Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:22])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:22][C:28]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])[S:14][C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Reactant: O=C(Cl)C1CCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(-c2nc(NC(=O)C3CCCC3)sc2-c2ccncc2)cc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 65.4 %

Procedure:
To a solution of [4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.62 mmol) and 4-dimethylaminopyridine (0.06 g, 0.49 mmol) in N,N-dimethylacetamide (5 mL) was added cyclopentanecarbonyl chloride (0.32 g, 2.42 mmol) and the mixture was stirred at 70° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.43 g, yield 66%).
Reaction SMILES: [C:1]([O:5][C:6](ON=C(C(C)=O)C(OCC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(C)(C)C.O>[C:1]([O:5][C:6]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(=NOC(=O)OC(C)(C)C)C(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A solution of ethyl 2-tert-butoxycarbonyloxyiminoacetoacetate (646 mg.) in a mixture of tert-butyl alcohol (5 ml.) and water (5 ml.) was added at once to a solution of L-phenylalanine (330 mg.) and triethylamine (0.28 ml.) in a mixture of tert-butyl alcohol (8 ml.) and water (8 ml.) at room temperature. The mixture was stirred for 2 hours at room temperature. Water (100 ml.) was added to the reaction mixture and the mixture was adjusted to pH 7 with a 0.5M citric acid aqueous solution and washed twice with ethyl acetate (40 ml). The aqueous layer was adjusted to pH 3 with a 0.5M citric acid aqueous solution, followed by addition of a sodium chloride aqueous solution, and extracted twice with ethyl acetate (40 ml.). The extract was washed with water and dried. The solvent was distilled off under reduced pressure to give N-tert-butoxycarbonyl-L-phenylalanine (286 mg.).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:15]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:15])=[O:8]
Reactant: CO
Reactant: O=C(O)CCCCCBr
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCBr
Yield: 90 %

Procedure:
22 g (0.11 mole) of 6-bromohexanoic acid, 50 ml of methanol, and 3 ml concentrated sulfuric acid were mixed in a 100 ml flask and refluxed for 3 hours, after which period the excess methanol was removed by distillation. 100 ml water and 100 ml chloroform were added to the residue in the flask. The water layer was extracted with several 50 ml portions of chloroform; the portions were combined, washed with 5% sodium bicarbonate, and with water, and then passed through magnesium sulfate. The chloroform was removed by rotary evaporation. The crude product was vacuum distilled to yield greater than 90% methyl 6-bromo-hexanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][OH:7].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]([C@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:50]([C:57](=[O:65])[C:58]3[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=3)[C@@H:49]([CH3:66])[CH2:48]2)[C:44](=[O:46])[CH3:45])=[CH:39][CH:38]=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:44]([N:43]([C:40]1[CH:39]=[CH:38][C:37]([Cl:36])=[CH:42][CH:41]=1)[C@H:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:50]([C:57]([C:58]2[CH:63]=[CH:62][C:61]([O:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[C:3]([O:2][CH3:1])=[O:16])=[CH:60][CH:59]=2)=[O:65])[C@@H:49]([CH3:66])[CH2:48]1)(=[O:46])[CH3:45]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: COC(=O)C(CCO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The ester was dissolved in 20 ml toluene at room temperature with PPh3 (0.94 g, 3.6 mmol), then added N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-hydroxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (0.31 g, 0.71 mmol) and stirred for 5 min. DEAD (0.626 g, 3.6 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by silica gel chromatography (45% CH2Cl2/55% EtOAc) to afford crude methyl 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2-[(tert-butoxycarbonyl)amino]butanoate (0.47 g).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][CH:22]=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+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:27][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([C:20]([F:30])([F:31])[F:19])=[CH:22][CH:23]=3)=[N:7][CH:6]=2)=[O:9])=[CH:11]1
Reactant: O=C(c1ccc(Br)nc1)c1c[nH]c2ncccc12
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(=O)c2c[nH]c3ncccc23)cn1)c1ccc(C(F)(F)F)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 0.2 %

Procedure:
A mixture of (6-bromo-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (87, 160 mg, 0.53 mmol), 4-trifluoromethyl benzamide (51, 130 mg, 0.69 mmol), xanthphos (9 mg, 0.02 mmol), cesium carbonate (245 mg, 0.752 mmol), and tris(dibenzylideneacetone)dipalladium (0) (5 mg, 0.005 mmol) in toluene (2 mL) in a sealed tube was stirred at 110° C. for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The organic layer was collected, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (P-0067, 0.42 mg, 19%). MS (ESI) [M+H+]+=411.17.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[S:13][C:12]([CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: CC(C)c1ncc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CC(C)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(2-iso-Propyl-thiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([Br:25])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Br:25][C:19]1[C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:7]2[N:6]3[C:2]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc2c(cc1Br)C(c1ccccn1)=NCc1nnc(Br)n1-2
Product: CN1CCN(c2nnc3n2-c2cc([N+](=O)[O-])c(Br)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1,8-dibromo-9-nitro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-methylpiperazine to give 8-bromo-9-nitro-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]1[C:6]([C@H:7]([CH2:12][NH2:13])[CH2:8][C:9](O)=[O:10])=[CH:5][CH:4]=[C:3]([Cl:14])[CH:2]=1>C(O)(=O)C>[Cl:14][C:3]1[CH:4]=[CH:5][C:6]([C@@H:7]2[CH2:12][NH:13][C:9](=[O:10])[CH2:8]2)=[CH:1][CH:2]=1
Reactant: NC[C@H](CC(=O)O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: O=C1C[C@H](c2ccc(Cl)cc2)CN1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To R-baclofen (50 g, 234.7 mmol) was added 235 mL of acetic acid. The reaction mixture was refluxed overnight. The following day, the mixture was cooled to room temperature, the acetic acid removed in vacuo and the resultant mixture treated with water (400 mL). An off-white product precipitated and was filtered, washed with hexane, and dried in vacuo to provide the title compound as a white solid (42.1 g, 92% yield). 1H-NMR (400 MHz, CD3OD): δ7.22-7.33 m, 4H), 3.64-3.79 (m, 2H), 3.32-3.39 (m, 1H), 2.66-2.73 (dd, J=16.8, 8.8 Hz, 1H), 2.40-2.47 (dd, J=16.8, 8.8 Hz, 1H); MS (ESI) m/z 195.97 (M+H)+.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH2:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:19])[C:13]=2[CH2:12][CH2:11][CH2:10]1.Br[CH2:21][CH2:22][NH:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>C(COC)OC>[CH2:9]1[C:18]2[C:13](=[C:14]([O:19][CH2:21][CH2:22][NH:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Oc1cccc2c1CCCC2
Reactant: CCOC(=O)c1ccc(NCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CCOC(=O)c1ccc(NCCOc2cccc3c2CCCC3)cc1

Procedure:
To a slurry of 2.3 g. of 57% sodium hydride-in-oil (previously washed free of oil with hexane) in 20 ml. of dimethoxyethane is added 7.4 g. of 1,2,3,4-tetrahydro-5-naphthol in 20 ml. of dimethoxyethane and then 13.6 g. of ethyl 4-(2-bromoethylamino)benzoate. After refluxing for 6 hours and dilution with 300 ml. of water, the solid is collected and recrystallized from acetonitrile, m.p. 133°-135° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].B(O)O.[Cl:38][C:39]1[N:44]=[C:43](Cl)[CH:42]=[CH:41][N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[Cl:38][C:39]1[N:44]=[C:43]([C:2]2[CH:3]=[N:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[CH:42]=[CH:41][N:40]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ncc(Br)cc1C#N
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2ccnc(Cl)n2)cc1C#N
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 51.9 %

Procedure:
To a stirred solution of 5-bromo-2-methoxy-nicotinonitrile (10 g, 46.9 mmol) and bis(pinacolato)diboron (17.9 g, 70.4 mmol) in 1,4-dioxane (300 mL) was added potassium acetate (13.8 g, 140.8 mmol). The reaction mixture was deoxygenated with argon, Pd(dppf)Cl2 was added and the mixture deoxygentated for a further 20 min. The resulting mixture was heated at 100° C. for 1.5 h. The reaction mixture was cooled to rt, diluted with water (100 mL) and filtered through Celite. The filtrate was extracted with EtOAc (2×150 mL), the combined organic layer dried over Na2SO4 and evaporated to obtained a crude mixture containing an approximate 1:1 mixture of boronic ester and boronic acid (12 g). The crude material was dissolved in 1,4-dioxane (100 mL) and 2,4 dichloropyrimidine (8.4 g, 56.2 mmol) was added followed by a solution sodium carbonate (17.9 g, 168.5 mmol) in water (25 mL). The reaction mixture was deoxygenated with argon gas, Pd(PPh3)4 was added and again deoxygenated for 30 min. The resulting mixture was heated at 100° C. for 3 h. The reaction mixture was cooled to rt, diluted with water (100 mL), extracted with EtOAc (3×100 mL), the combined organic layer was dried (Na2SO4) and evaporated. The crude compound was purified by flash column chromatography (100-200 mesh silica gel), eluting with 30% EtOAc/pet ether to obtain the desired compound (6 g, 51% (over two steps)) as a white solid; Rf: 0.3 (40% EtOAc/pet ether); (m/z): 247[M+1]+; 1H NMR (300 MHz, DMSO-d6): δ 9.24 (1H, d, J=2.4 Hz), 8.98 (1H, d, J=2.1 Hz), 8.89 (1H, d, J=5.1 Hz), 8.21 (1H, d, J=5.1 Hz), 4.04 (3H, s). 2-Methoxy-5-[2-(6-morpholin-4-ylmethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-nicotinonitrile (17)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[O:21]1[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([C:23]3[CH:24]=[CH:25][O:21][CH:22]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1ccoc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccoc1

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2, 2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 3-furancarboxylic acid (CAN 488-93-7) as starting materials; LC-MS (UV peak area/ESI) 98.2%, 395.0414 (M−H)−.
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1
Reactant: C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Temperature: 25 °C
Yield: 94 %

Procedure:
Part B: To a stirred boiling solution of ethyl 2-chloro[(4-chlorophenyl) hydrazono]acetate (22.95 gram, 0.088 mol) and styrene (30.3 ml, 0.264 mol) in benzene (140 ml) is added triethylamine (34.3 ml, 0.247 mol) and the resulting solution is heated at reflux temperature for 1 hour. The resulting solution is cooled to room temperature and the formed precipitate is removed by filtration and washed with toluene. The filtrate is concentrated in vacuo and purified by flash chromatography (silica gel, dichloromethane) to give ethyl 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylate (27.2 gram, 94% yield) as a syrup which slowly solidifies on standing. 1H-NMR (200 MHz, CDCl3): 1.38 (t, J=7 Hz, 3H), 3.06 (dd, J=18 and 7 Hz, 1H), 3.73 (dd, J=18 and 13 Hz, 1H), 4.33 (q, J=7 Hz, 2H), 5.38 (dd, J=13 and 7 Hz, 1H), 7.02 (br d, J=8 Hz, 2H), 7.08-7.40 (m, 7H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[C:13]2[CH:14]=[C:15]([C:30](O)=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][C:18]3=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[C:13]2[CH:14]=[C:15]([C:30]([N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:19][C:18]3=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc([C@H]2CCCN2c2cccc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Product: CN1CCN(C(=O)c2cc([C@H]3CCCN3c3cccc(F)c3)c3oc(N4CCOCC4)cc(=O)c3c2)CC1
Yield: 32.6 %

Procedure:
8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (see Example 1.06 for preparation; 100 mg, 0.23 mmol) was reacted with 1-methylpiperazine (0.076 ml, 0.68 mmol) using a procedure similar to the one described in example 1.00 to afford 8-[(2R)-(1-(3-fluorophenyl)pyrrolidin-2-yl)]-6-(4-methylpiperazine-1-carbonyl)-2-morpholino-4H-chromen-4-one (39 mg, 33%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH2:35]O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)(Br)(Br)[Br:38]>ClCCl>[Br:38][CH2:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCOCCOCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCOCCOCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
Triphenylphosphine (12.59 g), in dry dichloromethane was added dropwise over 20 min to a stirred solution of 3-[2-(3-phenylpropoxy)ethoxy]-1-propanol (8.8 g) and carbon tetrabromide (15.92 g) in dry dichloromethane (170 ml) at 0° C. under nitrogen. The solution was allowed to warm to room temperature and stirred under nitrogen for 30 min. The solution was concentrated to ca 30 ml and then purified by FCC eluting with System B (0:10→2:3) to give the title compound (9.94 g) as an oil. T.l.c. (System B 1:1) Rf 0.50
Reaction SMILES: B.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([CH2:22][CH2:23][C:24]([NH2:26])=O)=[CH:17][CH:16]=[CH:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([CH2:22][CH2:23][CH2:24][NH2:26])=[CH:17][CH:16]=[CH:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)CCc1cccc2cc(S(=O)(=O)c3cccc(F)c3)ccc12
Agent: B
Solvent: C1CCOC1
Product: NCCCc1cccc2cc(S(=O)(=O)c3cccc(F)c3)ccc12

Procedure:
Borane (8 mL of 1M THF solution) was added to a solution of 3-[6-(3-fluoro-benzenesulfonyl)-naphthalen-1-yl]-propionamide in 20 mL THF. The reaction mixture was refluxed for five hours, then cooled and quenched by addition of 10% aqueous HCl (25 mL). The mixture was heated to reflux for one hour, then cooled and THF was removed under reduced pressure. The resulting precipitate was collected by filtration to give 0.42 g of 3-[6-(3-Fluoro-benzenesulfonyl)-naphthalen-1-yl]-propylamine. MS (M+H)=344.
Reaction SMILES: [CH2:1]([C:5]([O:10][C:11]1[CH:33]=[CH:32][C:14]2[C:15]3[N:19]([CH2:20][CH2:21][O:22][C:13]=2[CH:12]=1)[CH:18]=[C:17]([C:23]1[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=1)[N:16]=3)([CH2:8][OH:9])[CH2:6][OH:7])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH:29]([N:24]1[C:23]([C:17]2[N:16]=[C:15]3[N:19]([CH2:20][CH2:21][O:22][C:13]4[CH:12]=[C:11]([O:10][C:5]([CH2:8][O:9][S:42]([CH3:41])(=[O:44])=[O:43])([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][O:7][S:42]([CH3:41])(=[O:44])=[O:43])[CH:33]=[CH:32][C:14]=43)[CH:18]=2)=[N:27][C:26]([CH3:28])=[N:25]1)([CH3:31])[CH3:30]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)(CO)CC(C)C)cc2OCC3)n(C(C)C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)(COS(C)(=O)=O)CC(C)C)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-isobutyl-2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-propane-1,3-diol (88.6 mg, 0.194 mmol) and Et3N (81.1 μL, 0.582 mmol) in DCM (10 mL) cooled at 0° C. was added methanesulfonyl chloride (37.9 μL, 0.485 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording the title compound as a colourless gum (quantitative). LCMS (Method B): RT 3.46 min [M+H]+ 612.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH3:10][C:11]([CH3:15])([CH3:14])[CH2:12][OH:13]>C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH3:10])=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: CC(C)(C)CO
Solvent: c1ccccc1
Product: CC(C)(C)COC(=O)CCCCCBr

Procedure:
A solution of 6-bromohexanoyl chloride (10.0 g, 0.047 mol) and 2,2-dimethylpropanol (4.96 g, 0.056 mol) in benzene (100 ml) was heated under reflux for 2 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in dichloromethane (200 ml), washed with aqueous sodium hydroxide (2M, 50 ml), water (50 ml) and dried (Na2SO4). The solvent was evaporated off under reduced pressure to give the crude product which was further purified by column chromatography (alumina, dichloromethane) to give neopentyl 6-bromohexanoate as a colourless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2([C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:24])[CH2:22][CH2:21]2)[CH2:7][CH2:6]1)=[O:4].[OH-].[K+].Cl>CO.O>[CH3:29][S:26]([NH:25][C:23]([C:20]1([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]2([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]2)[CH2:21][CH2:22]1)=[O:24])(=[O:28])=[O:27]
Reactant: COC(=O)C1(CCCCCCCCCCCCC2(C(=O)NS(C)(=O)=O)CC2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)NC(=O)C1(CCCCCCCCCCCCC2(C(=O)O)CC2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To a solution product of Example 36 (0.85 g, 1.97 mmol) in methanol (8.5 mL) was added KOH (0.39 g, 7.1 mmol) in water (2.1 mL) and the reaction mixture was stirred at 60° C. over a period of 16 h. The crude product obtained upon evaporation of the solvent was diluted with water (5.0 mL), acidified to pH=2 (1.5N HCl), extracted with ethyl acetate (100 mL×2). The organic layer was dried over sodium sulphate and concentrated. The residue obtained upon evaporation of the volatiles was purified by silica gel (230-400) column (25% ethyl acetate in petroleum ether) to give product as white solid 0.55 g (67%). mp: 97.5° C.-99.4° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].ClC(Cl)=C(Cl)C(Cl)=C(Cl)Cl.[CH3:16][N:17]([Si:19]([CH3:22])([CH3:21])Cl)[CH3:18]>>[CH3:16][N:17]([Si:19]([CH3:22])([CH3:21])[C:1]#[C:2][C:3]#[C:4][Si:19]([N:17]([CH3:18])[CH3:16])([CH3:22])[CH3:21])[CH3:18]
Reactant: CN(C)[Si](C)(C)Cl
Reactant: [Li]CCCC
Agent: ClC(Cl)=C(Cl)C(Cl)=C(Cl)Cl
Product: CN(C)[Si](C)(C)C#CC#C[Si](C)(C)N(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A flame dried 250 ml Schlenk flask containing TBF (20 ml) was cooled to −78° C. and n-butyl lithium (20 ml of 2.4 M in hexane, 48.0 mmol) was added by syringe. After several minutes hexachlorobutadiene (1.88 ml, 12.0 mmol) was added dropwise via syringe over a 10 minute period. After completion of addition, the cold bath was removed and the mixture stirred at room temperature for 3 hours. The resulting 1,4-dilithio-1,3-butadiyne was used without further purification. The flask was then recooled to −78° C., and dimethylaminodimethylchlorosilane (3.6 ml, 24 mmol) was added by syringe. The flask was removed from the cold bath and the reaction mixture stirred at room temperature for 16 hours. At this time 1H NMR analysis indicated complete disappearance of dimethylaminodimethylchlorosilane and formation of 1,4-bis(dimethylaminodimethylsilyl)butadiyne. The TBF was removed in vacuo, and the mixture was taken up in a minimum amount of pentane and filtered. The pentane was removed in vacuo to give 2.91 g (96%) of 1,4-bis(dimethylaminodimethylsilyl)butadiyne.