Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:14]3[O:13][CH:12]([CH2:15][NH2:16])[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([O:29][C:27](=[O:28])[NH:16][CH2:15][CH:12]1[CH2:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[C:14]=2[O:13]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3ccsc3)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccsc3)c2O1)OCc1ccccc1
Yield: 70.7 %

Procedure:
Treatment of (±)-1-(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methanamine (0.56 g, 2.09 mmol) with diisopropylethylamine (0.406 g, 3.14 mmol) and benzyl chloroformate (0.393 g, 2.30 mmol) generally according to the procedure described for Intermediate 12 provided 0.54 g (71%) of (±)-benzyl(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Rf=0.49 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C21H19NO3S.0.3H2O: C, 68.01; H, 5.33; N, 3.78. Found: C, 67.88; H, 5.18; N, 3.72. Chiral HPLC separation of (±)-benzyl(7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralcel AD, water:methanol 1:9) provided two fractions. Fraction 1 (Rt=13.00 min, (Chiralcel AD, water:methanol 1:9); Fraction 2 (Rt=14.1 min, (Chiralcel AD, water:methanol 1:9).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[C:15]=1[O:24][CH3:25]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:24][CH3:25])[C:16]=2[F:23])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nc(Cl)n1
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 80 °C
Yield: 53.5 %

Procedure:
6-Amino-2-chloropyrimidine-4-carboxylic acid methyl ester (2.25 g, 12 mmol, 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16 mmol), and bis(triphenylphosphine)palladium(II) dichloride (842 mg, 1.2 mmol) were combined in 12 mL of 1,2-dimethoxyethane and 12 mL of water. The reaction mixture was heated at 80° C. for 2 h and the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried, and concentrated under vacuum. The product was purified by flash chromatography on silica gel to yield the title compound (2.0 g, 53.5% yield): mp 188-190° C.: 1H NMR (CDCl3) δ 7.66 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 5.25 (br s, 2H), 4.0 (s, 3H), 3.99 (s, 3H).
Reaction SMILES: [C:1]([C@:9]([C@@H:16]([CH:18]([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:19])[OH:17])([OH:15])[C:10]([F:14])([F:13])[CH:11]=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].CN(C)C=[O:44]>>[Si:33]([O:12][C:11]([C:10]([F:13])([F:14])[C@@:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C@@H:16]([CH:18]([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:19])[OH:17])[OH:15])=[O:44])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CN(C)C=O
Reactant: O=CC(F)(F)[C@@](O)(C(=O)c1ccccc1)[C@H](O)C(O)C(=O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OC(=O)C(F)(F)[C@@](O)(C(=O)c1ccccc1)[C@H](O)C(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 22.1 g (58 mmol) of 3,5-bis(benzoyl)-2-deoxy-2,2-difluororibose and 8.0 g (116 mmol) of imidazole in 410 ml of dimethylformamide (DMF) was added 8.8 g (58 mmol) of t-butyldimethylsilyl chloride. This reaction mixture was stirred for 12 hours at ambient temperature. The mixture was evaporated to dryness under reduced pressure. The residue was mixed with ethyl acetate and washed with 1.0N hydrochloric acid, saturated sodium bicarbonate, water, saturated sodium chloride solution, dried with sodium sulfate and evaporated to dryness under reduced pressure to yield 24.5 g of 1-(t-butyldimethylsilyloxy)-3, 5-bis(benzoyl)-2-deoxy-2,2-difluororibose.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:17]([O-])=O)[CH:4]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:17])[C:6](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][Cl:16])[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1OCCCCl
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(C(=O)O)cc1OCCCCl
Temperature: 40 °C
Yield: 100.4 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 4.00 g (13.5 mmol) of 4-methoxy-5-(3-chloropropoxy)-2-nitrobenzoic acid (purity: 99%) obtained in Reference Example III-14, and 40 mL of methanol. The resulting mixture was heated to 40° C. under stirring. To the mixture was added 0.4 g of 5 wt. % palladium/carbon (containing 49% water) at the same temperature. The resulting mixture was heated to the same temperature for 4 hours, while hydrogen was introduced into the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to precipitate a crystalline product. The crystalline product was dried under reduced pressure, to give 3.52 g (isolated yield: 98.1%, purity: 98% in terms of area percentage determined by high performance liquid chromatography) of 4-methoxy-5-(3-chloropropoxy)-anthranilic acid as a white crystalline product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:17]3=[O:26])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[Cl-].[Na+].[CH3:29]O>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:29][CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:17]3=[O:26])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)(=[NH:3])[NH2:2]
Reactant: N=C(N)c1ccc(-c2ccc(N3CCN(CCC(=O)O)C3=O)cc2)cc1
Reactant: CO
Agent: [Cl-]
Agent: [Na+]
Product: N=C(N)c1ccc(-c2ccc(N3CCCN(CCC(=O)O)C3=O)cc2)cc1

Procedure:
Rf value: 0.54 (Reversed Phase Plate RP8; 1 0% sodium chloride solution/methanol=4:6)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1>C(O)C.[Pd]>[NH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: Cc1ccc2cc([N+](=O)[O-])ccc2n1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2cc(N)ccc2n1

Procedure:
2-Methyl-6-nitroquinoline (18.8 g) was stirred under a hydrogen atmosphere at 30 p.s.i. (equivalent to 206. 8 kPa) for 2 hours in ethanol solution containing 5% Pd/C. The catalyst was then removed by filtration, the filtrate evaporated to small volume in vacuo, and the resultant precipitate collected by filtration, washed with ethanol and ether, and dried to give the title compound, yield 13.2 g, m.p. 188°-189°.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1)=[O:5]>C(Cl)Cl.CO.O=[Mn]=O>[Cl:20][C:16]1[CH:17]=[N:18][CH:19]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=1)=[O:5]
Reactant: O=C(NCc1ccc(CO)cc1)c1c(Cl)cncc1Cl
Agent: O=[Mn]=O
Solvent: CO
Solvent: ClCCl
Product: O=Cc1ccc(CNC(=O)c2c(Cl)cncc2Cl)cc1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
To a partially dissolved solution of 3,5-dichloro-N-(4-hydroxymethyl-benzyl)-isonicotinamide (730 mg, 2.35 mmol) in CH2Cl2 (12 mL) and MeOH (1 mL) was added MnO2 (2.43 g, 23.5 mmol) and the resultant suspension was stirred at 40° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The cake was washed with CH2Cl2/MeOH (100:3) and the filtrate was concentrated under reduced pressure to afford a crude white solid (630 mg). Purification by column chromatography on silica gel (CH2Cl2MeOH/NH4OH, 100:1:1) afforded the desired aldehyde (480 mg, 66%) as a white solid. 1H NMR (CDCl3) δ 4.78 (d, 2H, J=6.0 Hz), 6.19 (br s, 1H), 7.58 (d, 2H, J=9.0 Hz), 7.90 (d, 2H, J=9.0 Hz), 8.55 (s, 2H), 10.02 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[C:10]([C:12]([NH2:14])=O)[CH:9]=[CH:8][N:7]3[C:15]=2[CH2:16][C:17]2[CH:40]=[CH:39][C:20]3/[C:21](=[C:31](\[C:33]4[NH:37][C:36](=[O:38])[O:35][N:34]=4)/[CH3:32])/[C:22]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=4[O:24][CH2:25][C:19]=3[CH:18]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[C:10]([C:12]#[N:14])[CH:9]=[CH:8][N:7]3[C:15]=2[CH2:16][C:17]2[CH:40]=[CH:39][C:20]3/[C:21](=[C:31](\[C:33]4[NH:37][C:36](=[O:38])[O:35][N:34]=4)/[CH3:32])/[C:22]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=4[O:24][CH2:25][C:19]=3[CH:18]=2)[CH2:3][CH2:2]1
Reactant: C/C(=C1/c2ccc(Cc3c(C4CC4)nc4cc(C(N)=O)ccn34)cc2COc2cc(F)ccc21)c1noc(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C/C(=C1/c2ccc(Cc3c(C4CC4)nc4cc(C#N)ccn34)cc2COc2cc(F)ccc21)c1noc(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.6 %

Procedure:
[step 2] (E)-2-cyclopropyl-3-({3-fluoro-11(6H)-[1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethylidene]dibenzo[b,e]oxepin-8-yl}methyl)imidazo[1,2-a]pyridine-7-carboxamide (83 mg, 0.15 mmol) obtained in step 1 was suspended in THF (0.77 mL), and triethylamine (0.11 mL, 0.77 mmol) was added. Under ice-cooling, trifluoroacetic anhydride (0.11 mL, 0.77 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted 3 times with chloroform-methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 v/v-90/10 v/v) to give the title compound (compound 14b) (41 mg, 51%).
Reaction SMILES: BrC=C([C:5]1[CH:15]=[CH:14][C:8]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:7][CH:6]=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CC[CH2:29][C@H:25]1[C:26](O)=O.[CH3:32][N:33]1[CH2:46][CH2:45][C:36]2[NH:37][C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][C:43]=3[C:35]=2[CH2:34]1>CN(C=O)C.[Cu]I>[CH3:32][N:33]1[CH2:46][CH2:45][C:36]2[N:37](/[CH:26]=[C:25](\[C:15]3[CH:14]=[C:8]([CH:7]=[CH:6][CH:5]=3)[C:9]([N:11]([CH3:12])[CH3:13])=[O:10])/[CH3:29])[C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][C:43]=3[C:35]=2[CH2:34]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1ccc(C(=O)N(C)C)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)c1cccc(C(=O)N(C)C)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
4-(1-Bromoprop-1-en-2-yl)-N,N-dimethylbenzamide (264 mg, 1 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (200 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude compound was purified on silica gel (100-200 mesh) using 0-7% MeOH:DCM as eluent. Yield: 60 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.30 (m, 2H), 7.20 (s, 2H), 7.10 (d, 1H), 6.95 (d, 1H), 6.86 (s, 1H), 6.80 (s, 1H), 4.58 (m, 1H), 4.30 (m, 1H), 3.60 (m, 1H), 3.10 (m, 1H), 3.0 (s, 3H), 2.92 (s, 3H), 2.80 (m, 2H), 2.50 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:16]=O)[CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:18]([S:20]([NH2:23])(=[O:22])=[O:21])[CH3:19].[CH:24]1([Mg]Br)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH:24]3[CH2:26][CH2:25]3)[NH:23][S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[CH:13]=[N:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Br[Mg]C1CC1
Reactant: N#Cc1ccc(-c2cncc(C=O)c2)cc1Cl
Reactant: CCS(N)(=O)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Temperature: -40 °C
Reaction time: 8 h

Procedure:
Titanium(IV) isopropoxide (0.365 mL, 1.245 mmol) was added to a mixture of 2-chloro-4-(5-formylpyridin-3-yl)benzonitrile (as prepared in Example 23, step 1; 0.151 g, 0.622 mmol), ethanesulfonamide (0.085 g, 0.778 mmol) in toluene (10 mL) at room temperature. The resulting mixture was heated to reflux for 4 h. After concentration, the residue was dissolved in THF (5 mL), and cooled to −40° C. Cyclopropylmagnesium bromide (3.73 mL, 1.867 mmol) was added dropwise, and the resulting mixture was slowly warmed up to room temperature and stirred overnight. After quenching by saturated NH4Cl solution, the residue was purified by flash column (ethyl acetate-heptane, v/v, 40%-60%) yielded a slightly yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][CH:3]=1.[CH2:14]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:15][C:16]#[CH:17]>>[CH3:13][O:12][CH2:11][CH2:10][NH:9][CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([C:17]#[C:16][CH2:15][CH2:14][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: C#CCCN1CCCCC1
Reactant: COCCNCc1cccc(Br)n1
Product: COCCNCc1cccc(C#CCCN2CCCCC2)n1
Yield: 13 %

Procedure:
The title compound (13%) was prepared in a manner similar to that described in Example 18, Step D, using (6-bromo-pyridin-2-ylmethyl)-(2-methoxy-ethyl)-amine (0.300 g, 1.23 mmol) and 1-but-3-ynyl-piperidine (0.336 g, 2.45 mmol). MS (ESI): exact mass calcd. for C18H27N3O, 301.44; m/z found, 302.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.56 (t, 7.7, 1H), 7.26 (d, J=7.1, 1H), 7.23 (d, J=7.7, 1H), 3.90 (s, 2H), 3.52-3.45 (m, 2H), 3.34 (s, 3H), 2.80 J=5.2, 2H), 2.70-2.59 (m, 4H), 2.48-2.40 (m, 4H), 1.67-1.54 (m, 5H), 1.46-1.38 (m, 2H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[CH3:14]O>>[Br:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([O:10][CH3:14])=[O:9])=[CH:5][CH:4]=1
Reactant: CO
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Agent: Cl
Product: COC(=O)C(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (3 mL, 18 mmol) was added to an ambient temperature solution of 4-bromomandelic acid (5 g, 21.6 mmol) in methanol (50 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated in vacuo to afford methyl (4-bromophenyl)(hydroxy)acetate which was used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=O.[C:14]([OH:20])(=[O:19])[CH2:15]C(O)=O.C([O-])(=O)C.[NH4+:25].CCO>CCOCC>[NH2:25][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:2]([F:1])[CH:3]=1)[CH2:15][C:14]([OH:20])=[O:19]
Reactant: [NH4+]
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCOCC
Product: NC(CC(=O)O)c1ccc(C(F)(F)F)c(F)c1
Yield: 31.8 %

Procedure:
A solution of 3-fluoro-4-(trifluoromethyl)benzaldehyde (4.8 g, 25 mmol), malonic acid (2.6 g, 25 mmol), ammonium acetate (0.85 g, 50 mmol) and EtOH (30 mL) was heated at 80° C. for 18 h. The reaction was cooled, diluted with Et2O (50 mL) and filtered to afford 2.0 g (16%) of 3-amino-3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoic acid (274) as a white solid which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH2:22]>>[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH:20][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3/[CH:22]=[CH:21]/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:7]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: C=Cc1ccccn1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(/C=C/c4ccccn4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=342.1 (M+H+), was prepared in accordance with the general method of example 2 from 5-bromo-2-chloroquinoline, 5-methyl-2-furanmethanamine and 2-vinylpyridine.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.CN([CH:18]=[O:19])C>C1COCC1.CCCCCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1nc2ccccc2s1
Reaction time: 0.33 h

Procedure:
To a stirred solution of benzothiazole (3.28 ml) in anydrous THF (40 ml), at −78°, under a nitrogen atmosphere, butyllithium (2.0 ml of a 1.6M solution in hexane) was added dropwise. After 0.33 h, a solution of DMF (7 ml) in anydrous THF (20 ml) was added dropwise and the reaction mixture was allowed to rise to 0° over 1 h. The reaction was quenched by pouring the mixture into water (100 ml) and extracted with EE (2×150 ml). The organic layer was washed with brine, dried and the solvent evaporated under reduced pressure. The crude residue was purified by flash chromatography (eluting with CH-EA in gradient from 95:5 to 8:2), and crystallized from PE to give the title compound as a yellow solid (1.88 g). M.p. 76-77°
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.Cl[C:14]1[CH:34]=[CH:33][CH:32]=[C:31](C)[C:15]=1[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[C:19]([CH3:30])=[N:18]1>>[CH3:30][C:19]1[C:20]2[C:25](=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=2)[N:17]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]3[C:12]=2[N:11]=[CH:10][CH:9]=[CH:8]3)[N:18]=1.[CH2:16]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:30]1)[C:15]1[CH:14]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1cccc2cccnc12
Reactant: Cc1cccc(Cl)c1Cn1nc(C)c2ccc(CC(=O)O)cc21
Product: Cc1nn(Cc2cccc3cccnc23)c2cc(CC(=O)O)ccc12
Product: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1

Procedure:
The titled compound (73.8 mg) as a yellow solid was prepared from the compound [102-4] obtained in the process (4) of Example 102 (102 mg) and 8-(bromomethyl)quinoline according to the method of the process (5) of Example 102.
Reaction SMILES: [NH:1]([C:8]1[C:16]2[C:15]([CH3:17])=[CH:14][C:13](=[O:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[S:10]C=1C(OCC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:33]([OH:35])[CH3:34])C.[NH3:36]>>[NH:1]([C:8]1[C:16]2[C:15]([CH3:17])=[CH:14][C:13](=[O:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[S:10][C:34]=1[C:33]([NH2:36])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)O
Reactant: CCOC(=O)c1sc2c(c(C)cc(=O)n2-c2ccccc2)c1Nc1ccccc1
Reactant: N
Product: Cc1cc(=O)n(-c2ccccc2)c2sc(C(N)=O)c(Nc3ccccc3)c12
Yield: 66 %

Procedure:
A mixture of Example 97 (150 mg, 0.37 mmol), ethoxyethanol and liquid ammonia was heated in a sealed vessel at 80° C. at 400 psi for 16 h. The mixture was concentrated in vacuo and the solid recrystallised from MeOH to give the title compound as a yellow solid (92 mg, 66%). δH (DMSO-d6) 8.05 (1H, s), 7.68-7.59 (3H, m), 7.53-7.51 (2H, m), 7.5 (1H, br), 7.24-7.20 (2H, m), 6.80 (1H, t, J 7.3 Hz), 6.64 (2H, d, J 7.7 Hz), 6.29 (1H, s), 2.22 (3H, s). LCMS (ES+) RT 3.074 minutes, 375.9 (M+H)+
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]1([C:37](O)=[O:38])[CH2:27][CH2:26][N:25]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:24][CH2:23]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O.CCOC(C)=O>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:37]([C:22]2([CH2:21][NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:23][CH2:24][N:25]([C:28]3[C:29]4[CH:36]=[CH:35][NH:34][C:30]=4[N:31]=[CH:32][N:33]=3)[CH2:26][CH2:27]2)=[O:38])[CH2:3][CH2:4][OH:5])=[CH:11][CH:10]=1
Reactant: N[C@@H](CCO)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
(S)-3-Amino-3-(4-chlorophenyl)propan-1-ol (Intermediate 47) (247 mg, 1.33 mmol) was added in one portion to 4-((tert-butoxycarbonylamino)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 12) (500 mg, 1.33 mmol) and DIPEA (0.698 mL, 4.00 mmol) in DMA (6 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (557 mg, 1.47 mmol) was added and the resulting solution was stirred at 20° C. for 2 hours then 20° C. for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-tert-butyl (4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (428 mg, 59.2%) as a colourless gum. The product (428 mg) was dissolved in dioxane (6.00 mL) and 4M hydrogen chloride in dioxane (0.925 mL, 26.64 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-(aminomethyl)-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (192 mg, 32.5%) as a white dry film.