Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([CH:10]([N+:18]#[C-:19])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=O)=O)=CC=1.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]=[N:28][CH:29]2[CH2:37][CH:36]3[N:32]([CH2:33][CH2:34][CH2:35]3)[CH2:31][CH2:30]2)=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[N:18]=[CH:19][N:28]([CH:29]3[CH2:37][CH:36]4[N:32]([CH2:33][CH2:34][CH2:35]4)[CH2:31][CH2:30]3)[C:27]=2[C:24]2[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=2)=[CH:16][CH:15]=1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: C(=NC1CCN2CCCC2C1)c1ccncc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Fc1ccc(-c2ncn(C3CCN4CCCC4C3)c2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
α-(p-Toluenesulfonyl)-4-fluorobenzylisocyanide (10.1 g, 34.9 mmol) and (±)-7-(4-pyridylmethyleneamino)-1,2,3,5,6,7,8,8a-octahydroindolizine (8.0 g (34.9 mmol), prepared as described in 2)) were dissolved in dichloromethane (150 ml). To the solution was added 1,8-diazabicyclo[5.4.0]-7-undecene (5.22 ml, 34.9 mmol), and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. To the residue was added a saturated aqueous solution of sodium hydrogencarbonate and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:methanol:isopropylamine=20:1:1), to give the title compound (1.87 g) as a pale yellow powder (yield 14%).
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[O:21])[CH2:11]1)=O)(C)(C)C.[ClH:32].O1[CH2:38][CH2:37][O:36][CH2:35]C1>>[NH2:24][C:25]1[C:26]([Cl:32])=[CH:27][C:38]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH3:31])[CH:23]=3)=[O:21])[CH2:11]2)=[O:5])=[C:37]([O:36][CH3:35])[CH:30]=1
Reactant: Cl
Reactant: Cn1cc(C(=O)NCCCCN2CC[C@H](CNC(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: C1COCCO1
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCNC(=O)c2cn(C)c3ccccc23)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-(4-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-butyl)-1-methyl-1 H-indole-3-carboxamide (1.94 g) was dissolved in 4N hydrochloric acid-dioxane solution (40 ml) and the mixture was stood at room temperature for 60 min. The reaction mixture was concentrated under reduced pressure. Dimethylformamide (30 ml) was added to the residue and the mixture was neutralized with triethylamine (1.25 ml). 4-Amino-5-chloro-2-methoxybenzoic acid (0.91 g) and 1-hydroxybenzotriazole (0.67 g) were added thereto, and the mixture was stirred at 0° C. for 15 min. Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.95 g) was added, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.75 g of N-(4-((3R)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)butyl)-l-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=O)[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:4][C:3]2[CH:50]=[CH:51][CH:52]=[CH:53][C:2]1=2.[CH2:54](Br)Br>C(Cl)Cl.C1COCC1.C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl.C(Br)Br.[Zn].[Zn].Cl[Ti](Cl)(Cl)Cl>[S:1]1[C:5]([C@H:6]([O:32][Si:33]([C:46]([CH3:48])([CH3:47])[CH3:49])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:54])[CH2:12][C@H:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:4][C:3]2[CH:50]=[CH:51][CH:52]=[CH:53][C:2]1=2
Reactant: COC(=O)CCC/C=C\C[C@H]1[C@@H](OC2CCCCO2)CC(=O)[C@@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Reactant: BrCBr
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1C[C@H](OC2CCCCO2)[C@H](C/C=C\CCCC(=O)OC)[C@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Temperature: 0 °C

Procedure:
(Z)-Methyl 7-((1R,2R,5S)-2-((R,E)-3-(benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-3-oxo-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (15a, limiting reagent) is dissolved in DCM (0.05 M) under a nitrogen atmosphere and cooled to 0° C. A solution consisting of zinc methylene dibromide titanium tetrachloride is prepared by combining zinc dust (2.3 g) in THF (40 mL) with methylene dibromide (0.81 mL) at −40° C. under a nitrogen atmosphere. To the suspension is slowly added TiCl4 (0.92 mL). Portions (2 mL) of the zinc methylene dibromide titanium tetrachloride solution are added until the reaction is complete as judged by TLC. Upon completion, the reaction mixture is diluted with ethyl acetate and filtered twice through a bed of Celite. The filtrate is washed with a saturated aqueous solution of sodium bicarbonate, then with a 50% aqueous solution of brine. The organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate 17a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:3]=1.[CH3:23]N>O1CCOCC1.C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:23])[CH:5]=[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2cc([N+](=O)[O-])cc(Br)n2)cc1
Reactant: CN
Solvent: C1COCCO1
Solvent: CCO
Product: CNc1cc(Br)nc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
0.10 g (0.00026 mol) of 2-bromo-4-nitro-6-(4-nitrobenzenesulphonyl)-pyridine was dissolved in 3.2 ml of dioxane and treated with 3.2 ml of 8M methylamine in ethanol. The mixture was stirred at room temperature for 3 hrs., the solvents were removed and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:4. There was obtained 0.065 g (68%) of [2-bromo-6-(4-nitrobenzenesulphonyl)-pyridin-4-yl]-methylamine as pale yellow crystals; m.p.: 191-192° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:14]([F:17])([F:16])[F:15])=[N:5][N:6](C)[C:7]=1[O:8][CH:9]1[CH2:12][O:11][CH2:10]1.NC(N)=S.[CH3:22][S:23]([C:26]1[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][N:27]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:31][C:29]1([CH3:32])[O:28][N:27]=[C:26]([SH:23]([CH2:2][C:3]2[C:4]([C:14]([F:17])([F:16])[F:15])=[N:5][NH:6][C:7]=2[O:8][CH:9]2[CH2:12][O:11][CH2:10]2)[CH3:22])[CH2:30]1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: Cn1nc(C(F)(F)F)c(CBr)c1OC1COC1
Agent: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[SH](Cc1c(C(F)(F)F)n[nH]c1OC1COC1)C1=NOC(C)(C)C1
Yield: 33.8 %

Procedure:
4-Bromomethyl-1-methyl-5-(oxetan-3-yloxy)-3-trifluoromethyl-1H-pyrazole (10.1 g, 32.2 mmol) and thiourea (2.7 g, 35.5 mmol) were stirred in ethanol (100 ml) at room temperature until the solids were dissolved. 3-Methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (6.28 g, 35.5 mmol) and potassium carbonate (4.91 g, 35.5 mmol) were added and the mixture was heated under reflux for 2 hours. The mixture was concentrated and purified by chromatography (eluent: ethyl acetate/hexane) to give the product as a white solid (4 g, 34% yield over two steps).
Reaction SMILES: C(O)(=O)C.[C:5]([NH2:9])(=[NH:8])[CH2:6][CH3:7].[C:10](OC)(=[O:16])[CH2:11][C:12](OC)=[O:13]>C[O-].[Na+]>[OH:13][C:12]1[CH:11]=[C:10]([OH:16])[N:9]=[C:5]([CH2:6][CH3:7])[N:8]=1
Reactant: CCC(=N)N
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(O)cc(O)n1
Yield: 84.1 %

Procedure:
Using the procedure of Example 1, Part B1, 18.5 g (0.14 mole) of propionamidine acetate and 90 ml of 25% sodium methoxide were reacted with dimethyl malonate (0.14 mole) to provide 16.5 g (89.5%) of 4,6-dihydroxy-2ethylpyrimidine according to Step (1).
Reaction SMILES: [CH:1](=[N+:19]([O-:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:39]([O:51][P:52]([O:66]CCCCCCCCCCCC)[O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50].[CH2:79](I)[CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH3:90].C(#N)C>C1(C)C=CC=CC=1>[CH2:1]([N:19]([CH:20]([P:52](=[O:66])([O:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[O:51][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:38][CH2:90][CH2:89][CH2:88][CH2:87][CH2:86][CH2:85][CH2:84][CH2:83][CH2:82][CH2:81][CH2:80][CH3:79])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCOP(OCCCCCCCCCCCC)OCCCCCCCCCCCC
Reactant: CCCCCCCCCCCCCCCCCC=[N+]([O-])CCCCCCCCCCCCCCCCCC
Reactant: CCCCCCCCCCCCI
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCN(OCCCCCCCCCCCC)C(CCCCCCCCCCCCCCCCC)P(=O)(OCCCCCCCCCCCC)OCCCCCCCCCCCC
Temperature: 70 °C
Yield: 29 %

Procedure:
Following the procedure of Example 7, the title compound is prepared from 2.5 g (4.6 mmol) of N-(1-octadecylidene)-octadecylamine N-oxide, 2.9 g (5.0 mmol) of tri-n-dodecylphosphite, 3.0 g (10 mmol) of n-dodecyl iodide, 20 ml of acetonitrile and 40 ml of toluene by heating at 70° C. for 24 hours. The residue is purified by flash chromatography (10:1 hexane:ethyl acetate eluent) to give 1.5 g (29% yield) of the title compound as a white, low melting wax.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.Cl[C:13]1[CH:18]=[N:17][CH:16]=[CH:15][N:14]=1>C1(C)C=CC=CC=1>[N:14]1[CH:15]=[CH:16][N:17]=[CH:18][C:13]=1[NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: Clc1cnccn1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Nc2cnccn2)cn1
Temperature: 95 °C

Procedure:
To a solution of 5-amino-2-trifluoromethylpyridine (0.81 g) in 3 Ml toluene was added chloropyrazine (0.45 Ml, 1.0 equiv) via syringe. The homogeneous solution was heated to 95° C., then cooled to room temperature and concentrated in vacuo. Purification by silica gel chromatography (40% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 7.5 (s, 1H) 7.6 (s, 1H) 8.0 (s, 1H) 8.2 (s, 1H) 8.4 (s, 2H) 8.8 (s, 1H); (M+H)+241.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[C:44]([F:48])=[CH:45][CH:46]=[CH:47][C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: CC1(C)OB(c2ccc(Oc3c(F)cccc3F)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4c(F)cccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 15 h
Yield: 84.7 %

Procedure:
Into a 250 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,6-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 15 h at 90° C. in an oil bath and then concentrated under vacuum. The residue was diluted with water and extracted with dichloromethane and the organic layers combined. The organics were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (10/1) to give 500 mg (85%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][O:15][CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C.CC(C)=O>[ClH:33].[C:24]1([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][O:15][CH2:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCCOC=C(c2ccccc2)c2ccccc2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCCOC=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
(R)-1-[3-[[2,2-Diphenylethenyl]oxy]propyl]-3-piperidine carboxylic acid ethyl ester (0.60 g, 0.0015 mol) (prepared as described in Method A) was dissolved in ethanol (5 ml) and 12N sodium hydroxide solution (0.4 ml) was introduced. After stirring the solution at room temperature for 2 h, 37% hydrochloric acid (ca. 0.52 ml) was added with cooling followed by dichloromethane (250 ml). The mixture was dried (Na2SO4). Filtration and evaporation of the filtrate gave a residue, which was co-evaporated with acetone. The solid product was triturated with acetone, collected by filtration and dried in vacuo to give the title compound (0.30 g, 50%), m.p. 176°-180°.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:31][CH:32]=[CH:33][CH2:34]Br.[Cl-].[NH4+:37]>O1CCCC1.CN1CCCN(C)C1=O>[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:29])[C@H:25]([CH:26]([CH3:27])[CH3:28])[CH2:31]/[CH:32]=[CH:33]/[CH2:34][C@@H:25]([CH:26]([CH3:28])[CH3:27])[C:24]([N:37]1[C@@H:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][O:21][C:20]1=[O:23])=[O:29])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrCC=CCBr
Reactant: [NH4+]
Reactant: CC(C)CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC(C)[C@H](C/C=C/C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(C)C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
With stirring at -75° C., 48 ml of a 1.0M solution of lithium hexamethyldisilazide in tetrahydrofuran are added dropwise in the course of 1 hour to a solution of 11.5 g of 4(S)-benzyl-3-isovaleroyl-oxazolidin-2-one in 32 ml of tetrahydrofuran. The reaction mixture is stirred further for 2 hours at -75° C. and for 20 minutes at -20° C., then 10 ml of 1,3-dimethyl-3,4,5,6-tetrahydro- -2-(1H)-pyrimidone (DMPU) and, in the course of 45 minutes, a solution of 4.28 g of 1,4-dibromo-2-butene in 10 ml of tetrahydrofuran are added thereto. The reaction mixture is stirred further for 15 hours at -20° C., and then in the course of 1 hour brought to 0° C. At -20° C., 10 ml of saturated ammonium chloride solution are then added thereto and after 15 minutes the reaction mixture is brought to room temperature. The reaction mixture is then partitioned between dichloromethane and saturated sodium chloride solution/water (1:1). The organic phases are combined, dried over sodium sulfate and concentrated by evaporation and the residue is purified by means of FC (hexane/ethyl acetate 4:1) to yield the title compound: Rf (hexane/ethyl acetate 4:1)=0.30; m.p.=110°-111° C. (crystallised from ethyl acetate/hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2C=NC(C)=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:37])[C:19]([N:21]3[CH2:30][CH2:29][C:28]4[C:27]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)=[N:26][CH:25]=[N:24][C:23]=4[CH2:22]3)=[O:20])[C:4]=12.Cl.[N:39]1C=CC=[CH:41][C:40]=1C1C2CCNCC=2N=CN=1.COC1C=NC(N2C=CN=N2)=C2NC=C(C(=O)C(O)=O)C=12>>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:41]=[CH:40][N:39]=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:37])[C:19]([N:21]3[CH2:30][CH2:29][C:28]4[C:27]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)=[N:26][CH:25]=[N:24][C:23]=4[CH2:22]3)=[O:20])[C:4]=12
Reactant: c1ccc(-c2ncnc3c2CCNC3)nc1
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12
Agent: COc1cnc(-n2ccnn2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: Cl
Product: COc1cnc(-n2ccnn2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ncnc4-c4ccccn4)C3)c12

Procedure:
The procedure described in Part E of preparation of compound 18 above was employed for the coupling of 4-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride with 2-(4-methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid to afford 1-(4-methoxy-7-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(pyridin-2-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethane-1,2-dione; HRMS: 486.1677 (M+H)+ [calc'd: 486.1684]; 1HNMR (500 MHz, DMSO-d6) δ 12.82 (br s, 1H), 9.18 (s, 2/3H), 9.09 (s, 1/3H), 8.95 (s, 1H), 8.78 (m, 1/3H), 8.68 (m, 2/3H), 8.34 (s, 2/3H), 8.26 (s, 1/3H), 8.12-8.01 (m, 3H), 7.97 (s, 1H), 7.58 (m, 1/3H), 7.53 (m, 2/3H), 4.93 (s, 4/3H), 4.73 (s, 2/3H), 3.96 (s, 1H), 3.93 (m, 2/3H), 3.90 (s, 2H), 3.70 (m, 4/3H), 3.32 (m, 2/3), 3.18 (m, 4/3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].O=[C:30]1[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCCl.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH:32]1[CH2:33][CH:30]([N:26]2[CH2:25][CH:24]=[C:23]([C:20]3[C:15]4[CH:16]=[N:17][C:18]([NH2:19])=[C:13]([O:12][C@@H:10]([C:3]5[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=5[Cl:1])[CH3:11])[C:14]=4[O:22][CH:21]=3)[CH2:28][CH2:27]2)[CH2:31]1
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C4CNC4)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (8.11 mg, 0.0474 mmol), sodium triacetoxyborohydride (25.1 mg, 0.118 mmol) and 1,2-dichloroethane (1.0 mL, 13 mmol) were mixed and stirred at 70° C. overnight. After extraction with DCM and water, the organic layer was dried and dissolved in DCM (1.0 mL, 16 mmol). TFA (1.0 mL, 13 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 hour. The crude was passed through SCX-2 SPE and product was released by 2 M NH3 in methanol for purification by the MDPS. MS (ES+): m/z 477.10/479.15 (100/80) [MH+]. HPLC: tR=0.57 min (HPLC-ACQUITY, Analytical). 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=6.8 Hz, 3H), 2.54 (br. s., 2H), 2.64-2.68 (m, 2H), 3.11-3.18 (m, 2H), 3.53 (t, J=6.9 Hz, 1H), 3.94-4.08 (m, 4H), 6.27 (br. s., 1H), 6.50 (q, J=7.0 Hz, 1H), 7.22 (t, J=8.6 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.63 (s, 1H), 8.18 (s, 1H).
Reaction SMILES: O[C:2]1([C:22]([F:25])([F:24])[F:23])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[C:4]([C:15]2[S:19][C:18]([S:20][CH3:21])=[N:17][N:16]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([C:22]([F:25])([F:24])[F:23])[N:3]=[C:4]2[C:15]2[S:19][C:18]([S:20][CH3:21])=[N:17][N:16]=2)=[CH:8][CH:9]=1
Reactant: CSc1ccc(N2CC(O)(C(F)(F)F)N=C2c2nnc(SC)s2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ccc(-n2cc(C(F)(F)F)nc2-c2nnc(SC)s2)cc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A mixture of 4-hydroxy-1-[4-(methylthio)phenyl]-2-[2-(methylthio)-1,3,4-thiadiazol-5-yl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (0.52 g, 1.28 mmol) and p-toluenesulfonic acid monohydrate (0.1 g) in toluene (20 mL) was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The crude residue was redissolved in ethyl acetate and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration, and concentration in vacuo, the crude mixture was purified by chromatography on silica gel using hexane/ethyl acetate to give the title product (0.4 g, 80%) as a white solid; 1H NMR δ (DMSO-d6) 8.38 (1H, s), 7.51 (2H, d, J=8.7 Hz), 7.38 (2H, d, J=8.3 Hz), 2.76 (3H, s), 2.55 (3H, s); 13C NMR δ (DMSO-d6) 168.8, 157.4, 140.4, 138.0, 133.0, 131.0(q), 127.2, 126.4, 125.7, 122.0(q), 16.4, 14.4.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[O:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]([NH2:37])[CH2:29][CH2:28]1>>[O:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]([NH:37][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][S:23]([C:18]3[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=3)(=[O:25])=[O:24])[N:9]=2)[CH2:29][CH2:28]1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: NC1CCOc2ccccc21
Product: O=S(=O)(Nc1cccc2nc(NC3CCOc4ccccc43)ccc12)c1cc(F)cc(F)c1

Procedure:
The title compound, MS: m/e=468.1 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline, 3,5-difluorophenyl sulfonylchloride and 3,4-dihydro-2H-chromen-4-ylamine.