Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl.[CH2:46]([N:53]1[CH:57]=[CH:56][N:55]=[C:54]1[CH2:58]Cl)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH3:44][O:43][C:39]1[CH:38]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]3[N:30]([CH2:58][C:54]4[N:53]([CH2:46][C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)[CH:57]=[CH:56][N:55]=4)[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: ClCc1nccn1Cc1ccccc1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)cc3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4nccn4Cc4ccccc4)CC3)(c3ccc(F)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 37.2 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(4-fluorophenyl) pyrrolidine and 1-benzyl-1H-imidazol-2-ylmethylchloride hydrochloride to give the title compound: mp; 95-100° C. Rf=0.04 (silica gel, 1/1 ethyl acetate/methanol).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH:13]([CH3:17])[CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[S:1]([O:16][CH2:15][CH2:14][CH:13]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:17])(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: CC(CCO)Oc1ccccc1
Product: CC(CCOS(N)(=O)=O)Oc1ccccc1
Yield: 67 %

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 3-phenoxy-1-butanol. The viscous oil obtained was purified by high pressure chromatography using a Waters Associates Prep LC/System 500A; Prepak 500® silica and methylene chloride as eluting agent at a flow rate of 200 ml/min. Fractions containing the title compound were combined and the solvent was evaporated under reduced pressure to give 12.7 g (67%) of title compound as yellow, viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH2:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:14]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23](O)=[O:24])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:23](=[O:24])[C@@H:22]3[CH2:26][CH2:27][CH2:28][N:21]3[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCc1ccc2c(N)nccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
5.00 g of 1-Amino-6-aminomethyl-isoquinoline and 6.20 g Boc-L-proline were dissolved in 88 mL DMF. 10.6 g of TBTU was added followed by a dropwise addition of N-methylmorpholine. Stirring was continued for 1 h at ambient temperature and the solvent was removed i.vac. The residue was extracted with 5% aqueous NaHCO3 solution and with ethyl acetate. The organic layer was separated and dried (NaSO4). The solvent was removed to give 10.7 g (quant.) of N-(1-Amino-isoquinolin-6-ylmethyl)-1-tert.butoxycarbonyl-prolinamide as an oil. Without purification, the compound was dissolved in 50 mL dichloromethane and 25.0 mL trifluoroacetic acid was added. Stirring was continued for 16 h and the solvent was removed i.vac. The residue was dissolved in methanol, the solvent was removed i. vac. And the residue was triturated with diethyl ether. The crystalline material was collected to give 12.9 g (89%) of N-(1-amino-isoquinolin-6-ylmethyl)-prolinamide. M.p. 140-142° C..
Reaction SMILES: [C:1]1([CH:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([Cl:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[Cl:28][C:25]([F:26])([F:27])[C:22]1[N:20]2[N:21]=[C:16]([N:12]3[CH2:11][CH2:10][N:9]([CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:8])[CH2:14][CH2:13]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: CC(c1ccccc1)N1CCNCC1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Product: CC(c1ccccc1)N1CCN(c2ccc3nnc(C(F)(F)Cl)n3n2)CC1
Yield: 64 %

Procedure:
A mixture of 1-(1-phenylethyl)piperazine and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 339 to give 3-[chloro(difluoro)methyl]-6-[4-(1-phenylethyl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 64% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>>[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: Nc1ccccc1Cl
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1Cl

Procedure:
Reaction of N-tert-butoxycarbonyl-L-methionine (1a) and 2-chloroaniline (2b) according to General Procedure A, gave after purification on a SILICA GEL column with hexane-acetone (3:1) as the eluent, an oily liquid of (3b) (C16H23N2O3S1Cl1, 79%), Rf=0.43 (hexane-acetone 3:1), [α]D23 =-41.5° (c 0.65, CHCl3), IR (KBr) ν: 536, 548, 606, 648, 667, 691, 752, 864, 963, 1036, 1055, 1165, 1250, 1298, 1368, 1393, 1441, 1524, 1593, 1616, 1684, 1696, 2338, 2361, 2870, 2920, 2978, 3036, 3061, 3121, 3314 cm-1, 1H NMR (CDCl3) δ: 8.551 (s, 1H, Ar--NH), 8.321-8.355 (m, 1H, ArH), 7.334-7.336 (m, 1H, ArH), 7.221-7.279 (m, 1H, ArH), 7.005-7.062 (m, 1H, ArH), 5.194-5.214 (br s, 1H, NH), 4.442-4.462 (m, 1H, Hα), 2.590-2.638 (m, 2H, CH2γ), 2.144-2.281 (m, 1H, Hβ), 2.112 (s, 3H, CH3ε), 1.966-2.112 (m, 1H, Hβ), 1.44 (s, 9H, t-Bu); EIMS (70 eV) m/z (%): 358 (M+, 2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][C:29]([F:32])([F:31])[CH2:28][N:27]3[C:33](=[O:37])[CH2:34][C:35]#[N:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:38]1([CH:41]=O)[CH2:40][CH2:39]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][C:29]([F:31])([F:32])[CH2:28][N:27]3[C:33]([C:34](=[CH:41][CH:38]3[CH2:40][CH2:39]3)[C:35]#[N:36])=[O:37])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CC(F)(F)C[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: O=CC1CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=CC1CC1)C(=O)N1CC(F)(F)C[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
A solution of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-4,4-difluoropyrrolidin-1-yl]-3-oxopropanenitrile (120 mg, 0.24 mmol, 1.00 equiv), cyclopropanecarbaldehyde (80 mg, 1.14 mmol, 5.00 equiv), piperidine (41 mg, 0.48 mmol, 2.00 equiv) in ethanol (10 mL) was stirred at 70° C. for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm, to give 24 mg (18%) of the title compound as a white solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][C:29]1[CH:33]=[C:32]([C:34](O)=[O:35])[O:31][N:30]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([C:32]5[O:31][N:30]=[C:29]([CH3:28])[CH:33]=5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: Cc1cc(C(=O)O)on1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: Cc1cc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)on1

Procedure:
The title compound, white solid (99 mg, 90%), MS (ISP) m/z=440.4 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 3-methyl-isoxazole-5-carboxylic acid.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[CH3:24])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:31]>CO.[OH-].[OH-].[Pd+2]>[ClH:31].[CH3:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17]1[CH:16]=[N:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: CC1CCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1CCCN1c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 8-benzyl-3-(2-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (0.51 g) in methanol (15 mL) was added 20% Pd(OH)2/C (0.08 g), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (15 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (430 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (0.30 g, 71%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:4][C:3]=1[F:18].C[O:20][CH:21]1[CH:25]([CH:26]=O)[CH2:24][CH:23](OC)O1>C(O)C>[F:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:1]1[CH:23]=[CH:24][C:25]([CH:21]=[O:20])=[CH:26]1)[NH:9][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7](=[O:17])[NH:6]2
Reactant: CCOC(=O)C1Nc2cc(N)c(F)cc2NC1=O
Reactant: COC1CC(C=O)C(OC)O1
Solvent: CCO
Product: CCOC(=O)C1Nc2cc(-n3ccc(C=O)c3)c(F)cc2NC1=O
Yield: 12.5 %

Procedure:
To a solution of ethyl 7-amino-6-fluoro-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxylate (2.03 g, 8.02 mmol) in ethanol (80 ml) was added dropwise 2,5-dimethoxytetrahydrofuran-3-aldehyde (1.36 ml, 9.62 mmol), and the mixture was refluxed for 3 hours. After cooling, the residue obtained by distilling off solvent was submitted to silica gel column chromatography [ethyl acetate-hexane=2:1] to obtain 333 mg of title compound as yellow powder. Yield 13%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22]>>[O:1]=[C:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:22][CH2:21][C:20]([O:19][CH3:18])=[O:23])=[O:14])=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: COC(=O)CN
Agent: Cl
Product: COC(=O)CNC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and glycine methyl ester hydrochloride according to the procedure of Example 154 as a gum; MS (ES) m/z: 291.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[CH3:18][NH:19][CH:20]1[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>CS(C)=O>[CH:20]1([N:19]([CH3:18])[C:2]2[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:22][CH2:21]1
Reactant: CNC1CC1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)C3CC3)nc2c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.26 mmol) in DMSO (2 mL), was added N-methylcyclopropanamine hydrochloride (175 mg, 1.63 mmol) and DIEA (325 mg, 2.52 mmol) with stirring for 2 h at 75° C. in an oil bath. Then the reaction was quenched by the addition of water (10 mL) to give the precipitate, which was collected by filtration to afford methyl 3-[cyclopropyl(methyl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as an off-white solid (297 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:14][Mg]Br.Cl>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH3:14])[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Reaction time: 8 h

Procedure:
Commercial 1-(4-bromophenyl)-2,2,2-trifluoroethanone (1 g, 4 mmoles) in diethyl ether (8 mL) was cooled to −78° C. for the addition of commercial methylmagnesium bromide (2.65 mL, 7.9 mmoles, 3 M in diethyl ether). The cloudy reaction media was allowed to reach room temperature and stirred overnight. The reaction mixture was transferred to a separatory funnel containing 1.2 M hydrochloric acid (20 mL). This aqueous layer was extracted 3 times with ethyl acetate (30 mL). The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The clear oil was pure enough to be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15](=[N:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]([NH:17][S:18]([C:20]([CH3:21])([CH3:23])[CH3:22])=[O:19])[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=NS(=O)C(C)(C)C)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Solvent: C1CCOC1
Product: CC(NS(=O)C(C)(C)C)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Temperature: -20 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
56 g (149.6 mmol) of 2-Methyl-propane-2-sulfinic acid {1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethylidene}-amide was dissolved in 1 L of THF. The solution was chilled to −20° C. and treated with 49 g (190 mmol) of Cp2ZrHCl. The mixture was allowed to warm to rt and left to stir overnight before cooling back to −20° C. and quenching with a saturated solution of NH4Cl. The mixture was warmed to rt extracted with EtOAc (3×). The combined organic layers were washed with H2O, brine and then dried over Na2SO4. All volatiles were then removed under reduced pressure. The resulting mixture was suspended in MTBE and filtered. All volatiles were again removed under reduced pressure to give 54 g (96%) of the title compound as a white solid in >90% chemical purity and was used without further purification. The diastereomeric ratio was determined to be >98% (reverse phase HPLC: Symmetry C18 column; solvent gradiant using H2O:ACN with 0.05% TFA): 1H NMR (300 MHz, CDCl3) δ 7.45-7.41 (m, 2 H), 7.20 (dd, 1 H, J=8.6, 2.3 Hz), 3.34-3.25 (m, 1 H), 3.01 (d, 1 H, J=6.9 Hz), 2.50-2.44 (m, 1 H), 2.23-2.17 (m, 1 H), 1.65-1.48 (m, 5 H), 1.34-1.17 (m, 3 H), 1.13 (s, 9 H), 0.98 (d, 3 H, J=6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 141.9, 132.8, 131.1, 130.6, 130.4, 128.5, 60.6, 56.1, 46.5, 33.7, 33.0, 26.6, 22.8, 22.3, 22.1, 16.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[CH3:9].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:11]=[O:13])[C:3]=1[CH3:9]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(N)cccc1Br
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1N=C=O
Yield: 106.3 %

Procedure:
A mixture of 1-bromo-2-methyl-3-aminobenzene 25.0 g, triphosgene 60.0 g and toluene 400 mL was stirred with heating under reflux for three hours. The reaction mixtures after standing to cool were concentrated under reduced pressure to give 1-bromo-3-isocyanato-2-methylbenzene 30.3 g.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH2:26])[CH:21]1[O:25][CH2:24][CH2:23][CH2:22]1>>[O:25]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:20][NH:26][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Reactant: NCC1CCCO1
Product: O=C(Nc1nc2cccc(NCC3CCCO3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and tetrahydrofurfurylamine (1.0 mL) as a white powder (17 mg, 16%). HPLC, Rt: 1.73 min. (purity 95.5%). LC/MS, M+(ESI): 339.1, M−(ESI): 337.1.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH2:12][C:9]=3[CH:10]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:4]([C:22]([O:24]CC)=[O:23])[C:3]1=[O:27].[OH-].[K+].C(O)C>O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][CH2:12][C:9]=3[CH:10]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:4]([C:22]([OH:24])=[O:23])[C:3]1=[O:27]
Reactant: CCOC(=O)c1c(-c2ccccc2C)c2cc3c(cc2n(C)c1=O)CCC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1-c1c(C(=O)O)c(=O)n(C)c2cc3c(cc12)CCC3
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 100.3 %

Procedure:
A mixture of ethyl 1-methyl-4-(2-methylphenyl)-2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylate (2.0 g), potassium hydroxide (1.55 g) and 80% ethanol (20 ml) was stirred at 80° C. for 20 minutes. The mixture was diluted with water and acidified with 2N NCl to give crystals of 1-methyl-4-(2-methylphenyl) -2-oxo-1,2,7,8-tetrahydro-6H-cyclopenta[g]quinoline-3-carboxylic acid (1.85 g, 99.6%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:15]([O:14][C:10](=[O:13])[CH:11]=[CH:12][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH3:16]
Reactant: N#Cc1ccc(Br)cc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(C#N)cc1
Temperature: 97.5 °C
Yield: 99.4 %

Procedure:
To a solution of 4-bromobenzonitrile (50 g, 0.275 mol) and ethyl acrylate (35.4 g, 0.412 mol) in dry DMF (250 mL), palladium acetate (0.61 g, 0.0027 mol), tris-o-tolylphosphine (3.34 g, 0.011 mol) and triethylamine (57.3 mL, 0.412 mol) were added and refluxed at 95-100° C. for 2 h under an argon atmosphere. The reaction was quenched by adding water (250 mL) and extracted with ether (3×250 mL). The combined extract was washed with 1.5 N HCl (250 mL), water and brine and dried over sodium sulfate (anhydrous). Solvent evaporation under reduced pressure and purification by column chromatography over neutral alumina, using ethyl acetate in petroleum ether as eluent, yielded 55 g (90%) of the sub-title compound as an off-white solid.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@@H:20]([NH2:45])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.C(N(C(C)C)C(C)C)C.Cl[C:56]([O:58][CH2:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:57]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:61][C:60]([CH3:63])([CH3:62])[CH2:59][O:58][C:56](=[O:57])[NH:45][C@@H:20]1[CH2:21][C@H:22]([C:24](=[O:44])[N:25]([CH:41]2[CH2:43][CH2:42]2)[CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[CH2:23][NH:18][CH2:19]1
Reactant: COCCCn1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Reactant: CC(C)(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCCn1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)OCC(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of (3R*,5S*)-3-amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-yl-methyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (121.4 mg, 0.2 mmol) (Starting Material 6), N-ethyldiisopropylamine (171.2 μL, 1 mmol) and 4-dimethylaminopyridine (10 mg) in CH2Cl2 (3 mL), neopentyl chloroformate (52.1 μL, 0.35 mmol) is added. After stirring at RT for 14 h, the mixture is diluted with CH2Cl2. The organic layer is washed with 1N HCl and saturated NaHCO3 solution, dried over Na2SO4 and evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (5 mL) for 2 h, the mixture is evaporated and the residue purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a yellowish solid. MS: 499.2 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.45 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1([CH2:23][CH2:24][OH:25])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.Cl>N1C=CC=CC=1>[CH3:1][S:2]([O:25][CH2:24][CH2:23][C:9]1([CH2:8][CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[O:16][C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1(CCO)c2ccccc2Oc2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)c2ccccc2Oc2ccccc21
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A mixture of 9,9-bis(2'-vinyloxyethyl)xanthene (57 g.) (prepared as in Example 2), water (400 ml.) and concentrated hydrochloric acid (15 ml.) is heated on the steambath with vigorous stirring for 5 hours. The cooled mixture is extracted three times with ether and the combined extracts are dried over MgSO4 and evaporated to dryness. The solid residue is recrystallised from chloroform-light petroleum (b.p. 60°-80° C.) to give 9,9-bis(2'-hydroxyethyl)xanthene, m.p. 144°-145° C. Methanesulphonyl chloride (588 mg.) is added dropwise over 5 minutes at 5° C. to a solution of 9,9-bis(2'-hydroxyethyl)xanthene (0.54 g.) in dry pyridine (5 ml.) with stirring. The mixture is allowed to stand at room temperature for 20 hours and is then poured into a mixture of 3 N hydrochloric acid (20 ml.) and ice (10 g.), and the resulting mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with 3 N hydrochloric acid and water, dried over MgSO4, and evaporated to dryness. The solid residue is recrystallised from acetone-light petroleum (b.p. 60°-80° C.) to give 9,9-bis(2'-methanesulphonyloxyethyl)-xanthene, m.p. 121°-122° C.