Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][C@@H:9]([NH:11][C:12](=[O:20])[CH2:13][P:14]([O:18]C)([O:16]C)=[O:15])[CH2:8][CH2:7][NH:6]1)=[O:4].C[Si](I)(C)C>C(Cl)Cl>[P:14]([CH2:13][C:12]([NH:11][C@H:9]1[CH2:8][CH2:7][NH:6][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:10]1)=[O:20])([OH:16])([OH:18])=[O:15]
Reactant: COC(=O)[C@H]1C[C@@H](NC(=O)CP(=O)(OC)OC)CCN1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=C(CP(=O)(O)O)N[C@H]1CCN[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 900 mg of cis-2-methoxycarbonyl-4-(α-dimethylphosphonoacetamido)-piperidine and 20 ml of methylene chloride is treated with 4 g trimethylsilyl iodide and the resulting mixture is stirred for 16 hours at room temperature. After removal of solvent the residue is stirred with water for 15 minutes and the solvent is removed in vacuo. A solution of the residue in 30 ml of 3N hydrochloric acid is heated under reflux for one hour and evaporated to dryness. A solution of the residue in 15 ml ethanol is treated with 1 ml of propylene oxide. Evaporation to dryness yields cis-4-(α-phosphonoacetamido)-piperidine-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13]O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1ccc(CCCO)cc1OC
Product: COc1ccc(CCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1OC

Procedure:
Prepared by Procedure O and Scheme W using 3-(3,4-dimethoxyphenyl)-1-propanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: COC1N=CC(C2N=CN(CCCC[N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])C=2)=CC=1.N1C=C(C2C=CC(OC)=NC=2)N=C1.C(=O)([O-])[O-].[K+].[K+].BrCCCCN1C(=O)C2=CC=CC=C2C1=O>CN(C=O)C>[C:19]1(=[O:28])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26](=[O:27])[NH:18]1
Reactant: COc1ccc(-c2cn(CCCCN3C(=O)c4ccccc4C3=O)cn2)cn1
Agent: COc1ccc(-c2c[nH]cn2)cn1
Agent: O=C([O-])[O-]
Agent: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 36 h
Yield: 70 %

Procedure:
2-{4-[4-(6-methoxy-pyridin-3-yl)-imidazol-1-yl]-butyl}-isoindole-1,3-dione. To a solution of 5-(1H-imidazol-4-yl)-2-methoxy-pyridine (6.7 g, 38.3 mmoles) in DMF (80 ml) was added potassium carbonate (26.5 g, 192 mmoles) and N-(4-bromobutyl)phthalimide (43.0 g, 153 mmoles) at room temperature under dry conditions. The solution was left stirring at room temperature for 36 hours. The reaction was filtered and the solid was washed with ethyl acetate (25 ml). The filtrate was diluted with ethyl acetate and washed with NH4Cl (sat.) (50 ml), H20 (50 ml), NaCl (sat.) (75 ml), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash 40 chromatography using an initial solvent gradient of 99% DCM, 1% MeOH, and 0.1% TEA (1 L), then a solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA (1 L) to yield 2-14-[4-(6-methoxy-pyridin-3-yl)-imidazol-1-yl]-butyl)-isoindole-1,3-dione (10.09 g, 70%). MH+(377).
Reaction SMILES: N[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:12]([O:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1C(Cl)=O)[CH2:13][CH3:14]>>[CH3:11][C:10]1[C:2]([C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[O:15][CH2:12][CH2:13][CH3:14])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([NH2:6])=[O:5]
Reactant: CCCOc1ccccc1C(=O)Cl
Reactant: Cc1cccc(C(N)=O)c1N
Product: CCCOc1ccccc1-c1c(C)cccc1C(N)=O

Procedure:
The title compound was prepared from 2-amino-3-methylbenzamide and 2-n-propoxybenzoyl chloride following the procedure of Preparation 5 and was obtained as a colorless solid (71%), m.p. 140°-142° C. Found: C,69.39; H,6.58; N,8.98. C18H20N2O3 requires C,69.21; H,6.45; N,8.97%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.B1([C:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH:39]=2)OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([C:38]3[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH:39]=3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c3c(nc4ccnn24)CCN(C(=O)OC(C)(C)C)CC3)CC1

Procedure:
To 0.075 g (0.23 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in a microwave tube were added 3 mL dioxane, 1 mL MeOH, 79 mg (0.25 mmol) (N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester, 0.6 mL aqueous Na2CO3 (2 M), 19 mg (0.023 mmol) 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium (II) under nitrogen and the reaction was subjected to microwave irradiation (discoverer, 100° C., 250 Watts) for 15 minutes. After evaporation of the solvent the product was purified by column chromatography (silica, DCM/MeOH 100:2).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([O:12][CH2:13][P:14]([O:20][CH:21]([CH3:23])[CH3:22])([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH3:11])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C.C1CCCCC=1>[CH:21]([O:20][P:14]([CH2:13][O:12][C@@H:10]([CH3:11])[CH2:9][OH:8])([O:16][CH:17]([CH3:18])[CH3:19])=[O:15])([CH3:22])[CH3:23]
Reactant: CC(C)OP(=O)(CO[C@@H](C)COCc1ccccc1)OC(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(C)OP(=O)(CO[C@@H](C)CO)OC(C)C
Yield: 104.1 %

Procedure:
A solution of (S)-1-O-benzyl-2-O-[(diisopropylphosphono)methyl]-1,2-propanediol (8.20 g, 23.8 mmol) in 1:1 ethanol/cyclohexene (80 mL) was treated with 20% palladium hydroxide on carbon (4.0 g), and the mixture was heated at reflux for 18 hours. The reaction mixture was then filtered through a 1" pad of Celite, and the filtrate was concentrated in vacuo to give 6.3 g of the title compound as a clear, colorless oil which was used in the following reaction without purification.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20][C:21]3[N:25]([CH3:26])[C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:23][N:22]=3)=[CH:16][C:15]=2[O:34][CH2:35][CH2:36][CH3:37])=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[CH2:27]([C:24]1[N:25]([CH3:26])[C:21]([S:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:38])=[O:3])=[CH:11][CH:10]=3)=[C:15]([O:34][CH2:35][CH2:36][CH3:37])[CH:16]=2)=[N:22][N:23]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCc1nnc(Sc2ccc(CNc3ccc(CC(=O)OCC)cc3)c(OCCC)c2)n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCCCc1nnc(Sc2ccc(CNc3ccc(CC(=O)O)cc3)c(OCCC)c2)n1C

Procedure:
A solution of {4-[4-(5-heptyl-4-methyl-4H-[1,2,4]-triazol-3-ylsulfanyl)-2-propoxybenzylamino]phenyl}acetic acid ethyl ester obtained in Example 31 (0.7 g, 2.39 mmol), 2M aqueous potassium carbonate (9 ml) in methanol (20 ml) is heated under reflux for 3 hours. The reaction medium is acidified at room temperature with a 2N hydrochloric acid solution to pH 5. The desired product is extracted by addition of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate. After evaporation of the solvents, 0.592 g (89%) of the expected compound are recovered in the form of a yellow amorphous solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[N:6]=[C:7]([NH:10][C:11]2[CH:18]=[C:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:14]([CH:15]=O)=[CH:13][N:12]=2)[S:8][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:1][N:2]([CH2:15][C:14]1[C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[CH:18][C:11]([NH:10][C:7]2[S:8][CH:9]=[C:5]([CH3:4])[N:6]=2)=[N:12][CH:13]=1)[CH3:3]
Reactant: CNC
Reactant: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(C=O)cn2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(CN(C)C)cn2)n1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
Dimethylamine (0.374 mL, 0.747 mmol) was added to a solution of 6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)nicotinaldehyde (0.090 g, 0.249 mmol) in THF (3 mL) and stirred for 10 minutes. Sodium triacetoxyborohydride (0.264 g, 1.25 mmol) was added and the reaction mixture was stirred for an additional 30 minutes. The mixture was quenched with saturated sodium bicarbonate, partitioned between ethyl acetate and water, washed with brine, dried, and concentrated. The residue was dissolved in THF (2 mL), 1M HCl in ether was added, the solution was diluted in hexanes (5 mL), triturated for 15 minutes, filtered, dried to afford 5-((dimethylamino)methyl)-N-(4-methylthiazol-2-yl)-4-(naphthalen-1-yloxy)pyridin-2-amine (0.071 g, 73.0% yield) as a white solid. 1H NMR (DMSO d6) δ 10.88 (bs, 1H), 8.58 (s, 1H), 8.09 (d, 1H), 7.98 (d, 1H), 7.90 (d, 1H), 7.52-7.67 (m, 4H), 6.67 (s, 1H), 6.37 (s, 1H), 4.54 (s, 2H), 2.88 (s, 6H), 2.18 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([CH3:12])[C:6]=2[CH:13]=1.IC1C=CC2CCNCC(C)C=2C=1.FC(F)(F)C1C=CC2CCNCC(C)C=2C=1.FC(F)(F)C1C=CC2CCNCC(CC)C=2C=1.[Cl:60]C1C=CC2CCNCC(CC)C=2C=1.BrC1C=CC2CCNCC(CC)C=2C=1.IC1C=CC2CCNCC(CC)C=2C=1.ClC1C(Cl)=CC2C(C)CNCCC=2C=1.ClC1C(F)=CC2CCNCC(C)C=2C=1.ClC1C(F)=CC2CCNCC(CC)C=2C=1>>[Cl:60][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([CH3:12])[C:6]=2[CH:13]=1
Reactant: CC1CNCCc2ccc(Br)cc21
Reactant: CCC1CNCCc2ccc(Cl)cc21
Agent: CC1CNCCc2cc(Cl)c(Cl)cc21
Agent: CC1CNCCc2cc(F)c(Cl)cc21
Agent: CC1CNCCc2ccc(C(F)(F)F)cc21
Product: CC1CNCCc2ccc(Cl)cc21

Procedure:
8-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8Chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 8-Iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 7,8-Dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-30 benzazepine; 8-Chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and 8-Chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:21])[C:9]=1[N:10]1[CH:20]=[C:13]2[C:14](Cl)=[N:15][CH:16]=[C:17]([Cl:18])[C:12]2=[N:11]1)[C:5]#[N:6].[CH3:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:21])[C:9]=1[N:10]1[CH:20]=[C:13]2[C:14]([NH:29][C:25]3[CH:24]=[C:23]([CH3:22])[N:28]=[CH:27][N:26]=3)=[N:15][CH:16]=[C:17]([Cl:18])[C:12]2=[N:11]1)[C:5]#[N:6]
Reactant: Cc1cc(N)ncn1
Reactant: N#Cc1cc(Cl)c(-n2cc3c(Cl)ncc(Cl)c3n2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(Cl)c3nn(-c4c(Cl)cc(C#N)cc4Cl)cc23)ncn1
Yield: 43 %

Procedure:
A suspension of 3,5-dichloro-4-(4,7-dichloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile (70 mg, 0.20 mmol), 6-methylpyrimidin-4-ylamine (23 mg, 0.22 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), Xantphos (12 mg, 0.02 mmol) and cesium carbonate (130 mg, 0.40 mmol) in dioxane (3 mL) was sealed in a microwave vial, purged with nitrogen and irradiated at 150° C. for 30 minutes in the microwave. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-80% ethyl acetate in pentane), then further triturated with ethyl acetate to afford the title compound as a yellow solid (37 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1H), 9.33 (s, 1H), 8.71 (d, J=1.2 Hz, 1H), 8.51 (s, 2H), 8.37 (s, 1H), 8.08 (s, 1H), 2.45 (s, 3H). LCMS (Method B): RT=3.69 min, m/z: 430 [M+H+].
Reaction SMILES: [N+:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([Br:11])(=O)[CH3:9].[OH-].[Na+]>>[Br:11][C:8]1[C:3]([CH3:4])=[CH:2][N+:1]([O-:7])=[C:6]([CH3:5])[CH:9]=1
Reactant: CC(=O)Br
Reactant: [O-][n+]1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[n+]([O-])c(C)cc1Br
Temperature: 55 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
A portion of the pyridine-N-oxide (106.4 g, 0.633 mol) was added slowly to 300 g of acetyl bromide at a rate that maintained the reaction temperature at 20°-30° C. (modification of procedure described in Ochiai, J. Org. Chem, 18, 549(1953)). After the addition was complete, the reaction was heated to 55° C. and left to stir overnight. The reaction mixture was cooled to room temperature and then slowly poured over ice. The mixture was slowly basified with 10M sodium hydroxide and extracted with chloroform. The chloroform extract was dried over sodium sulfate and then concentrated to dryness to give 119.2 g (93%) of 4-bromo-2,5-dimethylpyridine-N-oxide.
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[ClH:7].O.[CH2:9]1[S:17](=[O:19])(=[O:18])[O:16][CH2:15][CH2:14][O:13][S:10]1(=[O:12])=[O:11]>[OH-].[Na+]>[Cl:7][CH:9]1[S:10](=[O:11])(=[O:12])[O:13][CH2:14][CH2:15][O:16][S:17]1(=[O:19])=[O:18]
Reactant: O=S1(=O)CS(=O)(=O)OCCO1
Reactant: Cl
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=S1(=O)OCCOS(=O)(=O)C1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1.25 g of KMnO4 and 7.8 mL of conc. HCl in 115 mL of ice cooled H2O was stirred for 2 hrs. To this solution was added 2.02 g of ethylene methanedisulfonate in 25 mL of 0.5 molar NaOH. The solid obtained after acidification was placed in 15 mL of 0.5 M NaOH and the filtrate acidified to give 1.1 g of ethylene chloromethanedisulfonate, m.p. 85-88° C. (91-6).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)=[O:6].O.Cl>C(OCC)C>[Br:13][C:9]1[CH:8]=[C:7]([C:5]([OH:6])([CH3:1])[CH3:4])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)(O)c1cccc(Br)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of methylmagnesium bromide (60 mL of a 3.0 M solution in diethyl ether) at 0° C. was added dropwise a solution of 3-bromoacetophenone (29.8 grams) in 75 mL of diethyl ether. Once the addition was complete, the mixture was stirred for 0.5 hours and poured into water. The aqueous phase was acidified with 1M hydrochloric acid and extracted with three portions of diethyl ether. The combined ether layers were washed with saturated sodium bicarbonate, concentrated to afford 30.4 grams of the title compound. 1H NMR δ7.72 (br s, 1), 7.49 (d, 1, J=7.8), 7.37 (d, 1, J=7.9), 7.25 (dd, 1, J=7.8, 7.9), 4.19 (s, 1), 1.50 (br s, 6).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:34][C:35]1[CH:36]=[CH:37][C:38]([OH:67])=[C:39]2[C:44]=1[CH:43]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:42]([S:50]([C:53]1[CH:58]=[CH:57][C:56]([O:59][C:60]3[CH:65]=[CH:64][C:63]([F:66])=[CH:62][CH:61]=3)=[CH:55][CH:54]=1)(=[O:52])=[O:51])[CH2:41][CH2:40]2.C(N(CC)CC)C.[N:75]1([CH2:81][CH2:82]O)[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1>ClCCl>[Br:34][C:35]1[CH:36]=[CH:37][C:38]([O:67][CH2:82][CH2:81][N:75]2[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]2)=[C:39]2[C:44]=1[CH:43]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:42]([S:50]([C:53]1[CH:58]=[CH:57][C:56]([O:59][C:60]3[CH:61]=[CH:62][C:63]([F:66])=[CH:64][CH:65]=3)=[CH:55][CH:54]=1)(=[O:52])=[O:51])[CH2:41][CH2:40]2
Reactant: OCCN1CCCCC1
Reactant: CCOC(=O)C1c2c(Br)ccc(O)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1c2c(Br)ccc(OCCN3CCCCC3)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
0.515 g of PPh3 (polymer-bound, 1.2-1.5 mmol/g) are mixed with 0.13 g of diisopropyl azodicarboxylate in 5 ml of dichloromethane and shaken at room temperature for 15 min. Then 0.17 g (0.31 mmol) of ethyl 8-bromo-2-[4-(4-fluorophenoxy)benzene-sulfonyl]-5-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylate (crude product, 21D), 0.031 g (0.31 mmol) of triethylamine and 0.04 g (0.31 mmol) of 2-piperidin-1-ylethanol are added, and the mixture is shaken at room temperature until no further increase in conversion can be detected by means of an LCMS check. For workup, the mixture is filtered and the filtrate is washed twice with H2O. The aqueous phases are extracted twice with dichloromethane. The combined organic phases dried with MgSO4 and evaporated. The crude product obtained in this way is purified by prep. HPLC, resulting in 0.08 g of the title compound as trifluoroacetate.
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]([OH:16])=O)[CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:29]([NH2:32])[C:30]#[CH:31]>C1COCC1>[CH2:1]([N:8]1[CH2:9][C:10](=[O:12])[N:32]([CH2:29][C:30]#[CH:31])[C:14](=[O:16])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCN
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C#CCN1C(=O)CN(Cc2ccccc2)CC1=O
Yield: 61.9 %

Procedure:
To a suspension of N-benzyliminodiacetic acid (10 mmol) in THF (30 ml), 1,1′-carbonyldiimidazole (22 mmol) is added with stirring. The reaction mixture is refluxed with stirring for 15 minutes. Propargylamine (100 mmol) is added and then reaction mixture is stirred at 90° C. for 1 day. The organic solvent is evaporated and then the residue is dissolved in AcOEt. The organic layer is washed with 2×100 ml 0.1N HCl and then dried over sodium sulfate. The solvent is concentrated under vacuum. The purification of the residue by silica gel column chromatography affords 1.5 g of title compound in 62% yield. Rf=0.24 (n-hexane:AcOEt=3:1)
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:9]=1.CO[C:20](OC)([CH3:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:21][C:20]1([CH3:22])[N:4]([C:5]2[S:6][CH:7]=[C:8]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)[N:9]=2)[CH2:3][CH2:2][O:1]1
Reactant: COC(C)(C)OC
Reactant: N#Cc1ccc(-c2csc(NCCO)n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OCCN1c1nc(-c2ccc(C#N)cc2)cs1
Yield: 42.1 %

Procedure:
A mixture of 4-{2-[(2-hydroxyethyl)amino]-1,3-thiazol-4-yl}benzonitrile (1.0 g, 4.0 mmol), prepared in the previous step, 2,2-dimethoxypropane (7.2 mL, 61.2 mmol) and a catalytic amount of p-toluenesulfonic acid in toluene (90 mL) was heated at 90° C. overnight. The reaction was cooled and concentrated to a residue. Purification of the crude product on silica gel using 5% ethyl acetate:hexane as the eluent gave 480 mg of impure product. Final purification by reverse phase HPLC using an isocratic system of 80:20 acetonitrile:water gave the title compound (107 mg, 10%), mp 108-111° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[C:14]([NH:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]2[C:27]([CH:34]3[CH2:36][CH2:35]3)=[C:28](Br)[C:29]([C:30]([NH2:32])=[O:31])=[C:23]2[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O.O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:14]([NH:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]2[C:27]([CH:34]3[CH2:35][CH2:36]3)=[C:28]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=3)[C:29]([C:30]([NH2:32])=[O:31])=[C:23]2[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)NC(=O)N1CCn2c(c(C(N)=O)c(Br)c2C2CC2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCn2c(c(C(N)=O)c(-c3cccc(C(F)(F)F)c3)c2C2CC2)C1
Temperature: 70 °C
Reaction time: 20 h
Yield: 19 %

Procedure:
To a mixture of 57.0 mg (0.300 mmol) of (3-trifluoromethylphenyl)boronic acid and 76.7 mg (0.200 mmol) of N2-tert-butyl-7-bromo-6-cyclopropyl-3,4-dihydropyrrolo-[1,2-a]pyrazine-2,8(1H)-dicarboxamide in a reaction tube are added 2 ml of tetrahydrofuran degassed beforehand under argon for 15 minutes and 63.6 mg (0.60 mmol) of disodium carbonate dissolved in 1 ml of water. The tube is then purged with argon, and about 16 mg (0.02 mmol) of a complex of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) and dichloromethane (PdCl2(dppf).CH2Cl2—CAS 95464-05-4) suspended in 2 ml of tetrahydrofuran degassed beforehand under argon are added. The tube is then stirred at 70° C. for 20 hours, the mixture is cooled and the solvent is evaporated off under reduced pressure. The residue is taken up in 5 ml of tetrahydrofuran and 100 mg of propanethiol-grafted silica (Si-Thiol, Biotage) are added. The mixture is stirred for 4 hours at room temperature and the grafted silica is separated out by filtration on a Celite cartridge, the Celite is washed twice with 1 ml of tetrahydrofuran and the filtrate is concentrated under reduced pressure. The residue is then purified by SFC purification, to give 0.017 g of N2-tert-butyl-6-cyclopropyl-7-(3-trifluoromethyl-phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][NH:9][CH2:10]2)=[O:5])[CH3:2].C(=O)([O-])O.[Na+].Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]2[S:27][C:26]3[N:28]=[CH:29][CH:30]=[N:31][C:25]=3[NH:24][C:23]=2[CH:32]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]2[CH:7]1[CH2:8][N:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]3[S:27][C:26]4[N:28]=[CH:29][CH:30]=[N:31][C:25]=4[NH:24][C:23]=3[CH:32]=1)[CH2:10]2)=[O:5])[CH3:2]
Reactant: ClCc1ccc2c(c1)Nc1nccnc1S2
Reactant: CCOC(=O)C1C2CNCC21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1C2CN(Cc3ccc4c(c3)Nc3nccnc3S4)CC21
Temperature: 80 °C
Yield: 28 %

Procedure:
To a solution of 1.523 g of ethyl(3-azabicyclo[3.1.0]hex-6-yl)carboxylate in N,N-dimethylformamide (30 ml) were added 2.30 g of sodium hydrogencarbonate and 1.39 g of 8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and the resulting mixture was heated to 80° C. for 2 hours. After adding water and ethyl acetate, the organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Then the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.574 g of the title compound as pale yellow crystals.