Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:23][N:21]2[CH2:22][C@@H:5]([CH2:6][C@:7]([C:57]([O:59][CH3:60])=[O:58])([C:24]3[CH:25]=[C:26]4[C@:34]56[C@@H:38]7[C@:39]([CH2:54][CH3:55])([C@@H:43]([O:50][C:51]([CH3:53])=[O:52])[C@:44]([OH:49])([C:45]([O:47][CH3:48])=[O:46])[C@@H:33]5[N:32]([CH3:56])[C:27]4=[CH:28][C:29]=3[O:30][CH3:31])[CH:40]=[CH:41][CH2:42][N:37]7[CH2:36][CH2:35]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][C:12]([S:17][CH3:18])=[CH:11][C:10]=4[C:9]=3[CH2:19][CH2:20]2)[CH:4]=1.Cl.C(C[OH:67])(F)(F)F.[BH4-].[Na+]>O.O.O.O.O.O.O.C([O-])(=O)C([O-])=O.[Fe+3].C([O-])(=O)C([O-])=O.C([O-])(=O)C([O-])=O.[Fe+3].CO.CCN(CC)CC>[CH3:1][CH2:2][C@@:3]1([OH:67])[CH2:23][N:21]2[CH2:22][C@@H:5]([CH2:6][C@:7]([C:57]([O:59][CH3:60])=[O:58])([C:24]3[CH:25]=[C:26]4[C@:34]56[C@@H:38]7[C@:39]([CH2:54][CH3:55])([C@@H:43]([O:50][C:51]([CH3:53])=[O:52])[C@:44]([OH:49])([C:45]([O:47][CH3:48])=[O:46])[C@@H:33]5[N:32]([CH3:56])[C:27]4=[CH:28][C:29]=3[O:30][CH3:31])[CH:40]=[CH:41][CH2:42][N:37]7[CH2:36][CH2:35]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][C:12]([S:17][CH3:18])=[CH:11][C:10]=4[C:9]=3[CH2:19][CH2:20]2)[CH2:4]1
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccc(SC)cc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Reactant: OCC(F)(F)F
Agent: [Fe+3]
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccc(SC)cc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A mixture of iron(III) oxalate hexahydrate (280.3 mg, 0.58 mmol, 30 equiv) in H2O (77 mL) was cooled to 0° C. and air was bubbled through the mixture for 10 minutes. A solution of 10′-thiomethylanhydro-vinblastine (20a, 16.2 mg, 0.019 mmol) in H2O (0.5 mL), aqueous 0.1 N HCl (0.5 mL), and CF3CH2OH (0.1 mL) was transferred by pipette to the mixture and NaBH4 (14.6 mg, 0.39 mmol, 1 equiv) in H2O (1 mL) was added to the mixture at 0° C. The resulting mixture was stirred for 30 minutes before being quenched by addition of 28-30% aqueous NH4OH (10 mL). The mixture was extracted with 10% MeOH in CH2Cl2 and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. PTLC (SiO2, Et3N:MeOH:FtOAc=3:3:97) provided 10′-thiomethylvinblastine (20b, 5.1 mg, 0.0060 mmol, 31%) as a white solid and 10′-thiomethylleurosidine (2.5 mg, 0.0029 mmol, 15%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([NH2:16])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)(O)[O-].[Na+].[C:22](Cl)(Cl)=[S:23]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([N:16]=[C:22]=[S:23])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cnc(N)c(-c2ccc(F)c(F)c2)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cnc(N=C=S)c(-c2ccc(F)c(F)c2)c1
Reaction time: 0.25 h

Procedure:
To a solution of 3-(3,4-difluorophenyl)-5-methylpyridin-2-amine (0.6 g, 2.7 mmol) in dichloromethane (15 mL) was added a solution of sodium bicarbonate (2.3 g, 26.7 mmol) in water (25 mL) followed by a solution of thiophosgene (0.25 mL, 3.2 mmol) in dichloromethane (1 mL) and the mixture stirred for 15 minutes. The phases were separated and the organic phase was dried with sodium sulfate and the solvent was evaporated in vacuo to afford the title compound was obtained as a crystalline yellow solid (0.7 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3cnc(NCCN4CCNCC4)nc23)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCN(CCNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(1-piperazinyl)ethylamino]pyrimido[5,4-d]pyrimidine by reaction with acetic anhydride. Melting point: 196°-198° C.; Rf : 0.59 (alumina; methylene chloride/methanol=10:0.4)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=2.C([O-])=O.[Na+].O1CCCC1>O.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl.CC1C=CC(S(N[C@@H]([C@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C@H:12]([OH:14])[CH3:13])=[CH:7][CH:6]=2
Reactant: CC(=O)c1ccc2cnc(Cl)cc2c1
Agent: Cl[Ru]Cl
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: O=C[O-]
Solvent: Cc1ccc(C(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)c1ccc2cnc(Cl)cc2c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
Dichloro(p-cymene)ruthenium(II) dimer (3 mg, 0.005 mmol) and (1R,2R)-(−)-N-p-tosyl-1,2-diphenylethylenediamine (4.4 mg, 0.012 mmol) was suspended in degassed water (2 mL) and the mixture was degassed with nitrogen for 15 minutes. The mixture was stirred at 70° C. under nitrogen for 90 minutes. The resulting yellow solution was cooled to room temperature. 1-(3-Chloro-isoquinolin-6-yl)-ethanone (206 mg, 1 mmol), sodium formate (340 mg, 5 mmol) and degassed tetrahydrofuran (1 mL) were added and the reaction mixture was degassed with nitrogen for 5 minutes. The reaction mixture was vigorously stirred at 40° C. for 2.5 hours. The reaction mixture was cooled to room temperature and was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 4:1 to 2:1 to afford the title compound (193 mg, 92%) as a white solid. 1H NMR (300 MHz, CDCl3) δ1.60 (d, J=5.9 Hz, 3H), 2.14 (d, J=3.1 Hz, 1H), 5.08-5.16 (m, 1H), 7.63 (dd, J=8.6, 1.6 Hz, 1H), 7.72 (s, 1H), 7.77 (br s, 1H), 7.96 (d, J=8.6 Hz, 1H), 9.04 (s, 1H). LCMS (m/z) 208/210 [M+H], Tr=4.25 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH3:12])[NH:9]2)=[CH:5][CH:4]=1.ClS([N:17]=[C:18]=O)(=O)=O.C([O-])(O)=O.[Na+]>C(#N)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:18]#[N:17])=[C:8]([CH3:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc2cc(C)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc2c(C#N)c(C)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 6-methoxy-2-methyl-1H-indole (3.9 g, 24 mmol) in acetonitrile (200 mL) and DMF (20 mL) is added dropwise a solution of ClSO2NCO (4 mL, 1.3 eq.) in acetonitrile (31 mL) at 0° C. After the addition, the mixture is stirred at room temperature for 3 h. Then it is poured into ice water and saturated NaHCO3 is added to it until it becomes basic. The aqueous phase is extracted with CH2Cl2 and then evaporated. The residue is purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 81% of 6-methoxy-2-methyl-1H-indole-3-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]CC2C=CC=CC=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:21][CH2:20]1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[Cl:16][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[O:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:21][CH2:20]1
Reactant: FC(F)(F)c1ccc(N2CCC(COc3c(Cl)cc(OCc4ccccc4)cc3Cl)CC2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1cc(Cl)c(OCC2CCN(c3ccc(C(F)(F)F)cn3)CC2)c(Cl)c1

Procedure:
This compound was prepared in a manner analogous to that of Example 1 Step B, by the treatment of 2.5 grams (0.0049 mole) of 1,3-dichloro-5-(phenylmethoxy)-2-({1-[5-(trifluoromethyl)(2-pyridyl)](4-piperidyl)}methoxy)benzene with hydrogen gas in the presence of 0.3 gram (catalyst) of 10% palladium on carbon in 25 mL of ethyl acetate and 50 mL of ethanol using a Parr hydrogenation apparatus. The yield of the subject compound was 2.0 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CN1CCOCC1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9].[C:18](Cl)(=[O:26])[O:19][CH2:20][O:21][C:22](=[O:25])[CH2:23][CH3:24]>C(Cl)Cl>[C:18](=[O:26])([O:19][CH2:20][O:21][C:22](=[O:25])[CH2:23][CH3:24])[O:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCC(=O)OCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(=O)OCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 60.7 %

Procedure:
4-Methylmorpholine (0.67 mL, 6.0 mmol) is added to a suspension of 4-nitrophenol (0.83 g, 6.0 mmol) in CH2Cl2 (10 mL) with stirring. A solution of 7c (1.27 g, 95% purity, 7.2 mmol) in CH2Cl2 (3 mL) is added during 20 min followed by stirring at 0° C. (30 min) and overnight at room temperature. After filtration the filtrate is evaporated and the residue partitioned between ice-cold Et2O (25 mL) and H2O (25 mL). The organic phase is extracted with ice-cold 0.5N NaOH (10 mL), H2O (3×15 mL), dried (MgSO4) and evaporated. The residue (1.50 g) is extracted with hexane (2×10 mL) to leave the title compound (0.98 g, 61%), mp 35°-36° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[F:8][C:9]([F:17])([F:16])[C:10]1([CH3:15])[CH2:14][CH2:13][CH2:12][NH:11]1.C(N(CC)CC)C.Cl>C1COCC1>[C:3]([N:11]1[CH2:12][CH2:13][CH2:14][C:10]1([C:9]([F:17])([F:16])[F:8])[CH3:15])(=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C(F)(F)F)CCCN1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCCC1(C)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A solution of 6.03 g (0.05 mol) of 2,2-dimethylpropionyl chloride in 25 ml of THF was added dropwise to a solution of 7.65 g (0.05 mol) of 2-trifluoromethyl-2-methylpyrrolidine in 15 ml of THF, to which 5.6 g (0.055 mol) of triethylamine had been added. The course of the reaction is exothermic. The dropwise addition was effected slowly enough that the temperature did not rise to above 35° C. Stirring was continued for one hour at room temperature, and the mixture was then poured into 200 ml of ice-water, the pH was adjusted to 4-5 using dilute hydrochloric acid, and the mixture was extracted twice using 60 ml portions of dichloromethane. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was stripped off under a water pump vacuum. The oil which remained was chromatographed over a short silica gel column (mobile phase toluene/ethyl acetate 1:1). After the mobile phase had been removed, 9.12 g (77% yield of theory) of N-pivaloyl-2-trifluoromethyl-2-methylpyrrolidine are obtained as a pale yellow oil having a refractive index of nD20 : 1,4615 (GC purity: 97.7%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[CH:17]=[C:16]([C:18](OCC)=[O:19])[CH:15]=[CH:14][N:13]=2)[CH:7]=1)=O)C.[BH4-].[Na+].[Cl-].[NH4+].[BH4-]>C(O)C>[OH:19][CH2:18][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([C:8]2[CH:7]=[C:6]([CH2:4][OH:3])[CH:11]=[CH:10][N:9]=2)[CH:17]=1
Reactant: CCOC(=O)c1ccnc(-c2cc(C(=O)OCC)ccn2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: OCc1ccnc(-c2cc(CO)ccn2)c1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
To a suspension of the diester (1) (3.0 g, 10.0 mmol) in 200 mL of absolute ethanol, 8.2 g of sodium borohydride was added in one portion. The mixture was refluxed for 3 hours, cooled to room temperature, then 200 mL of a saturated aqueous solution of ammonium chloride was added to decompose the excess borohydride. The ethanol was removed and the precipitated solid was dissolved with a minimum amount of water. The resulting solution was extracted with ethyl acetate (5×200 mL) then dried over sodium sulfate and rotary-evaporated. The 1.7 g (80% yield) of solid (2) thus obtained was used without further purification. 1H NMR (300 MHz, CD3OD) δ ppm: 4.75 (4H, s, 2CH2OH), 7.43 (2H, d, 3JHH=6 Hz, aryl H on C5 and C5′), 8.25 (2H, s, aryl H on C3 and C3′), 9.00 (2H, d, 3JHH=6 Hz, aryl H on C6 and C6′). Elemental analysis of C12H12N2O2: calcd. C 66.65, H 5.59, N 12.95%, found C 65.90, H 5.70, N 12.32%.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:37])=[CH:7][CH:6]=1)(O)=[O:3].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>C(Cl)Cl.C(OCC)(=O)C.O>[CH3:24][O:23][C:21]([C:20]1[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:2]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[O:3])=[CH:6][CH:7]=2)[C:12](=[O:37])[C:13]2[C:18]([C:19]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:22]
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1-c1ccc(C(=O)O)cc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1-c1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A solution of the compound obtained in Example 21 (200 mg), 1-hydroxybenzotriazole (69 mg) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (86 mg) in methylene chloride (10 ml) is stirred at room temperature for 30 minutes. To the mixture is added a solution of morpholine (71 mg) in methylene chloride (2 ml), and the mixture is stirred at room temperature overnight. After the reaction is complete, to the mixture are added water and ethyl acetate. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from diethyl ether to give 3-methoxycarbonyl-2-[4-(morpholinocabonyl) phenyl]-4-(3,4,5-trimethoxyphenyl)-1(2H) isoquinolinone (210 mg) as listed in Table 4.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.ClC1C=C(N2[C:24]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[C:27](Cl)[CH:26]=3)=[CH:23][C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=N2)C=CC=1F>>[F:31][C:29]1[CH:30]=[C:25]([C:24]2[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=3)[N:11]=[C:22]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: COc1cccc(NN)c1
Agent: Cl
Product: CCOC(=O)c1cc(-c2cccc(F)c2)n(-c2cccc(OC)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 8A and 3-methoxyphenylhydrazine hydrochloride in analogy to the synthesis of the compound of Example 21A. 30.4 g (62% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:24][CH:25]=O)[CH2:9][N:10]([CH3:23])[C:11]([C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[O:27]=[C:28]1[NH:33][CH2:32][CH2:31][CH2:30][N:29]1[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[O:27]=[C:28]1[NH:33][CH2:32][CH2:31][CH2:30][N:29]1[CH:34]1[CH2:39][CH2:38][N:37]([CH2:25][CH2:24][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][N:10]([CH3:23])[C:11]([C:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[O:12])[CH2:36][CH2:35]1
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CN(CC(CC=O)c1ccc(Cl)cc1)C(=O)c1cccc2c1CCCC2
Product: CN(CC(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)cc1)C(=O)c1cccc2c1CCCC2

Procedure:
Using standard reductive amination conditions N-[2-(4-chlorophenyl)-4-oxobutyl]-N-methyl-5,6,7,8-tetrahydro-1-naphthamide was reacted with with 4-(tetrahydro-2-oxo-1(2H)-pyrimidinyl)piperidine and converted to the citrate salt. MS: m/z 537 (M+H). Analysis for C3H41CIN4O2.C6H8O7. H2O: calculated: C, 59.36; H, 6.87; N, 7.46; found: C, 59.42; H, 6.71; N, 7.12.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:15])(O)[CH:10]([CH3:13])[CH2:11][OH:12].C(N(CC)CC)C.ClCCl.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O>[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)([O:12][CH2:11][CH:10]([CH3:13])[CH:9]([OH:15])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:34])=[O:33]
Reactant: CC(CO)C(O)(O)Cc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(C)C(O)Cc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of 13.5 g (68.1 mmol) of 4-(2-fluorophenyl)-3-hydroxy-2-methylbutane-1,3-diol, 14.2 ml (21.3 mmol) of triethylamine, and 70 ml of dichloromethane was cooled with an ice bath and 13.0 g (68.1 mmol) of p-toluenesufonyl chloride was added to the mixture. After stirring overnight at room temperature, 100 ml of water was added thereto, followed by extraction 3 times each with 200 ml of dichloromethane, and the combined organic layer was dried with anhydrous sodium sulfate. After drying, the solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 21.1 g of the title compound as a colorless oil. (Yield: 88%)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:25])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=3Br)=[CH:11][CH:12]=2)[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH3:26])[CH2:6][C:5]1([CH3:34])[CH3:33])(=[O:3])[CH3:2].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[F-].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(COC)OC.C(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:25])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:11][CH:12]=2)[C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH3:26])[CH2:6][C:5]1([CH3:34])[CH3:33])(=[O:3])[CH3:2]
Reactant: COc1ccc(Br)c(C(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(-c2ccccc2)c(C(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)c1

Procedure:
Suzuki cross-coupling of 1-acetyl-4-phenyl-6-(2-bromo-5-methoxybenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (30 mg), benzeneboronic acid (25 mg), cesium fluoride (21 mg), triphenylphosphine (7.0 mg) and tris(dibenzylideneacetone)dipalladium(0) (6.0 mg) in dimethoxyethane/ethanol 4:1 (v/v) (5 ml) was performed according to the method described in example 13.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2.[Cl:12][C:13]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+].ClC1C(C2C=C3C(=CC=2)NN=C3)=CC=CN=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[C:18]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:11])[N:6]=[CH:5]3)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Reactant: Cn1ncc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Clc1ncccc1-c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1ncc2cc(-c3cccnc3Cl)ccc21
Yield: 73.3 %

Procedure:
Analogous to the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole,5-(2-chloropyridin-3-yl)-1-methyl-1H-indazole was prepared by heating the mixture of 5-bromo-1-methyl-1H-indazole (1.0 g, 4.7 mmol), 2-chloro-3-pyridine boronic acid pinacol ester (1.2 g, 5.2 mmol), Pd(PPh3)4 (270 mg, 0.23 mmol) and 2M aq. Na2CO3 (6 mL, 12 mmol) in 1,4-dioxane (75 mL) under argon atmosphere for 12 h. Upon work-up as discussed in the preparation of 5-(2-chloropyridin-3-yl)-1H-indazole and purification of the concentrate by flash silica gel column chromatography [Combiflash® companion System® with RediSep® silica gel column 40 g, 30-50% EtOAc/hexanes eluting solvent gradient upon dry loading the concentrate absorbed on silica gel] provided 5-(2-chloropyridin-3-yl)-1methyl-1H-indazole as white solid (0.84 g, 73%). 1H NMR (DMSO-d6): δ 8.41 (dd, 1H, J=1.7 and 4.7 Hz), 8.10 (s, 1H), 7.90 (dd, 1H, J=1.7 and 7.6 Hz), 7.83 (app t, 1H, J=0.6 Hz), 7.72 (dd, 1H, J=0.6 and 8.8 Hz), 7.51 (dd, 1H, J=4.7 and 7.6 Hz), 7.48 (dd, 1H, J=1.7 and 8.8 Hz), 4.07 (s, 3H).LCMS: rt 6.73 min (A), purity 99%, MS (m/e) 244 (MH+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([OH:12])([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17].CC1C=CC=CN=1>>[C:15]([O:12][C:3]([C:4]([F:7])([F:6])[F:5])([C:8]([F:9])([F:11])[F:10])[C:2]([F:13])([F:14])[F:1])(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)Cl
Reactant: OC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccn1
Product: C=C(C)C(=O)OC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Yield: 78 %

Procedure:
Perfluoro-tertiary-butyl methacrylate was prepared from perfluoro-tertiary-butyl alcohol and methacrylyl chloride with 2-methyl pyridine as the acid acceptor without added solvent. The yield was 78%. The boiling point was 30° C./0.5 mm. This material is useful as a monomer for making plastics and resins.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:26])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:14]=1)[C:9](O)=[O:10].[CH2:27]([O:29][C:30](=[O:39])[CH2:31][S:32][C:33]1[S:37][C:36]([NH2:38])=[N:35][CH:34]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:39])[CH2:31][S:32][C:33]1[S:37][C:36]([NH:38][C:9](=[O:10])[C:8]2[CH:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=3)[CH:14]=[C:6]([O:5][C@@H:4]([CH3:26])[CH2:3][O:2][CH3:1])[CH:7]=2)=[N:35][CH:34]=1)[CH3:28]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(F)(F)F)cc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(C(F)(F)F)cc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from 3-((S)-2-methoxy-1-methyl-ethoxy)-5-(4-trifluoromethyl-phenoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])[CH:8]=2)[NH:3]1.[CH:23](OCC)=[O:24].[O-]CC.[Na+].Cl>C(O)C>[OH:24][CH:23]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])[CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Temperature: 78 °C
Yield: 83.8 %

Procedure:
N-[3-(2-Oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (0.452 g, 1.54 mmol) and ethyl formate (0.370 mL, 4.60 mmol) were dissolved in anhydrous ethanol (6.50 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (2.90 mL, 7.69 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding pure N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (0.415 g, 1.29 mmol, 84%).