Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C:5]1[CH:9]([C:10]([CH3:12])=[CH2:11])[CH2:8][CH2:7][C:6]=1[CH3:13])=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]([CH2:3][CH2:4][C:5]1[CH:9]([CH:10]([CH3:11])[CH3:12])[CH2:8][CH2:7][C:6]=1[CH3:13])=[O:2]
Reactant: [H][H]
Reactant: C=C(C)C1CCC(C)=C1CCC=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1=C(CCC=O)C(C(C)C)CC1

Procedure:
3.6 g of 2-(2-formylethyl)-3-isopropenyl-1-methyl-cyclopent-1-ene were hydrogented in 80 ml of ethyl acetate in the presence of 500 mg of palladium on calcium carbonate (5%). After the uptake of one equivalent of hydrogen, the solution was filtered over Celite, concentrated and subjected under a high vacuum to a short-path distillation. 2-(2-Formylethyl)-3-isopropyl-1-methyl-cyclopent-1-ene having a fresh, woody fragrance was obtained in quantitative yield; boiling point 0.001 about 70° C; nD20 = 1.4703; IRfilm : νmax = 2740, 1728, 1470, 1385, 1368 and 1100 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:26][C:27](O)=[O:28])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[F:44][C:45]([F:51])([F:50])[S:46]([NH2:49])(=[O:48])=[O:47]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:26][C:27](=[O:28])[NH:49][S:46]([C:45]([F:51])([F:50])[F:44])(=[O:48])=[O:47])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CC(=O)O)Cc2ccc(Cl)cc2)c1
Reactant: NS(=O)(=O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CC(=O)NS(=O)(=O)C(F)(F)F)Cc2ccc(Cl)cc2)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of compound 49 ((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-acetic acid (1 eq.) in DMF was added EDC.HCl (1.3 eq.), DMAP (1.3 eq.) and trifluoromethanesulfonamide (1.3 eq.). The reaction was stirred for 15 h at 20° C. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by preparative LCMS to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-(2-oxo-2-trifluoromethanesulfonylamino-ethyl)-amide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:19]1([C:24](Cl)=[O:25])[S:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([C:24]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[O:25])[S:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCOc1ccncc1
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1ccncc1)c1cccs1
Yield: 70.4 %

Procedure:
To a solution of 700 mg (4.60 mmol) of 4-(3-aminopropyloxy)pyridine and 0.77 ml (5.52 mmol) of triethylamine in 30 ml of methylene chloride, 0.50 ml (4.68 mmol) of thenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 850 mg of the desired compound (yield: 70.0%, colorless crystals).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:29]1([CH2:28][O:27][C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:32])=[C:11]([C:9]([NH:8][CH:5]4[CH2:4][CH2:3][N:2]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:7][CH2:6]4)=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:30][CH2:31]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][CH2:15][CH2:16][NH2:17].Br[C:22]1[S:26][C:25]([NH2:27])=[N:24][N:23]=1>>[CH3:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[N:3]1[CH2:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][CH2:15][CH2:16][NH:17][C:22]1[S:26][C:25]([NH2:27])=[N:24][N:23]=1
Reactant: Nc1nnc(Br)s1
Reactant: CC1CCCC(C)N1Cc1cccc(OCCCN)c1
Product: CC1CCCC(C)N1Cc1cccc(OCCCNc2nnc(N)s2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(2,6-dimethyl-1-piperidinyl) methyl]phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](Cl)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3.[CH3:18][CH:19]([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]([C:19]([CH3:27])([CH3:18])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3
Reactant: Clc1nc2ccnc(Cl)c2c2cc(Br)ccc12
Reactant: CC(C)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(C)(C)c1nc2ccnc(Cl)c2c2cc(Br)ccc12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a stirred suspension of 9-bromo-1,6-dichlorobenzo[c]-1,6-naphthyridine (5 g, 15.24 mmol) in Toluene (50 ml) was added tert-butyl 2-methylpropanoate (2.64 g, 18.29 mmol). The reaction mixture was cooled to 0° C. A solution of NaHMDS (1M in THF, 3.35 g, 18.29 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature. After 5 hours, the reaction was quenched with aqueous saturated ammonium chloride (50 mL), and extracted with EtOAc (1×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was adsorbed on to silica gel and purified by column chromatography on silica gel, eluting with an EtOAc/Hexanes gradient to afford tert-butyl 2-(9-bromo-1-chlorobenzo[c]-1,6-naphthyridin-6-yl)-2-methylpropanoate. LRMS (ESI) calc'd for (C20H20BrClN2O2) [M+H]+, 437.0; found 437.0.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl[C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[CH3:8][O:9][N:10]([C:22]([O:24][CH3:25])=[O:23])[C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCC(=O)NOC
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)N(OC)C(=O)OC
Temperature: 25 °C

Procedure:
A 100 mL round-bottom flask equipped with a magnetic stir bar, argon inlet and pressure equalizing addition funnel is charged with tetrahydrofuran (14.0 mL), triethylamine (2.13 g, 1.5 eq) and N-methoxynonanamide (1.96 g, 1 eq). The reaction is cooled in an ice bath and methyl chloroformate (1.88 g, 1.4 eq) is added dropwise. The reaction is allowed to warm to room temperature overnight. The tetrahydrofuran is removed under vacuum and the residue is diluted with methylene chloride (25 mL). The reaction is washed with 0.1 M hydrochloric acid solution 1×20 mL), saturated aqueous sodium bicarbonate (3×20 mL)and brine 1×20 mL). The organic layer is dried over sodium sulfate, filtered and concentrated under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[N:21]=[C:20]2C([N:17]=[CH:18][N:19]2[CH3:22])=C(Cl)[N:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([Cl:12])[N:21]=[C:20]3[C:10]=2[N:17]=[CH:18][N:19]3[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2c(Nc3ccc(Br)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-bromo-phenyl)-acetamide and 2,6-dichloro-9-methyl-9H-purine.
Reaction SMILES: [CH:1](=[C:11]1/[C:12](=[O:17])[NH:13][C:14](=[O:16])[S:15]/1)\[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH:1](=[C:11]1/[C:12](=[O:17])[N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:14](=[O:16])[S:15]/1)\[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC/C=C1\SC(=O)NC1=O
Reactant: CCOC(=O)CBr
Product: CCCCCCCCC/C=C1\SC(=O)N(CC(=O)OCC)C1=O

Procedure:
TZD10EA was prepared according to General Procedure A2 presented hereinabove using (Z)-5-decylidenethiazolidine-2,4-dione and ethyl 2-bromoacetate as reactants.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([OH:38])=O.CCN(C(C)C)C(C)C.[C:48]1([CH2:54][CH:55]([C:57]2[N:61]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:60]=[N:59][CH:58]=2)[NH2:56])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([NH:56][CH:55]([C:57]1[N:61]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[N:60]=[N:59][CH:58]=1)[CH2:54][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:38]
Reactant: NC(Cc1ccccc1)c1cnnn1-c1ccccc1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1c[nH]c2ccc(O)cc12)NC(Cc1ccccc1)c1cnnn1-c1ccccc1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 9D (26.5 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, CD3OD) δ 7.76 (s, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.39 (t, J=7.6 Hz, 2H), 7.21-7.01 (m, 6H), 6.96 (s, 1H), 6.84 (d, J=1.9 Hz, 1H), 6.78 (d, J=6.8 Hz, 2H), 6.68 (dd, J=8.6, 2.3 Hz, 1H), 5.46 (s, 2H), 5.21 (t, J=7.6 Hz, 1H), 2.96 (ddd, J=21.5, 13.3, 7.6 Hz, 2H); MS (m/z) 438 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].CCCC[Sn]([C:59]1[N:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)(CCCC)CCCC>>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:63]2[CH:62]=[CH:61][CH:60]=[CH:59][N:64]=2)=[CH:40][CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2ccccn2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method A, using compound 19 (100 mg, 0.147 mmol), 2-(1,1,1-tributylstannyl)pyridine (220 mg, 0.598 mmol), Pd(PPh)3Cl2 (5.12 mg, 0.0072 mmol) and CuO (11.7 mg, 0.147 mmol). Purification by RP-LC-MS (40 min gradient of 10-100% CH3CN in 0.05% aqueous formic acid) gave the product (17.2 mg, 17%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11](=[O:23])[CH:10]=1.Br.Br[CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:11](=[O:23])[CH:10]=1
Reactant: BrCc1cccnc1
Reactant: CC(C)(C)OC(=O)Cn1ccc(-c2cc(Cl)ccc2Br)cc1=O
Agent: Br
Product: CC(C)(C)OC(=O)C(Cc1cccnc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
206 mg (purity 94%, 0.49 mmol) of tert-butyl [4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]acetate and 184 mg (0.73 mmol) of 3-(bromomethyl)pyridine monohydrobromide were reacted according to General Method 7A. Yield: 274 mg (purity 88%, quant.)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Br:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C=O)c(N)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(N)c(C=O)cc1Br
Yield: 54.7 %

Procedure:
To a stirred solution of 2-amino-4-methoxybenzaldehyde (6 g, 39.7 mmol) in dichloromethane (100 mL) was added N-bromosuccinimide (7 g, 39.7 mmol). The reaction mixture was diluted with dichloromethane and water. The separated organic layer was dried sodium sulfate, filtered and concentrated to give the title compound (5 g, 56%) as a yellow solid. MS (ES+) C8H8BrNO2 requires: 229, 231, found: 230, 232 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:24]([O:23][C:13](=[O:22])[CH:14]=[C:15]([C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:25]
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: COc1ccc2[nH]ccc2c1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(c1ccccc1)c1c(OC)ccc2[nH]ccc12
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 4-bromo-5-methoxyindole XLVI (104 mg, 0.46 mmol), ethyl cinnamate (162 mg, 0.92 mmol), tetra-butylammonium bromide (29.6 mg, 0.092 mmol), TEA (128 μl, 0.092 mmol) and palladium-dichloro-[bis(tri-ortho-tolyl)phosphine] (18 mg, 0.023 mmol) in DMF (2 ml) was stirred at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and partitioned between brine and EtOAc. The organic layers were combined, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 3-(5-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester XLVIII (37 mg, impure).
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([NH2:19])[C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]=[CH:7][CH:6]=1)[CH3:2].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.S(Cl)(Cl)(=O)=O>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:19][CH:4]([C:5]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[N:8]=[CH:7][CH:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:20][CH3:21])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCC(CC)C(N)c1ccnn1Cc1ccc(OC)cc1
Solvent: O=S(=O)(Cl)Cl
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Br)cc1)c1ccnn1Cc1ccc(OC)cc1
Yield: 67 %

Procedure:
The compound of example 3 was synthesized from {2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}amine in a manner similar to that of example 1 but using 4-bromobenzenesulfonyl chloride as the sulfonyl chloride in step 1D. The product was isolated as a white foam in 67% yield.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C@@H:10]([OH:16])[C@@H:11]([OH:15])[CH2:12][C:13]#[CH:14])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:17][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[C@@H:10]([OH:16])[C@@H:11]([OH:15])[CH2:12][C:13]#[CH:14]
Reactant: C#CC[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CC[C@H](O)[C@H](O)[C@@H](N)CC1CCCCC1
Yield: 104.3 %

Procedure:
A solution of compound of Step 6 (0,926 g, 2.85 mmol) and trifluoroacetic acid (5.49mL, 71.3mmol) in CH2Cl2 (5.49 mL) was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was dissolved in 1.0 N KOH (7 mL) and extracted with ethyl acetate (4×10 mL). The combined organic layers were dried over MgSO4 and then concentrated to give the title amine as an off-white solid (0.67 g, 100% yield). 1H and 13C NMR spectral data were consistent with the proposed structure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+].O>C(OCC)C>[C:5]1([C:1]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:4])[CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CCC(O)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a well-stirred solution of propiophenone (20.1 g, 0.15 mol) in dry diethyl ether (125 ml) kept under nitrogen at room temperature was added a solution of phenylmagnesium bromide (55 ml, 3 M in diethyl ether) in dry diethyl ether (25 ml). The reaction mixture was stirred for 1 h and a mixture of a saturated ammonium chloride solution (100 ml) and water (50 ml) was added. The phases were separated and the aqueous phase was extracted with diethyl ether (100 ml). The combined organic phases was washed with a 0.5 N hydrochloric acid solution and dried (Na2SO4). The solvent was evaporated in vacuo to give a solid residue which was triturated with cyclohexane (100 ml). The solid was collected by filtration and dried to give 26.4 g (83%) of 1,1-diphenyl-1-propanol.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]3[CH2:16][CH2:15]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.C(N(CC)CC)C>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]3[CH2:16][CH2:15]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(CC1CC1)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CC4CC4)c23)C1
Yield: 26.4 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide (204 mg, 0.654 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (393 mg, 1.96 mmol), and triethylamine (182 μL, 1.31 mmol) in n-BuOH (5 mL) was processed as in Example 56. The crude was purified by C-18 reverse phase chromatography (Biotage 25M+) on Biotage SP4 unit eluting with a gradient of 15-85% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(2-cyclopropylacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (85 mg, 26% yield) as a solid. LCMS (APCI+) m/z 492, 494 (M+H)+, Retention time=3.75 min (Method 2).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[C:7]([O:26][CH3:27])[CH:8]=2)[N:3]=1.[NH3:30]>C(O)C>[NH2:30][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([O:24][CH3:25])=[C:17]([O:22][CH3:23])[CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:28][CH3:29])=[C:7]([O:26][CH3:27])[CH:8]=2)[N:3]=1
Reactant: COc1cc2c(cc1OC)CN(c1nc(Cl)nc3cc(OC)c(OC)cc13)CC2
Reactant: N
Solvent: CCO
Product: COc1cc2c(cc1OC)CN(c1nc(N)nc3cc(OC)c(OC)cc13)CC2
Temperature: 25 °C

Procedure:
The product of (A), viz, 2-chloro-6,7-dimethoxy-4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)quinazoline (5.0 g.) and a saturated solution of ammonia in ethanol (60 ml.) were heated together in an autoclave at 100°C. for a period of approximately 16 hours. After the reaction mixture had been allowed to cool to room temperature (~26°C.), the solvent was removed by means of evaporation under reduced pressure and the resulting brown residue (5.0 g.) was partitioned between methylene chloride and water. The separated organic layer thus obtained was then evaported in vacuo and the residue (3.0 g.) was subsequently converted into the hydrochloride salt by conventional means. Recrystallization of the crude material from a mixture of e thanol and isopropanol then afforded 1.0 g. of pure final product as the hydrochloride hemihydrate, m.p. 245°C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=3)[NH2:18])=[N:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:39][C:40](=[CH2:44])[C:41](Cl)=[O:42]>C1COCC1>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([NH:18][C:41](=[O:42])[C:40]([CH3:44])=[CH2:39])[CH:19]=[CH:20][CH:21]=3)=[N:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:7]=1
Reactant: C=C(C)C(=O)Cl
Reactant: C[Si](C)(C)CCOCn1cc(C2CCCO2)c2c(-c3cccc(N)c3)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(C2CCCO2)cn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 0° C. solution of crude 3-(5-(tetrahydrofuran-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline (410 mg, 1.00 mmol) in THF (10 mL), was added DIPEA (258 mg, 2.00 mmol) followed by dropwise addition of 2-methylprop-2-enoyl chloride (125 mg, 1.20 mmol). The resulting solution was stirred for 4 hours at room temperature prior to being quenched by addition of water. The resulting solution was extracted with ethyl acetate (×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 0-100% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford N-(3-(5-(tetrahydrofuran-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a off-white solid. LRMS (ESI) calc'd for C26H35N4O3Si [M+H]+: 479, found 479.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])([CH3:9])[CH2:5][C:6](=[O:8])[CH:7]=1.[Se](=O)=[O:13]>O1CCOCC1.O>[CH3:9][C:4]1([CH3:10])[C:3](=[O:11])[C:2]([CH3:1])=[CH:7][C:6](=[O:8])[C:5]1=[O:13]
Reactant: CC1=CC(=O)CC(C)(C)C1=O
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CC1=CC(=O)C(=O)C(C)(C)C1=O

Procedure:
129.4 g of 2,6,6-trimethylcyclohex-2-ene-1,4-dione (from Example 1) were added to a solution of 100 g of selenium dioxide in a mixture of 800 ml of dioxane and 50 ml of water, and the mixture was refluxed for 9 hours with stirring. The precipitate of elemental selenium was then filtered off with suction, and then all the low boilers were removed in a rotary evaporator. The residue was distilled at 125° C./20 mbar. The distillate was melted, mortared with n-hexane and then extracted with 600 ml of n-hexane. The target product crystallized out in the form of yellow needles.