Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH3:12])[CH:8]([CH2:13][C:14]#[C:15][C:16]2[N:17]=[C:18]3[CH:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:19]3=[N:20][CH:21]=2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O.[Cu](I)I>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C@@H:9]([CH3:12])[C@H:8]([C:13]2[N:17]3[C:16]([CH:21]=[N:20][C:19]4[N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[CH:24][C:18]=43)=[CH:15][CH:14]=2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(C)C(CC#Cc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Agent: I[Cu]I
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CCS(=O)(=O)N1CC[C@@H](C)[C@H](c2ccc3cnc4c(ccn4COCC[Si](C)(C)C)n23)C1
Temperature: 130 °C
Reaction time: 5 h
Yield: 5.8 %

Procedure:
To a flask containing (+/−)-2-[3-(1-ethanesulfonyl-4-methyl-piperidin-3-yl)-prop-1-ynyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (395 mg, 0.83 mmol) was added copper iodide (79 mg, 0.41 mmol), and DBU (0.57 mL, 3.8 mmol) in dry dimethyl acetamide (4 mL). The mixture was vacuum degassed and the flask was wrapped with tin foil (protect from light) and heated to 130° C. and stirred for 5 hours. Additional copper iodide (110 mg) was added and the mixture was stirred for another 6 hours and then cooled to ambient with over-night stirring. The material was taken up in water (30 mL) and ethyl acetate (30 mL), transferred to a reparatory funnel and shaken. The organic phase was collected and shaken with an equal volume of brine. The aqueous phases were back extracted with ethyl acetate (2×25 ml), the organics combined, dried (MgSO4), filtered and stripped. The remainder was purified by preparative TLC eluting with 45% ethyl acetate in hexanes (develop plates in the dark). A less polar component was collected providing 23 mg of semi-pure trans-(+/−)-8-(1-ethanesulfonyl-4-methyl-piperidin-3-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-3,4,8a-triaza-as-indacene product. MS (M+H)+=477. Also 17 mg of a more polar cis-(+/−)-8-(1-ethanesulfonyl-4-methyl-piperidin-3-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-3,4,8a-triaza-as-indacene product was collected. MS (M+H)+=477.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH2:16][CH3:17])[C:10]=1[CH:18]1[C:26](=[O:27])[CH:25]2[CH:20]([CH:21]3[O:28][CH:24]2[CH2:23][CH2:22]3)[C:19]1=[O:29])[CH3:8].C(N(CC)CC)C>ClCCl>[CH2:5]([O:4][C:2](=[O:3])[O:29][C:19]1[CH:20]2[CH:25]([C:26](=[O:27])[C:18]=1[C:10]1[C:11]([CH2:16][CH3:17])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=1[CH2:7][CH3:8])[CH:24]1[O:28][CH:21]2[CH2:22][CH2:23]1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)C2C3CCC(O3)C2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)OC1=C(c2c(CC)cc(C)cc2CC)C(=O)C2C3CCC(O3)C12
Temperature: 25 °C

Procedure:
A solution of ethyl chloroformate (0.071 g, 0.65 mmol) in dichloromethane (0.5 ml) is added dropwise to a solution of (1RS,2SR,6RS,7SR)-4-(2,6-diethyl-4-methylphenyl)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (0.172 g, 0.55 mmol) in dichloromethane (2 ml) at 0° C. and the reaction mixture is stirred. A solution of triethylamine (0.066 g, 0.65 mmol) in dichloromethane (1 ml) is added and the reaction mixture is stirred at room temperature for 17 hours, warming slowly to room temperature. The reaction mixture is diluted with dichloromethane (3 ml) and washed with saturated aqueous sodium bicarbonate solution. The organic phase is separated, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give carbonic acid (1RS, 2SR,6RS,7SR)-5-oxo-4-(2,6-diethyl-4-methylphenyl)-10-oxatricyclo-[5.2.1.02,6]-dec-3-en-3-yl ester ethyl ester as a colourless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=[C:4]2[CH:3]=1.[CH:22]([NH:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27])([CH3:24])[CH3:23]>>[CH:22]([NH:25][C:26](=[O:27])[C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]3[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=[C:4]3[CH:3]=2)[CH:33]=1)([CH3:24])[CH3:23]
Reactant: CC(C)NC(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(Nc2nc(Cl)cc3nc(C(F)(F)F)cn23)n[nH]1
Product: Cc1cc(Nc2nc(-c3cccc(C(=O)NC(C)C)c3)cc3nc(C(F)(F)F)cn23)n[nH]1

Procedure:
Title compound was synthesized from 7-chloro-N-(5-methyl-1H-pyrazol-3-yl)-2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-amine and 3-(isopropylcarbamoyl)phenyl boronic acid using the procedure described in Example 278. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.57 Hz, 6H) 2.32 (s, 3H) 4.15 (td, J=13.45, 6.69 Hz, 2H) 6.74 (s, 1H) 7.60 (t, J=7.71 Hz, 1H) 7.78 (s, 1H) 7.90 (d, J=7.83 Hz, 1H) 8.27 (d, J=8.08 Hz, 1H) 8.38 (d, J=7.58 Hz, 1H) 8.57 (s, 1H) 9.03 (s, 1H) 10.55 (s, 1H); ESI-MS: m/z calc'd for C21H20F3N7O 443.43; found 444.3 (M+H)+.
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]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][NH:23][CH2:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[Si]([N:31]=[C:32]=[O:33])(C)(C)C.CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][N:23]([C:32]([NH2:31])=[O:33])[CH2:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCCNC3)cc12
Reactant: C[Si](C)(C)N=C=O
Solvent: CO
Solvent: ClCCl
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCCN(C(N)=O)C3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-[(S)-1-(2,6-Dichloro-3-fluorophenyl)ethyl]-5-(1,2,5,6-tetrahydropyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine (0.0030 g, 0.0077 mmol) in DCM (0.5 mL) was added a drop of TMS isocyanate. The reaction was stirred at 0° C. for 30 min. The solution was directly loaded onto Prep TLC (20×20 cm, silica gel, 5% MeOH in DCM) to afford the desired product. 1H-NMR (CD3OD, 400 MHz): δ=1.87 (d, J=7.1 Hz, 3 H), 2.22-2.44 (m, 2 H), 3.46-3.57 (m, 2H), 4.11-4.20 (m, 2 H), 5.27 (d, J=7.3 Hz, 1 H), 6.00 (t, J=2.0 Hz, 1 H), 7.11-7.24 (m, 1 H), 7.34 (dd, J=16.2, 1.8 Hz, 2 H), 8.19 (s, 1 H). MS (ES+): m/z 433.04/434.96 [MH+]. HPLC: tR=3.23 min (ZQ3, polar—5 min).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([OH:35])=O.C(N(C(C)C)CC)(C)C.[CH3:45][O:46][C:47]1[CH:48]=[C:49]([NH:57][C:58]2[N:59]=[CH:60][C:61]3[CH2:67][NH:66][CH2:65][CH2:64][C:62]=3[N:63]=2)[CH:50]=[C:51]([O:55][CH3:56])[C:52]=1[O:53][CH3:54]>CN(C=O)C.CCOC(C)=O>[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33]([N:66]1[CH2:65][CH2:64][C:62]2[N:63]=[C:58]([NH:57][C:49]3[CH:48]=[C:47]([O:46][CH3:45])[C:52]([O:53][CH3:54])=[C:51]([O:55][CH3:56])[CH:50]=3)[N:59]=[CH:60][C:61]=2[CH2:67]1)=[O:35]
Reactant: O=C(O)c1cccs1
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2cccs2)C3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.021 g, 0.047 mmol) in anhydrous DMF (1.5 mL) was treated sequentially with thiophene-2-carboxylic acid (0.008 g, 0.062 mmol) and diisopropylethylamine (0.025 mL, 0.095 mmol). The reaction mixture was allowed to stir for 30 minutes at room temperature. After 30 minutes, N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (0.015 g, 0.047 mmol) was added to the reaction mixture. The reaction was allowed to stir for 3 hours at room temperature. The reaction mixture was then diluted with EtOAc and washed three times with brine. The combined aqueous layers were then washed twice with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was then purified over silica using a MeOH/CHCl3 gradient affording the final product in 40% yield (0.008 g, 0.019 mmol).
Reaction SMILES: [Cl:1][CH:2]([Cl:24])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([Sn](C)(C)C)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])=[O:4].Br[C:26]1[CH:27]=[CH:28][C:29]([CH2:32][NH:33][S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])=[N:30][CH:31]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O.C(OC(=O)C)C.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][CH:2]([Cl:24])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:26]3[CH:27]=[CH:28][C:29]([CH2:32][NH:33][S:34]([CH2:37][CH3:38])(=[O:35])=[O:36])=[N:30][CH:31]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:23])[CH3:22])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc([Sn](C)(C)C)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Reactant: CCS(=O)(=O)NCc1ccc(Br)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(Cl)Cl)[C@@H]3CF)cc2)cn1
Temperature: 80 °C
Yield: 43.1 %

Procedure:
2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(trimethylstannyl)-phenyl)-oxazolidin-3-yl)ethanone (281 mg, 0.66 mmol) and N-((5-bromopyridin-2-yl)methyl)ethanesulfonamide (155 mg, 0.56 mmol) are dissolved in N-Methyl-2-pyrrolidone (40 mL) and purged with nitrogen gas. Pd2(dba)3 (51 mg, 0.055 mmol) and tri-2-furylphosphine (27 mg, 0.11 mmol) are added; the resulting mixture is heated to 80° C. for 18 hours. The reaction mixture is cooled, diluted with ethylacetate, and washed with water. The organic phase is dried (Na2SO4) and concentrated under vacuum. The crude material is chromatographed (24 g Redi-Sep column) eluting from 100% hexanes to 90:10 ethylacetate:hexanes to afford the title compound (125 mg): m/z (Cl) M+H 518.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH2:7][OH:8])(=[O:3])[CH3:2].C(Cl)Cl.CCN([CH2:25][CH3:26])CC.[S:27](Cl)([C:30]1C=C[C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>CCOC(C)=O.O>[C:25]1([CH3:26])[C:30]([S:27]([O:8][CH2:7][C@H:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:29])=[O:28])=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: CCOC(C[C@H](CO)COC(C)=O)OCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(C[C@@H](COC(C)=O)COS(=O)(=O)c1ccccc1C)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 100 mL 1-neck round bottom flask, equipped with a magnetic stir bar and septum under N2 was charged the crude product of Example 14 step c) (4.62 g, 19 mmol), dry CH2Cl2 (20 mL) and Et3N (5.62 mL, 40 mmol). To this solution was added tosyl chloride (4.76 g, 25 mmol). The resulting mixture was stirred at ambient temperature for 4 hours. Charged H2O (0.27 g, 15 mmol) and stirred vigorously for 4 hours. The reaction mixture was diluted with 80 mL EtOAc and 50 mL H2O and the aqueous layer was separated. To the organic layer was added 75 ml of a 5% aq. solution of KH2PO4. After mixing and separation of the layers, the aqueous layer was removed. The organic layer was washed with 50 mL of saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo to a constant weight of 7.40 g of the desired product.
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[N:28][CH:29]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[N:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(O)nc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(O)nc2)cc1)C(=O)O
Yield: 85.8 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(2-hydroxypyridine-5-carbonylamino)ethoxy]phenyl]propionate (300 mg), which is the product of Example 49, was reacted with aqueous sodium hydroxide solution (1N, 3.00 ml) and the reaction mixture was treated to give the title compound (240 mg) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[N-:31]=[C:32]=[O:33].N[C:35]1[C:44]2[NH:43][C:42](=[O:45])[CH2:41][O:40][C:39]=2[CH:38]=[CH:37][CH:36]=1>CCOC(C)=O.CN(C=O)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:32]([NH:31][C:35]2[C:44]3[NH:43][C:42](=[O:45])[CH2:41][O:40][C:39]=3[CH:38]=[CH:37][CH:36]=2)=[O:33])=[C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1
Reactant: Nc1cccc2c1NC(=O)CO2
Reactant: NCc1ccc(C(F)(F)F)cc1N1CCCCC1
Reactant: [N-]=C=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1COc2cccc(NC(=O)NCc3ccc(C(F)(F)F)cc3N3CCCCC3)c2N1
Temperature: 80 °C
Yield: 45 %

Procedure:
Amine 2c (1 g, 3.8 mmol) (Scheme 7) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1.13 g, 3.8 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 5 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1e (425 mg, 2.6 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 530 mg of a white solid. Yield=45% 1HNMR (DMSO, 400 MHz) δ 1.56 (2H, bs), 1.69 (4H, bs), 4.55 (2H, d, J=5.6 Hz), 4.64 (2H, s), 6.64 (2H, dd, J=14 Hz, J′=7.6 Hz), 6.88 (1H, t, J=8 Hz), 7.32 (1H, s), 7.39 (2H, s), 8.64 (1H, t), 10.66 (1H, bs), 10.88 (1H, bs); [M+1] 449.2 (C22H23F3N4O3 requires 448.4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([O:16]CC)=O>Cl.O1CCOCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:14](=[O:16])[CH:13]=[CH:12]2
Reactant: CCOC(=O)/C=C/c1cc(C(F)(F)F)ccc1N
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2cc(C(F)(F)F)ccc2[nH]1
Temperature: 100 °C

Procedure:
To a stirring mixture of (E)-ethyl 3-(2-amino-5-(trifluoromethyl)phenyl)acrylate (4 g, 15.4 mmol) in 4N HCl in dioxane (20 mL) was added concentrated HCl (3 mL). The resulting mixture was warmed to 100° C. overnight. The reaction mixture was cooled to rt and then slowly quenched with a cold saturated NaHCO3 solution until pH>7. A normal aqueous extraction with EtOAc was followed. The crude mixture was taken directly to the next reaction without further purification. Retention time(min)=1.849, method [1], MS(ESI) 214.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][C:24]1[O:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]2[CH2:23][C:24]2[O:32][C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: c1cnc2oc(CC3CCCCN3)cc2c1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3cccnc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared, using the method of Example 4, from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.171 g, 0.72 mmol) and (RS)-2-piperidin-2-ylmethyl-furo[2,3-b]pyridine, D11 (0.13 g, 0.60 mmol) as a colourless solid (0.129 g, 49%).
Reaction SMILES: Cl.C(C#N)(=O)[C:3]([CH3:6])([CH3:5])[CH3:4].[C:10]([OH:13])(=O)[CH3:11].[NH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17]>O>[NH2:19][N:18]1[C:10](=[O:13])[C:11]([C:3]([CH3:4])([CH3:5])[CH3:6])=[N:14][N:15]=[C:16]1[SH:17]
Reactant: CC(=O)O
Reactant: CC(C)(C)C(=O)C#N
Reactant: NNC(=S)NN
Agent: Cl
Solvent: O
Product: CC(C)(C)c1nnc(S)n(N)c1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Hydrogen chloride gas was passed into a mixture of 222 g (2 mol) of pivaloyl cyanide and 120 g (2 mol) of glacial acetic acid under 8 bars and at 20° to 25° C. for four hours. Thereafter, the mixture was let down and excess glacial acetic acid was stripped off in vacuo. The product was then added to a mixture of 212 g (2 mol) of thiocarbohydrazide, 840 g of water and 280 g of concentrated hydrochloric acid. When the addition had ended, the reaction mixture was warmed to 90° C. for 1.5 hours and then subsequently stirred at room temperature overnight. The mixture was then cooled to 0° C. and the solid obtained was filtered off, washed with 400 ml of cold water and dried at 40° C. in vacuo. 314.4 g (78.6% of theory) of 4-amino-6-tert.-butyl-3-mercapto-1,2,4-triazin-5(4H)-one (VII) of melting point 205°-209° C. were obtained.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15]C(C)([O-])C.[K+].C(OP(C=[N+]=[N-])(=O)OCC)C>CCOCC>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]#[CH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: CCOP(=O)(C=[N+]=[N-])OCC
Agent: [K+]
Solvent: CCOCC
Product: C#C[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
(S)-N-Boc-2-Ethynyl-pyrrolidine was prepared according to Method X above by the treatment of (S)-N-Boc-2-formyl-pyrrolidine (470 mg, 2.36 mmol) (Example 87A above) with potassium tert-butoxide (340 mg, 3.07 mmol) and diazomethyl-phosphonic-acid-diethylester (550 mg, 3.07 mmol) (also prepared according to Method X). The product was obtained after silica gel coloumn chromatography with 10% Et2O in hexanes. (Yield 200 mg, 43%).
Reaction SMILES: [Mg].Br[CH:3]1[CH2:5][CH2:4]1.[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)#N.C([O:16]CC)C>II>[CH:3]1([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:16])[CH2:5][CH2:4]1
Reactant: CCOCC
Reactant: N#Cc1ccccn1
Reactant: BrC1CC1
Agent: II
Agent: [Mg]
Product: O=C(c1ccccn1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Dry magnesium powder (0.79 g, 32.6 mmol), which had been previously crushed in a mortar with a pestle, was charged into a dry round bottom flask under a nitrogen atmosphere. To this was added diethyl ether (20 mL), followed by bromocyclopropane (3.95 g, 2.61 mL, 32.6 mmol). A small amount of iodine (0.002 g) was added to initiate formation of the Grignard reagent. The reaction was heated to a gentle reflux for a short period of time (˜1 h) until all of the magnesium metal had reacted. The material was allowed to stir at room temperature for 2 hours, and then cooled in an ice bath. To this was added 2-cyanopyridine (2.0 g, 19.2 mmol) in diethyl ether (10 mL). The mixture was stirred for 3 hours, and then carefully quenched with sat. ammonium chloride (3 mL). The reaction was then acidified with 15% aq. hydrochloric acid (3 mL). The mixture was stirred for 20 minutes, and then made basic by the addition of 10 N sodium hydroxide until the pH was approximately 9. To this solution was added ethyl acetate (300 mL), and the aqueous layer was extracted with water (30 mL). The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness giving a yellow oil. This oil was chromatographed (SiO2, hexanes/ethyl acetate: 75/25) to give the title compound as a yellow oil (1.48 g, 52%). 1H NMR (300 MHz, DMSO-d6): δ 1.10 (m, 4H); 3.46 (m, 1H); 7.70 (m, 1H); 7.96 (t, 1H, J=78. Hz); 8.01 (t, 1H, J=7.8 Hz); 8.77 (d, 1H, J=4.8 Hz).
Reaction SMILES: [OH:1][CH:2]([CH2:16]O)[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([CH3:14])[C:8]1=[O:15].[BrH:18].[C:19]([OH:22])(=O)[CH3:20].C(=O)(O)[O-].[Na+]>ClCCl.O>[C:19]([O:1][CH:2]([CH2:16][Br:18])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([CH3:14])[C:8]1=[O:15])(=[O:22])[CH3:20]
Reactant: Br
Reactant: Cn1ccc(=O)n(CCCCC(O)CO)c1=O
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC(CBr)CCCCn1c(=O)ccn(C)c1=O
Reaction time: 0.25 h
Yield: 100 %

Procedure:
3-(5,6-Dihydroxyhexyl)-1-methyluracil (350 mg, 1.4 mmol) was stirred with 30% hydrogen bromide in acetic acid (0.87 ml, 4.3 mmol) for 45 minutes. The solution was added to a mixture of sodium bicarbonate (1.6 g), water (10 ml) and dichloromethane (20 ml). After 15 minutes of vigorous stirring, the layers were separated and the aqueous layer was extracted with dichloromethane (3×40 ml). The combined organic layers were dried over sodium sulfate and the solvent was evaporated under vacuum to give 3-(5-acetoxy-6-bromohexyl)-1-methyluracil (500 mg, 100% yield). The bromoacetate thus obtained was used in the next step without further purification. 3-(5-Acetoxy-6-bromohexyl)-l-methyluracil (360 mg, 1.0 mmol) was dissolved in methanol (5 ml) and treated with a solution of 1M sodium methoxide in methanol (1 ml). After stirring for 15 minutes, the solution was poured into water (10 ml) and extracted with dichloromethane (3×30 ml). The combined organic layers were dried over sodium sulfate and the solvents were evaporated to give 3-(5,6-oxidohexyl)-1-methyluracil (150 mg, 67% yield) as a colorless oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH2:38][CH:37]=[C:36]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)[CH2:35][CH2:34]1>O1CCCC1.CN(C)C=O>[O:14]1[C:15]2[C:24]3[O:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][C:16]=2[O:25][CH2:26][CH:13]1[CH2:12][N:33]1[CH2:34][CH:35]=[C:36]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)OCCC4)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4c(c3O2)OCCC4)C1

Procedure:
To a mixture of (2R)-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-h]chromen-2-yl-methyl 4-methylbenzenesulfonate (0.30 g, 0.80 mmole) and potassium carbonate (0.22 g, 1.55 mmole) in 1:1 tetrahydrofuran/dimethylformamide (20 mL) was added 0.47 g (2.38 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The reaction mixture was refluxed under nitrogen for 6 hours. After the reaction was complete, the mixture was evaporated to dryness under reduced pressure and the residue was column chromatographed on silica gel with methylene chloride to remove impurities and with 3% methanol/methylene chloride to elute the desired product as an as an oil, which was crystallized from isopropanol with the addition of a solution of oxalic acid in hot isopropanol to give 0.070 g (6%) of the (S)-enantiomer of the title compound as an orange solid, m.p. 140° C.
Reaction SMILES: [OH:1][C:2]1([CH3:18])[CH2:7][CH2:6][C@@H:5]([NH:8]C(=O)OC(C)(C)C)[CH2:4][C:3]1([CH3:17])[CH3:16].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:5]1[CH2:6][CH2:7][C:2]([CH3:18])([OH:1])[C:3]([CH3:17])([CH3:16])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC(C)(O)C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C[C@H](N)CCC1(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 133.1 %

Procedure:
To a solution of tert-butyl ((1R)-4-hydroxy-3,3,4-trimethylcyclohexyl)carbamate (520 mg, 2.15 mmol) in DCM (6.00 mL) was added TFA (3.00 mL) at 0° C. The result mixture was stirred at room temperature for 1 h. The reaction was concentrated in vacuo to give a crude product (450 mg, crude), which was used directly for next step without further purification. MS (ESI) m/z 158.1 [M+H]+.