Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.Cl.[Cl:8][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:12][N:13]1[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:22])[CH2:14]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:12][N:13]1[CH2:18][CH2:17][O:16][C@@H:15]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:27][CH2:26]2)=[O:22])[CH2:14]1
Reactant: O=C(NCC1CCNCC1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(CNC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)CC1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
Methane sulphonyl choride (0.013 ml) was added to a solution of Intermediate 18 (0.054 g) and N,N-diisopropylethylamine (0.063 ml) in dichloromethane (2 ml). The solution was stirred for 16 h at 23° C. The solvent was removed in vacuo and the residue purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol, to give the title compound as a clear gum (0.035 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:5]([CH3:9])[C:6]([OH:8])=O.[C:19]([O-])(=[O:21])[CH3:20].[Na+]>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:9])=[C:6]([O:8][C:19](=[O:21])[CH3:20])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[CH:10]=1)=[O:18]
Reactant: CC(=O)[O-]
Reactant: COC(=O)C(=Cc1ccc(F)cc1)C(C)C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2ccc(F)cc2c(OC(C)=O)c1C
Temperature: 150 °C
Reaction time: 3 h
Yield: 34 %

Procedure:
To a solution of crude 2-(4-fluoro-benzylidene)-3-methyl-succinic acid 1-methyl ester (approximately 49 g, 0.196 mol) in acetic anhydride (490 mL) was added sodium acetate (32.15 g, 0.392 mol) in one portion. The reaction mixture was stirred at 150° C. for 3 hours. After this time, the reaction mixture was cooled to room temperature, then stirred overnight. Acetic anhydride was removed in vacuo, providing a viscous brown oil. This crude product was dissolved in ethyl acetate. The resulting solution was washed with a saturated, aqueous ammonium chloride solution. The organic phase was dried over Na2SO4, filtered, and concentrated. Flash chromatography (Analogix SuperFlash™ 10% ethyl acetate in hexane) gave 18.4 g (34%) of 4-acetoxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[F:20])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:21][NH:22][S:23](Cl)(=[O:25])=[O:24].[BH4-].[Na+]>N1C=CC=CC=1>[F:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[CH:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[NH:1][S:23](=[O:25])(=[O:24])[N:22]1[CH3:21]
Reactant: Nc1c(C(=O)c2ccncc2F)ccc2cccnc12
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1C(c2ccncc2F)c2ccc3cccnc3c2NS1(=O)=O
Yield: 31.7 %

Procedure:
In a similar fashion using route 27 general procedure 70, (8-amino-quinolin-7-yl)-(3-fluoro-pyridin-4-yl)-methanone (Intermediate 372) (60 mg, 0.22 mmol), N-methylsulfamoyl chloride (Intermediate 213) (87 mg, 0.67 mmol) and NaBH4 (8.5 mg, 0.22 mmol) in pyridine (5 ml) gave the title compound (24 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1.[Br:21]Br.O>O>[Br:21][C:17]1[C:18]([Cl:20])=[CH:19][C:4]2[N:3]=[C:2]([Cl:1])[N:6]([C@@H:7]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]3[OH:9])[C:5]=2[CH:16]=1
Reactant: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)ccc32)[C@H](O)[C@@H]1O
Reactant: BrBr
Solvent: O
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Br)cc32)[C@H](O)[C@@H]1O
Reaction time: 6 h

Procedure:
To a suspension of 0.110 g (0.313 mmol, as C12H12Cl2N2O4MeOH) of 2,5-dichloro-1-β-D-ribofuranosylbenzimidazole in 3 mL of H2O was added dropwise 10 mL of a sat. solution of Br2 /H2O at room temperature. After the addition has been completed, stirring was continued for 6 h. The reaction mixture was filtered and the solid was washed with portions of H2O, and then recrystallized from MeOH to give 0.091 g (73%, 2 crops) of 99 as white crystalline needles. MP 158°-159° C. MS (El) m/e 395.9274 (5% M+ =395.9279). 1H NMR (DMSO-d6): δ8.69 (s, 1, 7-H), 7.96 (s, 1, 4-H), 5.88 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.51 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.41 (t, 5'-OH, J5'-5'OH =4.5 Hz), 5.30 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.42 (m, 1, 2'-H, J2'-3' =5.5 Hz), 5.30 (d, 1, 3'-OH, J3'-4' =1.5 Hz), 4.01 (m, 1, 4'-H, J4'-5' =J4'-5'=2.5 Hz), 371 (m, 2, 5'-H and 5"-H, J5'-5" =1.20 Hz). Anal. Calcd. for C12H11BrCl2N2O4 : C, 36.21; H, 2.79; N, 7.04. Found: C, 36.14; H, 2.90; N, 6.90.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:27])[CH:11]=[C:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH2:23][CH2:24][CH:25]=[CH:26][C:15]=2[CH:14]=[CH:13]1.CO.[Li+].[OH-].Cl>O>[CH:22]1[C:17]2[C:16]3[CH2:23][CH2:24][CH:25]=[CH:26][C:15]=3[CH:14]=[CH:13][C:12](=[CH:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[O:27])[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CCCCCNC(=O)C=C1C=CC2=C(CCC=C2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCNC(=O)C=C1C=CC2=C(CCC=C2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
6-(2-(10,11-dihydro-5H-dibenzocyclohepten-5-ylidene)acetamido)hexanoic acid methyl ester (377 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (265 mg, 73% yield) as a white solid. LC-MS (m/z) 364 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH:13]1[C:17](B(O)O)=[CH:16][CH:15]=[N:14]1.C([O-])(O)=O.[Na+]>COCCOC.O>[F:12][C:9]1[CH:10]=[CH:11][C:2]([C:15]2[NH:14][N:13]=[CH:17][CH:16]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)ccc1Br
Reactant: OB(O)c1ccn[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(F)ccc1-c1ccn[nH]1
Temperature: 23 °C
Yield: 44.9 %

Procedure:
Methyl 2-bromo-5-fluorobenzoate (1.0 gram, 4.2 mmol) and (1H-pyrazol-5-yl)boronic acid (485 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 ml) then treated with NaHCO3 (706 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 (243 mg (0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. The reaction mixture was cooled to 23° C., filtered, and solid rinsed with EtOAc. The organic layers were separated, dried and concentrated. Purification via FCC (ethyl acatate/hexanes, 0-30%) afforded methyl 5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415 mg, 44%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)=[N:5]/[O:6][CH3:7].[H-].[Na+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1>CN(C=O)C.O>[CH3:1][NH:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:26]2[S:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)[CH:16]=1)=[N:5]/[O:6][CH3:7]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1cccc(O)c1
Reactant: Clc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1cccc(Oc2nc3ccccc3s2)c1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of (E)-N-methyl-2-[2-(3-hydroxyphenoxy)phenyl]-2-methoxyiminoacetamide (0.21 g) in DMF (3 ml), sodium hydride (34 mg) and 2-chloro-1,3-benzothiazole (0.18 g) were added, and the resultant mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water and extracted with ether. The solvent was dried and the residue was purified by silica gel column chromatography to give 0.27 g of the objective compound.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH2:14][CH2:15][O:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:17][O:16][CH2:15][CH2:14][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OCc1ccc2c(c1)NCCC2
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN1CCCc2ccc(CO)cc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (1,2,3,4-tetrahydroquinolin-7-yl)methanol (370 mg, 1.496 mmol), 1-bromo-2-methoxyethane (0.141 ml, 1.496 mmol) and Cs2CO3 (731 mg, 2.244 mmol) in DMF (10 ml). was stirred for 16 hr at 80° C. Additional 1-bromo-2-methoxyethane (0.070 ml, 0.748 mmol) was added and stirring was continued for 16 hr at 80° C. A third batch of 1-bromo-2-methoxyethane (0.070 ml, 0.748 mmol) was added and stirring was continued for 1 additional hour at 80° C. The reaction mixture was cooled to room temperature and water was added. The mixture was extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give the title compound. HPLC (Method A) Rt=1.173 min; MS (Method A) [M+H]+=221.9
Reaction SMILES: [F:1][C:2]([F:21])([C:7]1[CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4].[CH:22]([NH:24][C:25](=[O:27])[CH3:26])=[CH2:23].C(N(CC)CC)C.C1(P(C(P(C2C=CC=CC=2)C2C=CC=CC=2)(C)C)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:21])([C:7]1[CH:8]=[C:9]([C:22]([NH:24][C:25](=[O:27])[CH3:26])=[CH2:23])[CH:10]=[CH:11][CH:12]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: C=CNC(C)=O
Reactant: O=S(=O)(Oc1cccc(C(F)(F)C(F)(F)F)c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=C(NC(C)=O)c1cccc(C(F)(F)C(F)(F)F)c1
Temperature: 130 °C

Procedure:
To a solution of the crude product of step 1 (0.75 g, 2.2 mmol) in DMF (10 ml) was added N-vinylacetamide (0.37 g, 4.36 mmol), triethylamine (243 mg, 0.33 ml, 2.40 mmol), palladium acetate (20 mg, 4 mol %) and bis(diphenylphosphino)propane (40 mg, 0.1 mmol). The reaction mixture was heated for 30 min at 130° C. using microwaves. The red solution was diluted and washed with hydrochloric acid (1M, 2×15 ml) and sodium hydrogen carbonate (saturated, 20 ml). The organic phase was dried over sodium sulphate and evaporated. Purification of the crude product by silica gel chromatography using ethyl acetate/n-heptane (2:1) gave the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:25])=[C:8]([CH3:24])[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]=1)=[O:11].Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:25])=[C:8]([CH3:24])[C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][S:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=2)(=[O:33])=[O:32])=[C:14]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:13]=1)=[O:11]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Product: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Yield: 68.3 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (0.516 g, 1.14 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.540 g, 2.28 nmmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with a 15 & 25% EtOAc/hexane step gradient gave 0.509 g (68%) of the title compound as a brown solid, mp 72-82° C. 1H NMR (DMSO-d6) δ1.25-1.34 (m, 2H), 1.50-1.55 (m, 2H), 1.62-1.74 (m, 4H), 1.77 (s, 3H), 2.15 (s, 3H), 2.95 (quintet, 1H), 3.88 (s, 2H), 7.10-7.15 (m, 2H), 7.20 (d, 1H), 7.27 (t, 1H), 7.35-7.37 (m, 2H), 7.48-7.58 (m, 3H), 7.96 (dd, 1H). IR (KBr) 3400,2950, 1690, 1390 and 1190 cm−1. mass spectrum (−ESI) m/z 651 (M−H). Anal. Calcd. for C32H29BrO8S.0.4H2O: C, 58.17; H, 4.55; N, 0.00. Found: C, 58.20; H, 4.55; N, 0.03.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][N:15]([CH3:29])[C:16]([C:18]1[C:19]2[CH2:20][CH2:21][NH:22][CH:23]([CH3:28])[C:24]=2[CH:25]=[CH:26][CH:27]=1)=[O:17]>>[CH3:14][N:15]([CH3:29])[C:16]([C:18]1[C:19]2[CH2:20][CH2:21][N:22]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:23]([CH3:28])[C:24]=2[CH:25]=[CH:26][CH:27]=1)=[O:17]
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(C(=O)N(C)C)cccc21
Product: CC1c2cccc(C(=O)N(C)C)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-1,2,3,4-tetrahydro-isoquinoline-5-carboxylic acid dimethylamide to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([Cl:12])[Cl:11].CS(O)(=O)=O>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([Cl:12])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[SiH](Cl)Cl
Reactant: C=Cc1ccccc1
Agent: [Pt]
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CCCc1ccccc1
Yield: 71 %

Procedure:
Reaction between styrene and methyldichlorosilane with platinum catalyst in the presence of trimethylsilyl ester of methanesulfonic acid. 624 mg Styrene and 732 mg methyldichlorosilane were introduced into a glass tube, and 51 mg of a trimethylsilyl ester of methanesulfonic acid was added with a microsyringe. 0.9 mg Of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.04 wt % platinum content) was added. The tube was sealed with Teflon tape and a rubber septum and placed in a 50° C. oil bath where it was heated for 30 minutes. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 95% and a phenethylmethyldichlorosilane yield of 71%. The ratio between the phenethylmethyldichlorosilane and the (α-methylbenzyl)methyldichlorosilane was 4.6:1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C:20](=[O:21])[N:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[N:43][C:44]([NH2:47])=[CH:45][CH:46]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[N:43][C:44]([NH:47][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])[C:20](=[O:21])[N:19]([CH:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)[C:11]=4[N:12]=3)=[CH:45][CH:46]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CS(=O)c1ncc2cc(NC(=O)OC(C)(C)C)c(=O)n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 105 °C
Yield: 16.8 %

Procedure:
(8-Cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (1.2 g, 3.06 ml, prepared according to Example 9) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.36 g, 8.48 mmol) were combined in toluene (4 ml) and heated to 105° C. for 12 hours. The resulting paste was diluted with toluene, filtered, washed with toluene and partitioned between diethyl ether and 1 N citric acid. The mixture was filtered, and the solid was washed with water and diethyl ether. The solid then was dissolved in chloroform, dried over anhydrous magnesium sulfate, filtered, and the filtrate diluted with diethyl ether, giving a solid precipitate. This solid was collected by filtration and dried in vacuo to give 4-[6-(6-tert-butoxycarbonylamino-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.311 g, 17%). MS (APCI) M++1; Calc'd, 607.3, Found, 607.2.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH:5]([OH:11])[C:6](=[CH2:10])[CH:7]([CH3:9])[CH3:8])=[CH2:3].[C:12](OC)(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>>[C:12]([O:11][CH:5]([C:6](=[CH2:10])[CH:7]([CH3:9])[CH3:8])[CH2:4][C:2]([CH3:1])=[CH2:3])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]
Reactant: COC(=O)CC(C)=O
Reactant: C=C(C)CC(O)C(=C)C(C)C
Product: C=C(C)CC(OC(=O)CC(C)=O)C(=C)C(C)C

Procedure:
reaction of 2,6-dimethyl-5-methylene-1-hepten-4-ol with methyl aceto acetate in order to form 2,6-dimethyl-5-methylene-1-hepten-4-yl aceto acetate or, directly, 5-isopropyl-8-methyl-5,8-nonadiene-2-one;
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])=[CH:9][CH:8]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:36])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.197 mL, 0.197 mmol) was added to a solution of (4′-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 130-(6); 34.4 mg, 0.066 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature overnight. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol:water=4:1:0.3) to give the target compound as a colorless oil (32.1 mg, 95%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([CH2:9][N:10]=[C:11]=[O:12])([CH3:8])[CH2:5][CH:4]([N:13]=[C:14]=[O:15])[CH2:3]1.[OH2:17].[CH3:18][CH:19]([OH:21])[CH3:20]>>[CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([CH2:9][N:10]=[C:11]=[O:12])([CH3:8])[CH2:5][CH:4]([N:13]=[C:14]=[O:15])[CH2:3]1.[CH3:3][CH:4]([NH2:13])[CH2:5][O:17][CH2:18][CH:19]([O:21][CH2:18][CH:19]([O:21][CH2:5][CH:4]([NH2:13])[CH3:3])[CH3:20])[CH3:20]
Reactant: O
Reactant: CC(C)O
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Product: CC(N)COCC(C)OCC(C)OCC(C)N

Procedure:
The same experimental procedures were repeated. A mixture of IPDI (22.2 g, 0.10 M) in i-PrOH (11.2 g) was added into the solution of D-230 (46 g, 0.20 M) in i-PrOH (18 g)-and water (5 g) over a 3 hour period at 20°-30° C. The resulting product solution was analyzed to be 1.88 meq/g for amine (calc. 1.95 meq/g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2.Cl.N([O-])=O.[Na+].O>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([O:20][CH3:21])[C:14]([O:22][CH3:23])=[CH:13]2
Reactant: COc1ccc(N)c(-c2ccc3cc(OC)c(OC)cc3c2)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ccc(-c3ccccc3N)cc2cc1OC
Reaction time: 8 h
Yield: 28.6 %

Procedure:
6-(2-Amino-5-methoxyphenyl)-2,3-dimethoxynaphthalene (33) (60 mg, 0.20 mmol) was dissolved in acetic acid (1.5 mL) and concentrated hydrochloric acid (0.3 mL). The solution was cooled in an ice bath and diazotized by dropwise addition of a solution of sodium nitrite (0.12 g in 1.2 mL water). The resulting diazonium solution was allowed to rise to room temperature slowly and left overnight. To the resulting red solution with some precipitate, 50 mL water was added and then extracted with ethyl acetate (40 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. Dried with anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 35:65 hexanes:ethyl acetate to give the pure 5 (16 mg) in 26% yield; mp 215-217° C.; IR (KBr) 2987, 1617, 1504, 1486, 1394, 1277, 1231, 1167 cm−1; UV (MeOH) 288, 262, 232 nm (log ε=4.71, 4.66, 4.58); 1H NMR (CDCl3) δ4.07 (3H, s), 4.09 (3H, s), 4.22 (1H, s), 7.29 (1H, s), 7.46 (1H, dd, J1=9.1, J2=2.6), 7.72 (1H, J=2.5), 7.99 (1H, d, J=8.9), 8.20 (1H, d, J=9.0), 8.60 (1H, d, J=9.1), 9.17 (1H, s); 13C NMR δ56.31, 56.51, 56.90, 100.27, 104.61, 107.73, 117.00, 118.66, 121.31, 124.25, 126.98, 129.09, 131.40, 133.34, 141.76, 143.70, 151.23, 151.31, 161.95; HRMS (EI) calcd for C19H16N2O3 m/z: 320.1161; found: 320.1144.
Reaction SMILES: [F:1][C:2]([F:15])(F)[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.ClC1C=CC(C#N)=CN=1.[F:25][C:26]([F:32])(C(F)F)CO>>[F:1][C:2]([F:15])([CH:26]([F:32])[F:25])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: OCC(F)(F)C(F)F
Agent: N#Cc1ccc(Cl)nc1
Product: CC(N)c1ccc(OCC(F)(F)C(F)F)nc1

Procedure:
The title compound was synthesised according to the 2-step procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine starting from 6-chloronicotinonitrile and 2,2,3,3-tetrafluoropropan-1-ol.
Reaction SMILES: [Mg].Br[C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[CH2:12]1[O:15][C@H:13]1[CH3:14]>O1CCCC1.CCOCC.[Cu]I>[CH3:12][C@H:13]([OH:15])[CH2:14][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: C[C@H]1CO1
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](O)Cc1ccc2c(c1)OCO2
Temperature: -50 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a suspension of magnesium turnings (17 g) in 50 mL tetrahydrofuran was added dropwise a solution of 5-bromo-1,3-benzodioxole (93.6 g). After complete addition, the mixture was diluted with 250 mL tetrahydrofuran and the resulting mixture was stirred overnight. 13 mL of the solution (0.78 M) was transferred to a round bottom flask containing copper(I) iodide (0.12 g). The resulting mixture was cooled to −50 ° C. and a solution of (S)-(−)-propylene oxide in 3 mL tetrahydrofuran was slowly added then stirred 10 min. The mixture was diluted with ether. The isolated organic phase was washed with water and brine. The aqueous wash was extracted with ether (2×) and the combined organic solutions were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (50% ether in pentane) to give 1.66 g of the desired product (91%). Chiral HPLC analysis indicated that the optical purity of the material was 98.3%.