compound (0.62 g, 83%) as a white solid. mp 163-165° C. HRMS: calcd for C14H10BrF3N2O2S+H+, 406.96712; found (ESI, [M+H]+), 406.9679. Analytical HPLC: retention time 10.8 min, 210-370 nm the Xterra® RP18 column, 3.5%, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]([C:32]1[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35])=[C:30]=[O:31]>C(Cl)Cl>[CH3:37][O:36][C:34](=[O:35])[C:33]1[CH:38]=[CH:39][CH:40]=[CH:41][C:32]=1[NH:29][C:30]([N:9]1[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:28])=[O:31]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.1 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (70.3 mg, 0.166 mmol) and methyl 2-isocyanatobenzoate (Aldrich, 150.7 mg, 0.851 mmol) in CH2Cl2 (9 mL) was stirred at rt for 18 hrs. The reaction mixture was then concentrated and purified by flash column to give rac-2-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (67.9 mg, 68.1%). HRMS (ES+) m/z Calcd for C31H29Cl2F2N3O3+Na [(M+Na): 622.1446; Found: 622.1449.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:10][C:9]2[NH:8][C:7]([S:11][C:12]#N)=[CH:6][C:5]=2[C:4](=[O:14])[CH2:3]1.CI.[OH-].[K+].CO.O>CO>[CH3:1][C:2]1([CH3:15])[CH2:10][C:9]2[NH:8][C:7]([S:11][CH3:12])=[CH:6][C:5]=2[C:4](=[O:14])[CH2:3]1
Reactant: CC1(C)CC(=O)c2cc(SC#N)[nH]c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Solvent: CO
Product: CSc1cc2c([nH]1)CC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
To a stirred solution of 6,6-dimethyl-2-thiocyanato-4,5,6,7-tetrahydro-1H-indol-4-one (400 mg, 1.8 mmol) and MeI (124 μL, 2.0 mmol) in MeOH (10 mL) at −5° C. was added a solution of KOH (117 mg, 2.1 mmol) in 1:1 MeOH/water (6 mL), maintaining the temperature below 0° C. The mixture was stirred for 3 h at room temperature, after which time the MeOH was removed and the residue partitioned between DCM and water. The organic layer was separated and the aqueous phase re-extracted with DCM. The combined organic layers were dried (Na2SO4) and evaporated to afford the title compound (350 mg, 88%) as a colourless solid. mp 195-196° C. Found: C, 62.20; H, 7.13; N, 6.34%. Calc. C11H15NOS.0.2(H2O): C, 62.06; H, 7.29; N, 6.58%. 1H NMR (360 MHz, d6-DMSO) δ 1.02 (6H,s), 2.19 (2H,s), 2.34 (3H,s), 2.61 (2H,s), 6.30 (1H,d, J=2.4 Hz), 11.59 (1H,br s). MS (ES+) 210 (M+1).
Reaction SMILES: [CH:1]1([CH2:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])[CH2:4][CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:26].[Na+]>CO.O>[CH:1]1([CH2:5][C:6]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:24])=[O:26])=[CH:21][CH:22]=2)([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[OH:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CSc1ccc(C(O)(CC2CCC2)c2cc3cccnc3[nH]2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccc(C(O)(CC2CCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
A solution of 2-cyclobutyl-1-(4-methylsulfanyl-phenyl)-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanol (90 mg, 0.266 mmol) in methanol (6 mL) was added a sodium metaperiodate (171 mg, 0.798 mmol) solution in water (3 mL). The resulting mixture was stirred for 12 h at room temperature, extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to afford 2-cyclobutyl-1-(4-methanesulfinyl-phenyl)-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanol (94.2 mg, 100%) which was used in the next step without purification: LC/MS m/e calcd for C20H22N2O2S [M+H]+ 355.47, observed 355.4.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([OH:12])[C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.[CH2:13]([N:31]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[C:32](=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].Cl>N1C=CC=CC=1>[CH2:44]([N:31]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:32](=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](=[O:40])(=[O:41])[NH:1][C:2]2[CH:11]=[C:10]([OH:12])[C:5]3[N:6]=[C:7]([CH3:9])[O:8][C:4]=3[CH:3]=2)[CH:34]=1)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1nc2c(O)cc(N)cc2o1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Nc2cc(O)c3nc(C)oc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a stirred solution of the 6-amino-4-hydroxy-2-methylbenzoxazole (4.1 g, 0.025 mole) in pyridine (190 ml) was added N,N-dioctadecyl-3-chlorosulfonylbenzamide (Example 5) (18.8 g, 0.026 mole). The mixture was stirred at ambient temperature overnight, then poured into ice water (2 liters) and acidified with hydrochloric acid (200 ml). The resulting precipitate was collected, washed well with water, and dried to yield a tan solid (17.3 g, 81.2 percent). TLC showed the product to be homogeneous.