Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[F-].[Cs+].Cl[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])=[N:20][N:21]2[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:17][CH:16]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])=[N:20][N:21]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(SC)cc3)ccc12
Temperature: 100 °C
Reaction time: 72 h
Yield: 48.4 %

Procedure:
0.81 g of 86% 4-methylthiophenylboronic acid, 1.24 g of caesium fluoride, 13.5 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously in Example 25, in 30 cm3 of dioxane. The mixture is then heated at about 100° C. for 20 hours, the temperature is allowed to return to room temperature over 72 hours and the reaction medium is then filtered on a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The work-up and the purification are performed by analogy with Example 41 above; 0.60 g of N-[6-(4-methylthiophenyl)-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-3-yl]butanamide is thus obtained in the form of a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(=O)O[CH2:13][CH2:12][O:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[N:1]1([CH2:13][CH2:12][OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1OCCO1
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OCCn1ccc2ccccc21

Procedure:
A mixture of indole (5.71 g, 48.7 mmol), ethylene carbonate (4.72 g, 53.6 mmol) and K2CO3 (6.73 g, 48.7 mmol) in DMF (20 mL) was heated under reflux for 2 h. The reaction mixture was diluted with dichloromethane, filtered, and concentrated in vacuo. The light brown oily residue was purified by chromatography on silica gel (13×6 cm) using n-hexane/ethyl acetate (1:1) as eluent. This gave 1.78 g (23%) of the title compound as a beige oil. HRMS m/z calcd for C10H11NO (M)+ 161.0841, found 161.0849. Anal. (C10H11NO.0.1H2O) C, H, N. *Previously described in a) J. Med. Chem. 1992, 35, 994-1001; b) ibid. 1998, 41, 1619-1630.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C([N:13]1[CH2:18][CH:17]=[C:16]([CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][S:22]2(=[O:27])=[O:26])[CH2:15][CH2:14]1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:5][O:4][C:2]([N:13]1[CH2:14][CH:15]=[C:16]([CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][CH2:23][S:22]2(=[O:27])=[O:26])[CH2:17][CH2:18]1)=[O:3]
Reactant: O=S1(=O)CCCN1CCC1=CCN(Cc2ccccc2)CC1
Reactant: COC(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)N1CC=C(CCN2CCCS2(=O)=O)CC1

Procedure:
Methyl chloroformate (3.3 cm3) was added at room temperature to a stirred solution of 2-[2-(1-benzyl-1,2,3,6-tetrahydropyrid-4-yl)ethyl]isothiazolidine-1,1-dioxide (4.5 g) in toluene (20 cm3) and the mixture was heated under reflux for 16 hours. Volatile material was removed in vacuo to give the crude 2-[2-(1-methoxycarbonyl-1,2,3,6-tetrahydropyrid-4-yl)ethyl]isothiazolidine-1,1-dioxide as an oil (5.0 g).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].C(N(CC)CC)C.[C:32](OCC)(=[O:38])[C:33](OCC)=[O:34]>COC(O)C>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[NH:10][C:11](=[O:14])[C:12]2[NH:13][C:33](=[O:34])[C:32](=[O:38])[NH:6][C:7]=2[N:8]=1)[CH2:23][CH3:24]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: COC(C)O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1-c1nc2[nH]c(=O)c(=O)[nH]c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.0 g), triethylamine (0.42 ml) and diethyl oxalate (1.2 ml) in methoxyethanol (10 ml) was heated under reflux for 7 hours. The reaction mixture was stirred overnight at ambient temperature and a precipitate was collected and washed with water and ethanol to afford a crude product (0.70 g, m.p. 312-315° C.). The crude product together with another sample (0.34 g) similarly prepared was twice recrystallized from dimethylformamide to afford th e title compound, 0.40 g, m.p. 320-321° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[CH:9](O)([CH3:11])[CH3:10]>OS(O)(=O)=O>[F:1][C:2]1([CH:9]([CH3:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH2:3]1
Reactant: CC(C)O
Reactant: Fc1cccc(F)c1
Agent: O=S(=O)(O)O
Product: CC(C)C1(F)C=CC=C(F)C1
Temperature: 65 °C
Reaction time: 4 h
Yield: 55.3 %

Procedure:
To a rapidly stirred mixture of 1,3-Difluorobenzene (31.5 ml, 320 mmol) and 80% H2SO4 (150 ml), Isopropanol (25 ml, 320 mmol) was added at room temperature. The mixture was heated to 65° C. and stirred for four hours. The resulting light brown mixture was cooled to room temperature. The organic layer was separated from the H2SO4 and washed twice with 50 ml saturated NaCl (aqueous). The organic layer was subjected to fractional distillation to give 55.2% (27.6 g, 177 mmol) of the title compound and 27.1% (9.9 g, 86.8 mmol) recovered 1,3- Difluorobenzene.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:43])([CH3:42])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[CH:21]1[C@:12]([CH3:41])([C@@:13]3([CH3:40])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([C:32](=[O:39])[NH:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[CH3:46][O:47][C:48]([C:50]1[S:54][C:53](B(O)O)=[CH:52][CH:51]=1)=[O:49].C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[CH3:38][N:36]([CH3:37])[CH2:35][CH2:34][NH:33][C:32]([C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:40])([CH2:14][CH2:15]2)[C@@:12]2([CH3:41])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:42])([CH3:43])[C:7]([C:53]2[S:54][C:50]([C:48]([O:47][CH3:46])=[O:49])=[CH:51][CH:52]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1)=[O:39]
Reactant: COC(=O)c1ccc(B(O)O)s1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)s6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 90 °C
Yield: 60.8 %

Procedure:
A mixture of (1R,3aS,5aR,5bR,7aR,11aR,13aR,13bR)-3a-(2-(dimethylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (100 mg, 0.152 mmol), 5-(methoxycarbonyl)thiophen-2-ylboronic acid (36 mg, 0.228 mmol), tetrakis(triphenylphosphine)palladium(0) (5.2 mg, 0.0045 mmol) and sodium carbonate (48 mg, 0.456 mmol) in water (1 mL) and DME (1 mL) was heated up at 90° C. for 2 hours. The reaction mixture was quenched with distilled water, extracted with ethyl acetate (3×5 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a brown oil (60 mg, 32%). LCMS: m/e 647.63 (M−H)−, 2.67 min (method 1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[N:25]([CH2:31][CH3:32])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=2[C:22]=1[O:35][CH3:36].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[N:25]([CH2:31][CH3:32])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=3[C:22]=2[O:35][CH3:36])=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Reactant: CS(=O)(=O)N[C@@H]1CCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(N[C@@H]3CCC[C@H]3NS(C)(=O)=O)n1)c2OC
Temperature: 120 °C
Yield: 40.3 %

Procedure:
N-[trans-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclopentyl]-methanesulfonamide (60 mg, 0.185 mmol), 7-amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (43 mg, 0.185 mmol) and camphorsulfonic acid (64 mg, 0.278 mmol) were combined in 3 mL isopropanol and heated at 120° C. in microwave for a total of 110 min. The reaction was concentrated to be taken up in dichloromethane and washed with saturated sodium bicarbonate solution (2×30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on a 4 g amine capped ISCO flash column from 0-100% ethyl acetate in hexanes. The product was collected as a foam after concentrating to afford 39 mg (40%) of a white foam. Compound 4: mp 141° C.; MS (ES+ calculated—523; found—524 M+H). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8, 1H), 8.01 (s, 1H), 7.37 (s, 1H), 7.01 (d, J=8, 1H), 6.11 (s, 1H), 5.46 (d, 1H), 4.25 (m, 1H), 3.82 (s, 3H), 2.89 (m, 1H), 2.89 (s, 4H), 2.32 (br s, 6H), 1.89 (m, 2H), 1.73 (m, 1H), 1.59 (s, 3H), 1.15 (t, J=7, 4H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+]([O-])=O)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].[CH3:17][O-:18].[Na+].[Na]>CO>[CH3:17][O:18][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Five (5) g (22 mmol) methyl 3,5-dinitrobenzoate (Aldrich) were suspended in 80 mL methanol (A.C.S. grade) and heated to reflux for app. 1 h under nitrogen, until a clear brown solution had formed. A simultaneously prepared sodium methoxide solution (prepared by portionwise addition of 0.76 g (33 mmol, 1.5 eq.) sodium to 10 mL methanol, the reaction flask was purged with nitrogen until all sodium had reacted) was added dropwise to the hot solution by syringe, each drop causing a deep red color. The reaction mixture was refluxed for an additional 15 h. After cooling to r.t., it was concentrated to dryness, the remaining brown-purple solid was taken up in 30 mL distilled water and acidified with 2 N HCl. The addition of ethyl acetate caused the present light orange solid to dissolve, phases were separated and extraction with ethyl acetate was repeated twice. The combined organic layers were washed with sat. aq. NaHCO3, with brine, then dried with MgSO4 and concentrated, leaving 3.7 g of a pale yellow solid. The crude product was purified by column chromatography (7:3 hexanes/ethyl acetate, Rf=0.6, UV; note: starting material coelutes but should be gone after the reaction time given) to afford 2.3 g (50%) of a light yellow solid. The procedure can be scaled up to 30 g starting material: depending on the course of the reaction, crude product material might be sufficiently pure to be carried on into the next step without further purification. mp 88-89° C. 2; 1H NMR (CDCl3) δ 8.46 (dd, J1=1.5 Hz, J2=2.4 Hz, 1H), 7.92 (t, J1=2.4 Hz, J2=2.4 Hz, 1H), 7.88 (dd, J1=1.5 Hz, J2=2.4 Hz, 1H), 3.99 (s, 3H, OCH3), 3.95 (s, 3H, OCH3); 13C NMR (CDCl3) δ 164.59, 160.00, 148.95, 132.37, 120.84, 116.36, 112.65, 56.02, 52.60.
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>>[OH:36][CH2:35][CH2:37][NH:38][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: NCCO
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCO)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
4-{5-[2-Chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19, 50 mg, 0.104 mmol) in ethanolamine (1.5 mL) was heated under microwave irradiation at 150° C. for 30 mins. The reaction mixture was partitioned between water and DCM and the organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated in MeCN and then purified by preparative C18 HPLC, eluting with a gradient of 20-90% MeCN in water (+0.1% formic acid) to give the title compound as a white solid (8 mg).
Reaction SMILES: C(C1C=[CH:23][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=CC=1)C.[CH3:25][C:26]1[O:27]C=C(CCl)[N:30]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:7][C:6]2[N:30]=[C:26]([CH3:25])[O:27][CH:23]=2)[CH:10]=1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Reactant: Cc1nc(CCl)co1
Product: COCOc1cc(SCc2coc(C)n2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 2-methyl-4-chloromethyl-1,3-oxazole instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:5]([NH:25]CC2C=CC(OC)=CC=2)=[N:6][C:7]([O:23][CH3:24])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[O:21][CH3:22])[N:9]=1)[CH3:3]>CCOCC.[Pd].CO>[CH2:2]([C:4]1[C:5]([NH2:25])=[N:6][C:7]([O:23][CH3:24])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:12][C:11]=2[O:21][CH3:22])[N:9]=1)[CH3:3]
Reactant: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1NCc1ccc(OC)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1N
Reaction time: 18 h
Yield: 93.2 %

Procedure:
1M hydrochloric acid in ether (2 mL) and 10% palladium on carbon (40 mg) are added to {3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl}[(4-methoxyphenyl)methyl]amine (115 mg, 0.25 mmol) in methanol (3 mL) under a nitrogen atmosphere. The mixture is then hydrogenated at 1 ATM for 18 hours, filtered through Celite and evaporated to give 3-ethyl-6-methoxy-5-[2-methoxy-4(trifluoromethoxy)phenyl]pyrazin-2-ylamine (80 mg).
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[O:1]=[C:2]([CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCC(O)CCCCCCCCCCCCCCC(=O)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CCC(=O)CCCCCCCCCCCCCCC(=O)O

Procedure:
16-hydroxystearic acid was selectively oxidized with Dess-Martin reagent to yield 16-oxostearic acid. The crude product was purified by chromatography using silica gel as separating agent.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([CH2:20][O:21][C:22]3[C:27]([F:28])=[CH:26][C:25]([CH2:29][CH:30]([CH3:36])[C:31](OCC)=[O:32])=[CH:24][C:23]=3[F:37])=[C:18]([C:38]([F:41])([F:40])[F:39])[S:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8]>>[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([CH2:20][O:21][C:22]3[C:27]([F:28])=[CH:26][C:25]([CH2:29][CH:30]([CH3:36])[CH2:31][OH:32])=[CH:24][C:23]=3[F:37])=[C:18]([C:38]([F:39])([F:40])[F:41])[S:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCOC(=O)C(C)Cc1cc(F)c(OCc2c(-c3ccc(CC)cc3)nsc2C(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CC(C)CO)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 111 by LAH reduction of ethyl 3-(4-((3-(4-ethylphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)-3,5-difluorophenyl)-2-methylpropanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 7.71 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 6.78-6.84 (m, 2H), 5.21 (s, 2H), 3.41 (d, J=6.8 Hz, 2H), 2.71-2.79 (m, 3H), 2.30-2.36 (m, 1H), 1.82-1.91 (m, 1H), 1.30 (t, J=7.6 Hz, 3H), 0.89 (d, J=6.8 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H22F5NO2S, 472.2 (M+H). found 472.2.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2([CH3:31])[C:25](=[C:26]=[S:27])[C:24](=[C:28]=[S:29])[CH2:23][CH2:22][C:21]2=O)[CH:15]=1>O1CCCC1.C(OCC)(=O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2([CH3:31])[C:25](=[C:26]=[S:27])[C:24](=[C:28]=[S:29])[CH2:23][CH2:22][C:21]2=[CH:3][C:1]#[N:2])[CH:15]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC1(c2cccnc2)C(=O)CCC(=C=S)C1=C=S
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2cccnc2)C(=C=S)C(=C=S)CCC1=CC#N
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of diethyl cyanomethylphosphonate (18.2 g, 0.1 mol) in dry tetrahydrofuran (200 ml) at 25° C. was treated with sodium hydride (4.5 g of a 60% oil dispersion). After 30 mins at 25° C. the mixture was treated with 2-(pyrid-3-yl)-2-methyldithiocarbonylcyclohexanone (24.7 g, 0.93 mol) in dry tetrahydrofuran (100 ml). After 3 hrs at reflux the mixture was cooled to 25° C. over 30 mins, diluted with ethyl acetate (500 ml) and then washed with water (500 ml). The organic phase was removed and dried over magnesium sulphate and then filtered. Concentration in-vacuo (50° C.; 20 mm Hg) afforded a crude oil which wa purified by flash chromatography over silica gel, eluting with ethyl acetate/n-hexane (25:75) to give 2-(pyrid-3-yl)-2-methyldithiocarbonyl-1-cyanomethylenecyclohexane (7.4 g, 0.026 mol) as an orange gum.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[CH2:66]([N:68]([CH2:73][CH3:74])[CH2:69][CH2:70][CH2:71][NH2:72])[CH3:67]>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:72][CH2:71][CH2:70][CH2:69][N:68]([CH2:73][CH3:74])[CH2:66][CH3:67])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CCN(CC)CCCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCCNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)c(OC)c1
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.02 g (0.15 mmole) N,N-diethyl-propane-1,3-diamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.041 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-diethylamino-propyl)-3-methoxy-benzamide (I-123) as a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[C:17]([C:24]4[C:25](=[O:34])[NH:26][C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:18]3C([O-])=O)=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].O.CSC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[C:17]([C:24]4[C:25](=[O:34])[NH:26][C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)[NH:18]3)=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CCN(Cc2ccc3cc(-c4cc5ccccc5[nH]c4=O)n(C(=O)[O-])c3c2)CC1
Solvent: ClCCl
Solvent: O
Solvent: CSC
Product: CS(=O)(=O)N1CCN(Cc2ccc3cc(-c4cc5ccccc5[nH]c4=O)[nH]c3c2)CC1
Reaction time: 1.5 h

Procedure:
Boc-indole 2-3 (120 mg, 0.22 mmol) was slurried in 3 mL of CH2Cl2, H2O (10 μL) and dimethylsulfide (10 μL). TFA (3 mL) was added and the reaction was observed to become homogenous. The reaction was then stirred for 1.5 hours. The excess TFA/CH2Cl2 was removed under reduced pressure. The residue was dissolved in DMSO and purified via reverse phase HPLC (95%-5% H2O/AcCN). The pure fractions were combined in a separatory funnel and the pH adjusted to 11 by the addition of 0.5N NaOH. The mixture was then extracted with CH2Cl2/nBuOH (3:1, 2×100 mL). The organic layer was washed with brine, dried with Na2SO4 and concentrated to give 2-4 as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 12.06 (s, 1H), 11.43 (s, 1H), 8.52 (s, 1H), 7.73 (d, 1H, J=7.8 Hz), 7.51 (d, 2H, J=7.3 Hz), 7.44 (bs, 1H), 7.37 (d, 1H, J=8.1 Hz), 7.31 (bs, 1H), 7.24 (t, 1H, J=7.3 Hz), 6.98 (d, 1H, J=7.6 Hz), 3.62 (s, 2H), 3.12 (m, 4H), 2.87 (s, 3H), 2.48 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8].[CH3:27][C:28]1[C:32]([S:33]([NH2:36])(=[O:35])=[O:34])=[C:31]([CH3:37])[O:30][N:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:5][N:6]([CH3:22])[C:7]([C:9]1[CH2:13][N:12]([CH2:14][CH2:15][CH2:16][C:17]([NH:36][S:33]([C:32]2[C:28]([CH3:27])=[N:29][O:30][C:31]=2[CH3:37])(=[O:34])=[O:35])=[O:18])[C:11](=[O:20])[C:10]=1[OH:21])=[O:8]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Reactant: Cc1noc(C)c1S(N)(=O)=O
Product: Cc1noc(C)c1S(=O)(=O)NC(=O)CCCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O

Procedure:
Compound 756 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and 3,5-dimethyl-isoxazole-4-sulfonic acid amide using the method described for compound 751. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 40% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0296 g, 21% yield). HRMS (M−H) calcd for C22H23N4Cl2O7S: 557.06645. found: 557.0663.