Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][O:5][CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][CH:8]=1.[OH-].[Na+]>CO.Cl>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][O:5][CH:6]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCOC(c1ccccc1)c1ccc(C(=O)O)cc1
Yield: 87 %

Procedure:
0.53 g(1.69 mmol) of methyl α-(2-dimethylaminoethoxy)-α-phenyl-p-toluate) was dissolved in 10 ml of methanol. 2.54 ml of a 1N sodium hydroxide aqueous solution was added thereto and the mixture was refluxed under heating for 1 hour. After the reaction mixture was cooled, 2.54 ml of IN hydrochloric acid was added thereto and the mixture was concentrated to dryness. A mixture of chloroform and methanol (5:1 (v/v)) was added to the residue, and the resulting mixture was stirred for a while, then filtered with Celite. The solvent was distilled off and the residue was triturated with diethyl ether. The resulting precipitate was collected by filtration to obtain 0.44 g (1.47 mmol) of α-(2-dimethylaminoethoxy)-α-phenyl-p-toluic acid as pale yellow brown powder. ##STR11## Its spectroscopic data are as follows: 1H-NMR (CDCl1) δ (ppm) 2.62 (6H, s), 3.00 (2H, m), 3.59 (1H, m), 3.82 (1H, m), 5.37 (1H, s), 7.21~7.36 (7H, m), 7.77 (2H, d, J=8.4 Hz).
Reaction SMILES: [I:1][CH:2]=[CH:3][CH2:4][CH:5]([O:10][Si](C)(C)C)[CH2:6][CH2:7][CH2:8][CH3:9]>C(O)(=O)C.O1CCCC1.O>[OH:10][CH:5]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4]/[CH:3]=[CH:2]/[I:1]
Reactant: CCCCC(CC=CI)O[Si](C)(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(O)C/C=C/I

Procedure:
A 23 g portion of 1-iodo-4-trimethylsilyloxy-1-octene is dissolved in a mixture of 200 ml of glacial acetic acid, 100 ml of tetrahydrofuran, and 50 ml of water. Concentration provides the named product.
Reaction SMILES: [Cl-].[CH:2]1([NH2+:10][CH2:11][CH2:12]Cl)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:25]=[C:26]=[S:27]>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[N:25]=[C:26]1[N:10]([CH:2]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:11][CH2:12][S:27]1
Reactant: COc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: ClCC[NH2+]C1CCCCCCC1
Agent: [Cl-]
Product: COc1cc([N+](=O)[O-])ccc1N=C1SCCN1C1CCCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methoxy-4-nitrophenyl isothiocyanate to give 2-(2-methoxy-4-nitrophenylimino)-3-cyclooctyl-1,3-thiazolidine.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1.BrCl>>[Br:7][C:5]1[CH:6]=[C:2]([C:22]#[C:21][C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)=[CH:20][N:19]=2)[S:3][CH:4]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Brc1csc(Br)c1
Agent: ClBr
Product: Clc1ccc(-c2ccc(C#Cc3cc(Br)cs3)nc2)cc1

Procedure:
The product was obtained analogously to Example 7.1e starting from 2,4-dibromothiophene and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 0.78 g (50% of theoretical); C17H9BrClNS (M=374.683); calc.: molpeak (M+H)+: 374/376/378 (BrCl); found: molpeak (M+H)+: 374/376/378 (BrCl); HPLC-MS: 7.40 minutes (method B).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][CH:21]([CH3:27])[CH2:22][CH2:23][C:24](O)=[O:25]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:24](=[O:25])[CH2:23][CH2:22][CH:21]([CH3:27])[CH3:20])[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: CC(C)CCC(=O)O
Product: CC(C)CCC(=O)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 4-methylpentanoic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.42 (m, 1H), 7.88-8.04 (m, 2H), 7.72-7.75 (m, 1H), 7.59-7.69 (m, 4H), 2.34 (t, J=7.7 Hz, 2H), 1.57-1.68 (m, 1H), 1.49-1.54 (m, 2H), 0.92 (d, J=6.6 Hz, 6H); MS (ESI−) M/Z 368 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[S:4][N:3]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16].O>O1CCCC1>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])[S:4][N:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1cc(N)sn1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)sn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
To a solution of 3-methylisothiazol-5-amine (1.00 g, 6.64 mmol) and pyridine (1.30 ml, 7.97 mmol) in tetrahydrofuran (22 ml) was added 2,2,2-trichloroethyl chloroformate (1.10 ml, 7.97 mmol) with ice-cooling and the mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (767 mg, 39.9%) as a solid.
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35](O)=[O:36])[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:40]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:25]([C:35](=[O:36])[NH2:40])[CH2:24][CH2:23]1)[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of (2S,5R)-5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (8.56 g, 16 mmol), EDCI (3.2 g, 16 mmol), HOBt (2.2 g, 16 mmol), NH4Cl (1.7 g, 32 mmol), and DIPEA (4.0 g, 32 mmol) in dry DMF (40 mL) was stirred at rt overnight. The mixture was diluted with EtOAc (300 mL), and washed with water (3×). The organic layer was dried over Na2SO4 and concentrated to give (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-piperidine-1-carboxylate as yellow solid (7.4 g, 86%). ESI-MS (EI+, m/z): 557 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16](=O)[CH3:17])[CH2:11][C:10]=3[C:19](=[O:21])[O:20][C:4]=2[CH:3]=1.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[CH:16]([CH3:17])[CH2:15][N:12]1[CH2:13][CH2:14][C:9]2[C:5]3[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=3[O:20][C:19](=[O:21])[C:10]=2[CH2:11]1
Reactant: CNC
Reactant: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c(C)cc23)C1
Product: Cc1cc2oc(=O)c3c(c2cc1C)CCN(CC(C)N(C)C)C3
Yield: 8.6 %

Procedure:
Prepared by the method described in Example 38 from 1,2,3,4-tetrahydro-8,9-dimethyl-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (7.3 g, 0.026 moles) and dimethylamine (10.0 g, 0.22 moles). Several recrystallizations from acetonitrile yielded the product as the free base (0.7 g) mp 105°-107° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:13]=2)[CH:8]=1)(=O)=O.[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[C:28]1[SH:32].C(N(C(C)C)CC)(C)C.O>O1CCOCC1.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].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([S:32][C:28]2[N:27]([CH3:26])[CH:31]=[CH:30][N:29]=2)[CH:16]=[CH:15]3)=[CH:22][CH:21]=1
Reactant: Cn1ccnc1S
Reactant: O=S(=O)(Oc1ccc2cc(-c3ccc(F)cc3)ccc2c1)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1Sc1ccc2cc(-c3ccc(F)cc3)ccc2c1
Temperature: 125 °C
Yield: 91.2 %

Procedure:
A mixture of 6-(4-fluorophenyl)-2-naphthyl trifluoromethanesulfonate (Ex 1 Step 2, 150 mg, 0.41 mmol), 1-methyl-1H-imidazole-2-thiol (47 mg, 0.41 mmol), tris(dibenzylideneacetone)dipalladium(0) (16 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg) and diisopropylethylamine (0.15 mL, 0.82 mmol) in dioxane (3 mL) was heated to 125° C. under nitrogen for 15 h. The cooled reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with water and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 25% ethyl acetate/isohexane, to give the title compound as an oil (125 mg). 1H NMR (500 MHz, CDCl3): δ 7.90 (1H, s), 7.75 (2H, t, J=8.6 Hz), 7.66-7.59 (4H, m), 7.27 (2H, m), 7.15 (2H, m), 7.10 (1H, s), 3.65 (3H, s); m/z (ES+) 335 [MH+].
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:27]=[CH:26][C:15]([CH2:16][CH:17]([CH2:23][CH:24]=[CH2:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:27]=[CH:26][C:15]([CH2:16][CH:17]([CH2:23][CH:24]=[CH2:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1
Reactant: C=CCC(Cc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCC(Cc1ccc(OCCO)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)benzyl]pent-4-enoate from the previous step (1 eq.) in THF (0.2 M) was added tetrabutylammonium fluoride (1.0 M THF solution, 2 eq.). The resulting reaction mixture was stirred at RT for 2 h. After quenching the reaction with sat. aq. NH4Cl, the mixture was extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 10:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13](N)[C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1.N([O-])=O.[Na+].[ClH:23]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:23])[C:12]([Cl:16])=[CH:11][C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc(N)c(Cl)cc1Cl
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(N)nc(N)c1-c1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4-diamino-5-(5-amino-2,4-dichlorophenyl)-6-methylpyrimidine (1.95 g, 7 mmol) was dissolved in a mixture of concentrated hydrochloric acid (3.6 ml) and water (6 ml). The temperature was lowered to 10° C. A chilled aqueous solution (3.6 ml) of sodium nitrite (0.50 g, 7 mmol) was added dropwise, keeping the temperature at 10° C. This mixture was stirred at room temperature for 2 hours, then chilled before adding it dropwise to a cold solution of cuprous chloride (1.7 g, 17 mmol) in concentrated hydrochloric acid (50 ml). A grey solid precipitated which was filtered off and dried. This crude product (2.30 g) was dissolved in ethyl acetate and washed twice with ammonium hydroxide solution and once with brine. After evaporating the ethyl acetate an off-white solid was obtained (2.04 g). After recrystallisation from 10% methanol in chloroform the pure product was obtained (0.55 g, 2 mmol), mp. 262° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:23])[CH2:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[N:31]1[CH:36]=[C:35]([C:37](O)=[O:38])[CH:34]=[N:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:23][C:37]([C:35]4[CH:36]=[N:31][CH:32]=[N:33][CH:34]=4)=[O:38])[CH2:21][CH2:22]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)CC2)no1
Reactant: O=C(O)c1cncnc1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)c3cncnc3)CC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 24) was coupled with pyrimidine-5-carboxylic acid to yield the title compound as yellow solid. MS: 533.2 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].[ClH:29]>CO>[ClH:29].[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH:19]([NH2:21])[CH3:20])=[CH:16][CH:17]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C#Cc2ccc(CC(C)NC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: CO
Product: CCOc1ccc(C#Cc2ccc(CC(C)N)cc2)cc1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
To 3.30 g (8.70 mmol) tert-butyl 1-(4-((4-ethoxyphenyl)ethynyl)phenyl)propan-2-yl-carbamate (I60) in 40 mL MeOH are added 20 mL (25 mmol) HCl (1.25M in MeOH). The mixture is stirred at 70° C. for 7 h. The solvent is removed in vacuo and the crude product is triturated with DIPE and dried in normal atmosphere.
Reaction SMILES: [IH:1].CS[C:4](=[N:8][C:9](=[NH:11])[NH2:10])[NH:5][CH2:6][CH3:7].[CH:12]([NH2:15])([CH3:14])[CH3:13]>O>[IH:1].[CH2:6]([NH:5][C:4]([NH:8][C:9]([NH2:10])=[NH:11])=[N:15][CH:12]([CH3:14])[CH3:13])[CH3:7]
Reactant: CC(C)N
Reactant: CCNC(=NC(=N)N)SC
Agent: I
Solvent: O
Product: CCNC(=NC(C)C)NC(=N)N
Reaction time: 2 h

Procedure:
9.2 g. (30 mmol) of 2-methyl-1-ethyl-3-guanyl isothiourea hydroiodide is agitated with 30 ml. of water and 11.8 g. (200 mmol) of isopropylamine for 48 hours at 30° C. and then for 2 hours at the boiling temperature. Excess isopropylamine, methyl mercaptan, and water are removed. To the oily residue, 2 ml. of concentrated aqueous sodium iodide solution and then water are added until a clear solution is obtained. The product is crystallized during standing in a refrigerator and is recrystallized from acetone-petroleum ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])=[C:24](B(O)O)[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:22]2[CH:21]=[C:20]([Cl:19])[CH:25]=[CH:24][C:23]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(F)cc1F
Product: CCOC(=O)c1cc(F)cc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-fluorobenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic acid ethyl ester and using [5-chloro-2-(2,4-di-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:37])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1>CO.O1CCCC1>[N:31]1([CH2:30][C:21]2[C:22]([C:26]([F:27])([F:29])[F:28])=[CH:23][CH:24]=[C:25]3[C:20]=2[CH2:19][CH2:18][C@H:17]3[O:16][C:14]2[CH:13]=[CH:12][C:11]3[C@H:7]([CH2:6][C:5]([OH:37])=[O:4])[CH2:8][O:9][C:10]=3[CH:15]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCOCC3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4 M aqueous NaOH solution (0.20 mL) is added to a solution of {(S)-6-[(R)-4-morpholin-4-ylmethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (91 mg) in methanol (1 mL) and tetrahydrofuran (1 mL) at room temperature. The mixture is stirred at room temperature for 3 h. The organic solvent is evaporated, water is added to the residue, and the resulting solution is neutralized with 1 M aqueous HCl solution. The solution is stirred at room temperature for 1 h. The precipitate formed is separated by filtration, washed with water, and dried to give the title compound (if the title compound does not precipitate, the solution is concentrated, and the residue is purified by HPLC on reversed phase using acetonitrile and water as eluent). LC (method 1): tR=0.94 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: C(=O)(OC(Cl)(Cl)Cl)[O:2][C:3]([Cl:6])(Cl)Cl.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>C(Cl)Cl.C(N(CC)CC)C>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[C:3]([Cl:6])=[O:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cl)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 282.7 %

Procedure:
A solution of 1.47 g of bis(trichloromethyl) carbonate in 10 ml of methylene chloride was added dropwise within 20 min. to a solution of 2 g of 1,2,3,4-tetrahydro-isoquinoline in 30 ml of methylene chloride and 2.5 ml of triethylamine under argon at 0° C. The reaction mixture was stirred at room temperature for 2 h., then diluted with 50 ml of methylene chloride and washed with 50 ml of water, 50 ml of a 5% hydrochloric acid solution, 50 ml of a saturated sodium hydrogen carbonate solution and 50 ml of a saturated sodium chloride solution. The organic phases were dried over magnesium sulfate, concentrated, and the residue was dried at room temperature and about 12 mbar. 2.74 g (94%) of 3,4-dihydro-1H-isoquinoline-2-carbonyl chloride were obtained as a pale orange oil. MS (EI): 195M30 .
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].[CH:11]1(B(O)O)[CH2:13][CH2:12]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1.O>[CH:11]1([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:9][CH3:10])[CH2:13][CH2:12]1
Reactant: COc1cc(N)ccc1Br
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(N)ccc1C1CC1
Temperature: 100 °C
Reaction time: 10 h
Yield: 24.6 %

Procedure:
To a stirred solution of 4-bromo-3-methoxyaniline (1 g, 4.98 mmol) in 3:2 toluene/water (10 mL) was added cyclopropylboronic acid (514 mg, 5.98 mmol), Pd(OAc)2 (56 mg, 0.25 mmol), PCy3 (140 mg, 0.5 mmol) and K3PO4 (3.18 g, 15 mmol) at room temperature. The mixture was stirred at 100° C. for 10 h. The solid was filtered and the filtrate concentrated in vacuo. Purification by silica gel chromatography (2-10% ethyl acetate/hexanes) provided 4-cyclopropyl-3-methoxyaniline (200 mg, 25%) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 6.67 (d, J=7.8 Hz, 1H), 6.24-6.20 (m, 2H), 3.82 (s, 3H), 3.50 (brs, 2H), 2.02-1.95 (m, 1H), 0.85-0.79 (m, 2H), 0.57-0.51 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH3:12])=[C:6]([C:8](OC)=[O:9])[N:7]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([CH3:12])=[C:6]([CH2:8][OH:9])[N:7]=1)[CH3:2]
Reactant: CCc1nc(C(=O)OC)c(C)s1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(CO)c(C)s1
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of methyl 2-ethyl-5-methyl-1,3-thiazole-4-carboxylate (8.1 g) in tetrahydrofuran (400 mL) was added lithium aluminum hydride (1.8 g) at 0° C., and the mixture was stirred for 2 hrs. Sodium sulfate decahydrate (15.5 g) was added to the reaction mixture, and the mixture was stirred for 1 hr. The reaction mixture was filtered and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (5:95-70:30, v/v) to give (2-ethyl-5-methyl-1,3-thiazol-4-yl)methanol as a yellow oil (3.7 g, yield 53%).
Reaction SMILES: [CH:1]1([NH:6][CH:7]([CH3:13])[CH2:8][C:9]([NH:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:14][C:15]1[C:16](Cl)=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:14][C:15]1[C:16]([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]([CH3:13])[CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1
Reactant: CNC(=O)CC(C)NC1CCCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNC(=O)CC(C)N(c1nc(Cl)ncc1Br)C1CCCC1
Reaction time: 16 h
Yield: 6.5 %

Procedure:
A stirred solution of 3-(cyclopentylamino)-N-methyl-butanamide (Intermediate 122; 887 mg, 4.80 mmol), 5-bromo-2,4-dichloropyrimidine (1.15 g, 5.04 mmol) and potassium carbonate (1.34 g, 9.60 mmol) in acetone (20 mL) were heated under reflux conditions to 65° C. for 3 days and then at 75° C. for a further 16 hrs. The solvent was evaporated and the residue taken up in Ethyl Acetate (200 mL) and water (200 mL). The aqueous phase was separated and the organic phase further washed with water (200 mL) and brine (200 mL). The organic phase was evaporated and the residue purified by flash silica chromatography (companion, 40 g, 0-10% MeOH/DCM) followed by base modified preparative HPLC (30-50% gradient) to give the title compound as a yellow solid (117 mg, 6%).