Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH:21]3[CH2:24][CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:22]3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33].C[O-].[Na+:37]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:31])[NH:20][CH:21]3[CH2:22][CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:24]3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O-:34])=[O:33].[Na+:37]
Reactant: O=C(NC1CC(c2ccccc2)C1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC1CC(c2ccccc2)C1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of 6-chloro-7-(4-(3-phenylcyclobutylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.067 g, 0.140 mmol) in methanol (2 ml) was added 0.5M sodium methanolate in methanol (0.294 ml, 0.147 mmol), and the reaction was stirred for 16 hours. The reaction was concentrated to yield 70 mg of the title compound (99.9% yield). MS (apci) m/z=471.1 (M-Na+2H).
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[CH3:5][C:6](O)([CH2:8][CH:9](O)[CH3:10])[CH3:7]>CCCCCCC>[OH:2][B:1]1[O:4][C:6]([CH3:7])([CH3:5])[CH2:8][CH:9]([CH3:10])[O:3]1
Reactant: OB(O)O
Reactant: CC(O)CC(C)(C)O
Solvent: CCCCCCC
Product: CC1CC(C)(C)OB(O)O1
Temperature: 95 °C

Procedure:
61.2 g of boric acid (1 mol) and 118.2 g of 2-methyl-2,4-pentanediol (1 mol) and 200 ml of heptane are charged to a reaction flask equipped with stirrer, Marcusson apparatus and reflux condenser. The reaction mixture is heated up to its reflux temperature (about 95° C.), with stirring, and is kept at that temperature for a 4-hour period.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][NH2:30].O>CCO>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([NH:29][NH2:30])=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NN
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)NN)no1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
A solution of ethyl 5-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-4-cyclohexylbutyl]-1,2,4-oxadiazole-3-carboxylate (preparation 170) (1.14 g, 2.89 mmol) in EtOH (20 ml) was treated with NH2NH2.H2O (280 μl, 5.78 mmol) and stirred at room temperature for 45 minutes. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc and H2O/brine. The organic solvent was removed under reduced pressure to afford the title compound (1.06 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:18]4[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=4)[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)cc(Cl)c2n1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Fc1ccc(N2CCN(Cc3cn4cc(Cl)cc(Cl)c4n3)CC2)cc1
Temperature: 82.5 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A mixture of 6,8-dichloro-2-(chloromethyl)imidazo[1,2-α]pyridine (0.3064 g), 1-(4-fluorophenyl)piperazine (Aldrich; 0.266 g), triethylamine (Aldrich; 0.21 mL), and ethylene glycol (2 mL) is stirred for 1 h at 80-85° C. After cooling, the mixture is partitioned between water and dichloromethane and the organic layers are washed with brine and dried over MgSO4. After concentration under reduced pressure, the residue is chromatographed on silica gel using methanol/dichloromethane (4/96) and the appropriate fractions are combined and concentrated and the residue is crystallized from ethyl acetate/hexane to give 0.3098 g of the title compound; mp 126.5-127.5° C.; MS m/z 378, 380; IR (mineral oil) 1510, 1215, 1335, 826, 1224 cm-1 ; 1H NMR (CDCl3) δ2.75, 3.15, 3.83, 6.87, 6.96, 7.26, 7.62, 8.09.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:58])([C:54]([F:57])([F:56])[F:55])[C:24]([F:53])([F:52])[C:25]([F:51])([F:50])[C:26]([F:49])([F:48])[C:27]([F:47])([F:46])[O:28][C:29]([F:45])([F:44])[C:30]([F:43])([F:42])[O:31][C:32]([F:41])([F:40])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38]Br>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([O:31][C:30]([F:42])([F:43])[C:29]([F:44])([F:45])[O:28][C:27]([F:46])([F:47])[C:26]([F:48])([F:49])[C:25]([F:50])([F:51])[C:24]([F:52])([F:53])[C:23]([F:22])([F:58])[C:54]([F:57])([F:55])[F:56])([F:41])[F:40])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (1.03 g, 3.61 mmol) and 4-(2-(2-(tridecafluorohexyloxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromobutane (2.68 g, 4.02 mmol; prepared from 1,4-dibromobutane and 2-(2-(tridecafluorohexyloxy)tetrafluoroethoxy)-2,2-difluoroethanol). The resulting crude product was isolated essentially as described in Example 3 and further purified by recrystallization from cyclohexane/ethyl acetate to yield 1.85 g of purified product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:18]([O:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[Cl:13])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Reaction time: 5 h
Yield: 50.8 %

Procedure:
To a solution of 10.00 g (45.2 mmol) of methyl 3.5-dichloro-4-hydroxybenzoate dissolved in 100 mL of CH2Cl2 was added 11.06 g (90.2 mmol) of 4-dimethylaminopyridine and 8.18 g (54.2 mmol) of tertbutyldimethylchlorosilane and the mixture was stirred under N2 for 5 hours. The reaction mixture was then filtered and the filtrate was diluted with ethyl acetate. The solution was washed with water, 1N HCl, saturated NaHCO3, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 7.70 g (51%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1.[C:23]([O:27][C:28]([N:30]([CH:43]([CH3:45])[CH3:44])[CH2:31][C@H:32]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[C:33](O)=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C@H:32]([C:33]([N:20]2[CH2:19][CH2:18][N:17]([C:9]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[CH:13][N:12]=[C:11]4[NH:14][CH:15]=[CH:16][C:10]=34)[CH2:22][CH2:21]2)=[O:34])[CH2:31][N:30]([CH:43]([CH3:44])[CH3:45])[C:28](=[O:29])[O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:37][CH:38]=1
Reactant: Fc1ccccc1-c1cnc2[nH]ccc2c1N1CCNCC1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3ccccc3F)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
5-(2-Fluorophenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyri dine (0.034 g, 0.0921 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0330 g, 0.0967 mmol, see Example H), HOBT-H2O (0.0197 g, 0.129 mmol), and EDCI (0.0229 g, 0.120 mmol) were placed in DCM (5 mL) at room temperature. DIEA (d 0.742; 0.0802 mL, 0.460 mmol) was then added, and the reaction was stirred at room temperature for 5 hours. The reaction was then poured into saturated Na2CO3 and extracted into DCM. The organic fractions were combined, dried, filtered and concentrated to give a crude residue that was purified by column chromatography (500:10 DCM:MeOH) to give tert-butyl (2S)-2-(4-chlorophenyl)-3-(4-(5-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.040 g, 70.0% yield). MS APCI (+) m/z 520 detected.
Reaction SMILES: [CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2].[C:54]([O:60][CH2:61][CH3:62])(=[O:59])[CH2:55][C:56]([O-])=[O:57].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:31][N:32]=[N:33][N:34]=3)=[CH:22][CH:23]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([C:56](=[O:57])[CH2:55][C:54]([O:60][CH2:61][CH3:62])=[O:59])[CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c21
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N1CCc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2C1C(=O)OCC
Yield: 67.5 %

Procedure:
A solution of ethyl 2-ethyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.94 g), monoethyl malonate (0.74 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.80 g), triethylamine (1.40 g) in dichloromethane (20 ml) is stirred overnight at room temperature. The reaction mixture is washed with water and dried over sodium sulfate, and then evaporated. The residue is dissolved in ethanol (30 ml), fumaric acid (2.00 g) is added, and the solution is refluxed for three hours. The solvent is evaporated and the residue is treated with a saturated sodium hydrogen carbonate solution and then extracted with chloroform. The organic layer is dried and evaporated. Purification by silica gel column chromatography (solvent; chloroform/methanol) gives ethyl 2-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.07 g) as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][CH2:41][C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrCCCc1cccnc1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCc3cccnc3)cc2)c2ccccc21
Temperature: 90 °C

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was dissolved in DMF (5 mL) at room temperature. K2CO3 was added followed by 3-(3-bromo-propyl)-pyridine and the reaction was allowed to stir at 90° C. over night. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by HPLC to afford the product.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:12])([CH3:11])[CH2:7][NH:8]2)=[CH:4][C:3]=1[CH3:13].C[C:15]([N:17](C)C)=O>[C-]#N.[Zn+2].[C-]#N.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].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].[Zn]>[CH3:11][C:6]1([CH3:12])[C:5]2[C:9](=[CH:10][C:2]([C:15]#[N:17])=[C:3]([CH3:13])[CH:4]=2)[NH:8][CH2:7]1
Reactant: Cc1cc2c(cc1Br)NCC2(C)C
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc2c(cc1C#N)NCC2(C)C
Temperature: 150 °C

Procedure:
6-Bromo-3,3,5-trimethyl-2,3-dihydro-1H-indole (1.0 g, 4.17 mmol), zinc cyanide (0.563 g, 4.79 mmol), tris(dibenzylideneacetone)dipalladium (0.094 g, 0.42 mmol), 1,1′-bisdiphenylphosphino)ferrocene (0.462 g, 0.83 mmol) and powdered zinc (0.054 g, 0.83 mmol) were combined and dissolved in dimethylacetamide (20.8 mL). The reaction was degassed under nitrogen for 5 minutes, then heated with microwave irradiation for 30 minutes at 150° C. The reaction was cooled to room temperature and water was added. The mixture was extracted with diethyl ether (3×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-20%, EtOAc in petrol 40-60), gave the title compound (110 mg) MS: [M+H]+=185.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:16]3[C:17]([O:26][CH3:27])=[N:18][C:19]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:20][CH:21]=3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[C:28]([NH2:31])(=[O:30])[CH3:29].C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CCOC(C)=O.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]>[CH:23]([NH:22][C:19]1[N:18]=[C:17]([O:26][CH3:27])[C:16]([C:12]2[N:13]=[C:14]([CH3:15])[C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:31][C:28](=[O:30])[CH3:29])[CH:7]=3)=[CH:10][CH:11]=2)=[CH:21][N:20]=1)([CH3:25])[CH3:24]
Reactant: CC(N)=O
Reactant: COc1nc(NC(C)C)ncc1-c1ccc(Oc2ccnc(Cl)c2)c(C)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1nc(NC(C)C)ncc1-c1ccc(Oc2ccnc(NC(C)=O)c2)c(C)n1
Temperature: 80 °C
Yield: 36 %

Procedure:
A solution of Example C4 in dioxane (3 mL) was treated with acetamide (0.06 g, 1.0 mmol), Cs2CO3 (0.11 g, 0.34 mmol), X-Phos (0.03 g, 0.077 mmol) and Pd2(dba)3 (0.03 g, 0.034 mmol) and heated at 80° C. overnight. The mixture was diluted with EtOAc, the solids removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate was washed with water, then brine, dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM) to afford N-(4-((6-(2-(isopropylamino)-4-methoxypyrimidin-5-yl)-2-methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide (60 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1.[CH2:14]1CCN2C(=NCCC2)C[CH2:15]1.C(Cl)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([O:13][CH2:14][CH3:15])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2cccc(Cl)c12
Reactant: C1CCC2=NCCCN2CC1
Agent: CC(C)Cl
Product: CCOc1cnc(Cl)c2cccc(Cl)c12
Temperature: 120 °C
Yield: 53.2 %

Procedure:
To a solution of 1,5-dichloroisoquinoline-4-ol (0.5 g, 2.33 mmol) in DBU (1.06 g, 7.01 mmol) was added isopropyl chloride (0.27 g, 3.5 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 120° C. for 6 h. The reaction mass was quenched with 1.5 N HCl solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.3 g, 50.1%) as pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([CH3:18])[CH:3]1[CH2:19][CH3:20].[Cl:21]Cl.[N+](C)([O-])=O>C(O)(=O)C.Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH:4]([CH3:18])[C:3]1([CH2:19][CH3:20])[Cl:21]
Reactant: CCC1C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1C
Reactant: ClCl
Agent: Cl
Solvent: CC(=O)O
Solvent: C[N+](=O)[O-]
Product: CCC1(Cl)C(=O)c2c(cc(OCC(=O)O)c(Cl)c2Cl)C1C
Temperature: 0 °C
Yield: 93 %

Procedure:
To a suspension of (1-oxo-2-ethyl-3-methyl-6,7-dichloro-5-indanyloxy)acetic acid (3.5 g., 0.011 mole) in glacial acetic acid (75 ml.) and concentrated hydrochloric acid (2 drops) is added, with stirring, a solution of glacial acetic acid (50 ml.) and chlorine (0.9 g., 0.0127 mole) over a period of 10 minutes. During the addition the reaction vessel is heated on a steam bath. After the addition is complete, the mixture is stirred without heating for 30 minutes and then poured into ice water (600 ml.). The white solid that separates is collected by filtration, washed with water and dried. The yield of product is 3.6 g. (93% yield) of (1-oxo-2-ethyl-3-methyl-2,6,7-trichloro-5-indanyloxy)acetic acid which, after recrystallization from nitromethane, melts at 208.5°-210.5° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([CH3:29])[CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f54) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=2[N+:19]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCCCC=1>C(O)C.[Pd]>[NH2:19][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:8]=1[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)c1ccc(NC2CCCCC2)c(N)c1
Temperature: 83 °C
Yield: 85.1 %

Procedure:
In a 250 mL round bottom flask ethyl 4-(cyclohexylamino)-3-nitrobenzoate (3.01 g, 0.0103 mol) was dissolved in ethanol (40 mL) and 1 gram of 5% palladium on carbon (54.62% water) was added. Cyclohexene (7 mL, 0.07 mol) was then added and the reaction heated at 83° C. for 3 hours. The reaction mixture was filtered through celite and the filter cake washed with ethanol. The combined filtrates were concentrated to give 2.3 g title compound as a brownish tan solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH:32][C@@H:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:36]([O:43][C:44]3[CH:45]=[CH:46][C:47]4[N:48]([C:50]([N:53]5[CH2:58][CH2:57][CH:56]([CH2:59][O:60][Si](C(C)C)(C(C)C)C(C)C)[CH2:55][CH2:54]5)=[N:51][N:52]=4)[CH:49]=3)[CH2:35][CH2:34]2)=[O:31])[N:26]([CH3:28])[N:27]=1)([CH3:22])([CH3:21])[CH3:20]>C1COCC1.C(Cl)Cl>[C:19]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH:32][C@@H:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@H:36]([O:43][C:44]3[CH:45]=[CH:46][C:47]4[N:48]([C:50]([N:53]5[CH2:58][CH2:57][CH:56]([CH2:59][OH:60])[CH2:55][CH2:54]5)=[N:51][N:52]=4)[CH:49]=3)[CH2:35][CH2:34]2)=[O:31])[N:26]([CH3:28])[N:27]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5C)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCC(CO)CC4)n3c2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
Tetrabutylammonium fluoride (1M solution in THF, 211 μL, 0.211 mmol) was added to a solution of Intermediate 14f (110 mg, 0.151 mmol) in THF (3 mL) and the reaction mixture was stirred at RT for 1 h. The mixture was diluted with DCM (5 mL) and washed with water (2×5 mL) and brine (5 mL). The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound (52 mg, 60%). LCMS (Method 3): Rt: 2.91 min, m/z 573 [MH+].
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I.[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]1[N:14]([CH3:18])[C:13](=[O:15])[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A THF (20 ml) solution of the (5R)-5-[(tert-butyldimethylsilyloxy)methyl]pyrrolidin-2-one (5.73 g, 25 mmols) was added dropwise, during cooling with ice, to a THF (100 ml) suspension of NaH (60% oil disp. 1.20 g, 30 mmols), whereafter the mixture was stirred for 30 minutes at room temperature. To the mixture, MeI (7.8 ml, 125 mmols) was added during cooling with ice, and the mixture was stirred for 15 hours at room temperature. During cooling with ice, a saturated aqueous solution (50 ml) of NH4Cl was added, and the solvent was distilled off under reduced pressure. The residue was diluted with water, whereafter the dilution was extracted with AcOEt (50 ml×3), and the organic layer was dried over MgSO4. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 250 g, MeOH—CHCl3 3:97 v/v) to obtain (5R)-5-[(tert-butyldimethylsilyloxy)methyl]-1-methylpyrrolidin-2-one (6.00 g, 98.8%).
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH2:33])=[CH:28][N:27]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)(C)(C)C>C(Cl)Cl>[NH2:14][CH:15]([CH:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[O:34])=[CH:28][N:27]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)[CH3:1]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Solvent: ClCCl
Product: CC(N)C1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.8 %

Procedure:
Add TFA (6.54 g, 57.4 mmol) to a suspension of [5-(5-carbamoyl-pyridin-2-yloxy)-indan-1-ylmethyl]-carbamic acid tert-butyl ester (1.05 g, 2.87 mmol) in DCM (20 ml) and stir at ambient temperature for four hours. Concentrate mixture on rotary evaporator and purify on cation exchange column (10 g, Varian) to give the title compound (519 mg) as a white solid. Mass spectrum (ion spray): m/z=284 (M+1); 1HNMR (DMSO-d6): 8.58 (s, 1H), 8.21 (d, 1H), 8.00 (br s, 1H), 7.44 (br s, 1H), 7.27 (d, 1H), 7.01 (d, 1H), 6.96 (s, 1H), 6.87 (d, 1H), 3.05 (m, 1H), 2.84 (m, 2H), 2.77 (m, 1H), 2.62 (m, 1H), 2.18 (m, 1H), 1.82 (m, 1H), 1.71 (br s, 2H).