Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][N:67]([CH3:70])[C:66](=[O:71])[CH:65]=1>ClCCCl>[CH3:70][N:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][C:66]1=[O:71]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Cn1ccc(N)cc1=O
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.33 g, 0.57 mmol) in 1,2-dichloroethane (30 mL) was added diisopropylethylamine (0.59 g, 4.6 mmol), diphenylphosphinic chloride (Aldrich) (0.54 g, 2.3 mmol) respectively. The mixture was stirred at room temperature for 0.5 h, then 4-amino-1-methyl-pyridin-2-one (Molbridge) (0.07 g, 0.57 mmol) was added. The reaction mixture was heated and stirred at 60° C. for 10 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over Na2SO4, then concentrated. The residue was purified by chromatography (5-10% of MeOH in EtOAc) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a off white solid (32 mg, 10%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([Cl:19])[CH:6]=2.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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>[Cl:19][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:2]([CH:22]3[CH2:24][CH2:23]3)[C:3]([CH3:21])([CH3:20])[O:4]2)=[CH:9][CH:8]=1
Reactant: OB(O)C1CC1
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1C1CC1

Procedure:
A mixture of 3-bromo-7-chloro-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen (a compound obtained in Reference Example 8(1); 200 mg), cyclopropylboronic acid (100 mg), potassium phosphate (410 mg) and tetrakis(triphenylphosphine)palladium(0) (65 mg) in dioxane (5 mL) was heated under reflux for 23 hours. After cooling, to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and filtered through a column of porous diatomite (Chem Elut), and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/chloroform=100/0 to 95/5) to give the titled compound (114 mg) as a colorless viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.N1[CH2:16][CH2:15][CH2:14][CH2:13]1.C1(=O)CCC1>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:13]1([CH2:16][CH2:15][CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: C1CCNC1
Agent: O=C1CCC1
Solvent: O
Solvent: CO
Product: O=C1CC2(CCC2)Oc2ccc(Cl)cc21
Yield: 96.5 %

Procedure:
To a stirred solution of 5′-chloro-2′-hydroxy acetophenone (5.0 g, 29.308 mmol) in methanol (50 ml) was added pyrrolidine (4.16 g, 58.616 mmol) followed by cyclobutanone (4.1 g, 58.616 mmol) at room temperature. The reaction mixture was heated to reflux under nitrogen for 14 h. The solvent was evaporated under reduced pressure and the residue obtained was diluted with water (100 ml) and the mixture was acidified to pH 4.0. The mixture was extracted with chloroform (3×100 ml). The combined organic extracts were washed with water (100 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The residue obtained after evaporation of the solvent was purified by silica gel column chromatography using 15% ethyl acetate in petroleum ether to give 6.3 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.69-1.88 (m, 5H), 1.96-2.04 (m, 1H), 2.88 (s, 2H), 6.91 (d, J=9.0 Hz, 1H), 7.38 (d, J=6.6 Hz, 1H), 7.76 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][C@H:20]1[O:25][C@@H:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:21][C@@H:20]([CH3:19])[O:25][C@@H:24]([CH3:26])[CH2:23]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: C[C@@H]1CN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 mL) was added cis-2,6-Dimethylmorpholine (105 mL, 0.848 mmol). The resulting mixture was stirred at RT overnight. An additional 2 equ. of cis-2,6-Dimethylmorpholine was then added and the mixture was again stirred overnight at RT. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (Silica, EtOAc/Hexanes) to give (2S,6R)-4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,6-dimethylmorpholine (223 mg, 0.616 mmol, 87% yield). LC-MS (M+H)+=332.1. 1H NMR (500 MHz, MeOD) δ ppm 7.11-7.24 (2 H, m), 6.99-7.09 (2 H, m), 4.39-4.51 (2 H, m), 4.20 (1 H, s), 3.70 (2 H, td, J=4.12, 2.44 Hz), 3.14-3.25 (1 H, m), 3.03-3.13 (1 H, m), 2.69-2.80 (2 H, m), 2.54-2.68 (1 H, m), 1.95-2.13 (1 H, m), 1.23 (6 H, d, J=6.10 Hz).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@H:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[P:30](Cl)(Cl)(=[O:42])[O:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.C(Cl)[Cl:46]>>[Cl:46][C:33]1[CH:34]=[CH:35][C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:32]=1[O:31][P:30](=[N:12][C@H:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:42]
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: N[C@@H](C(=O)OCc1ccccc1)c1ccccc1
Reactant: ClCCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: O=C(OCc1ccccc1)[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)c1ccccc1
Yield: 72 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates the tosylate salt of (R)-benzyl 2-amino-2-phenylacetate (1.50 g, 3.63 mmol), and naphthalen-1-yl phosphorodichloridate (0.95 g, 3.63 mmol) and TEA (1.01 mL, 7.26 mmol) in 20 mL of dry DCM, were combined to give (2R)-benzyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)-2-phenylacetate in 72% yield (1.21 g), as a clear, yellow, thick oil.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([NH:19][CH2:20][C:21]([OH:23])=O)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].CN1CCOCC1.[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:38]=[C:39]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44]>O1CCCC1>[CH3:53][C:51]([CH3:54])([O:50][C:49]([NH:48][C:39]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:21](=[O:23])[CH2:20][NH:19][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[N:40][C:41]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:47])=[O:55])[CH3:52]
Reactant: CC(C)(C)OC(=O)NC(=NCCCCCCN)NC(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N=C(NCCCCCCNC(=O)CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of 1.6 g (14×10-3 mol) of isobutyl chloroformate in 5 ml of tetrahydrofuran is added dropwise to a solution, cooled to -30° C., of 3 g (14×10-3 mol) of carbobenzyloxyglycine and 2.8 g (28×10-3 mol) of N-methylmorpholine in 50 ml of tetrahydrofuran. The reaction medium is stirred for 0.5 hour and a solution of 5.4 g (14×10-3 mol) of bis(1,1-dimethylethyl) [[(6-aminohexyl)imino]methylene]biscarbamate in 20 ml of tetrahydrofuran is added. Stirring is continued for 2 hours at -30° C. and then for 24 hours at room temperature. After filtration of the reaction medium and evaporation of the filtrate under reduced pressure, the residue obtained is purified by chromatography on silica using an ethyl acetate/methylcyclohexane mixture (1/1 v/v) as the eluent to give 7.16 g (yield: 91%) of the expected product in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.C(N(CC)CC)C.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:20]1[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]1
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a stirred solution of 1-bromo-3-(bromomethyl)benzene (677 mg, 2.71 mmol) in THF (10 ml) was added triethylamine (380 μL, 2.71 mmol), followed by tert-butyl piperazine-1-carboxylate (504 mg, 2.71 mmol). The mixture was allowed to stir at RT for one hour. The solvent was evaporated and the residue was purified with a silica gel column eluting with 1:10 EtOAc/hexanes to give the title compound as an oil (888 mg, 2.49 mmol, 92%). [M+H] calc'd for C16H24BrN2O2, 355; found, 355.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([NH2:16])=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][CH2:6]1.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:16][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[NH:25])=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][CH2:6]1
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCN1CCCc2cc(N)cc(F)c21
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)CCN1CCCc2cc(NC(=N)c3cccs3)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-(Dimethylamino)ethyl)-8-fluoro-1,2,3,4-tetrahydroquinolin-6-amine (222 mg, 0.935 mmol) was stirred to dissolve in ethanol in a round bottom flask. To this solution was added methyl thiophene-2-carbimidothioate hydroiodide (533 mg, 1.87 mmol). The resulting suspension was stirred overnight at room temperature. When TLC analysis showed that the reaction was finished, the mixture was diluted with water and aqueous sodium carbonate, then extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated and the crude product then chromatographed on silica gel using 0-10% (2M NH3 in MeOH) in ethyl acetate, then a second time using 20-80% MeCN in an aqueous buffer of ammonium carbonate and ammonium hydroxide adjusted to pH 10.6. Yield: 46 mg, 15%. 1H NMR (DMSO-d6) δ 1.75 (m, 2H), 2.16 (s, 6H), 2.46 (m, 2H), 2.66 (m, 2H), 3.12 (m, 4H), 6.40 (m, 4H), 7.07 (m, 1H), 7.57 (m, 1H), 7.71 (m, 1H). ESI-MS: 347 (MH+, 33), 276 (100), 143 (12).
Reaction SMILES: CN1C(=O)N(C)CCC1.[F:10][C:11]([F:24])([F:23])[C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:16][CH:17]=1.Br[CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].Cl>C1COCC1>[O:37]=[C:28]1[C:29]2[C:30](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:32])[N:27]1[CH2:26][CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:23])([F:24])[F:10])[CH:13]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: COC(=O)Cc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Over about 5 min, a solution of n-butyllithium (1.6 M in hexane, 18.75 ml, 30 mmol) was added dropwise to a solution, pre-cooled to −20° C., of 4.91 ml (35 mmol) of diisopropylamine in 50 ml of THF. The LDA solution obtained in this manner was cooled to −78° C., and 15.1 ml of DMPU (1,3-dimethyltetrahydro-2(1H)-pyrimidinone, 125 mmol) were added. After 20 min at −78° C., a solution of 5.45 g (25 mmol) of methyl [3-(trifluoromethyl)phenyl]acetate in 35 ml of THF was slowly added dropwise. After a further 20 min at −78° C., a solution of 7.20 g (30 mmol) of N-bromomethylphthalimide in 50 ml of THF was added dropwise. Stirring of the reaction mixture was continued initially at −78° C. for 1 h, then without cooling bath at RT overnight. After addition of 100 ml of 1 N hydrochloric acid, the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue was dissolved in 50 ml of DMSO and purified in several portions by preparative HPLC [Method 8]. This gave 2.20 g (22% of theory) of the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:10][C:11]1[C:16]([N+:1]([O-:4])=[O:2])=[C:15]([OH:17])[CH:14]=[CH:13][N:12]=1
Reactant: Cc1cc(O)ccn1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nccc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of fuming nitric acid (14.51 mL, 345 mmol), and sulfuric acid (14.45 ml, 271 mmol) was added 2-methylpyridin-4-ol (6.5 g, 59.6 mmol) portion wise at 25° C. and then stirred in oil bat set at 130° C. for 2 hours. The reaction was cooled to room temperature, poured over ice and the pH was adjusted to ˜7 using sodium carbonate. The mixture was cooled and a yellow precipitate formed which was then filtered and dried under vacuum for 2 hours in a rotovap set at 60° C. The solids were then slurried in methanol (100 mL) and sonicated 2×. The suspension was filtered and the solids discarded and the filtrate was concentrated under vacuum to give 2-methyl-3-nitropyridin-4-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (3H, br. s.) 6.18-6.42 (1H, m) 7.71 (1H, d, J=7.58 Hz) 12.09 (1H, br. s.); MS [M+H] found 155.0.
Reaction SMILES: [NH:1]1[CH2:3][CH:2]1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[Cl:15][C:16]1[S:20][C:19]([C:21](Cl)=[O:22])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[S:20][C:19]([C:21]([N:1]2[CH2:3][CH:2]2[C:4]([O:6][CH3:7])=[O:5])=[O:22])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)s1
Reactant: COC(=O)C1CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN1C(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4.40 g (43.5 mmol) methyl aziridine-2-carboxylate and 13.5 ml (97.3 mmol) triethylamine in 30 ml methylene chloride is combined with 8.80 g (48.6 mmol) 5-chlorothiophenecarboxylic acid chloride in 30 ml methylene chloride while cooling with ice and subsequently after removal of the cooling bath stirred for 3 h at room temperature. Then the mixture is diluted with water, extracted with methylene chloride, dried with sodium sulphate, concentrated and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/15->80/20) to obtain the slightly contaminated title compound.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[NH:43]1[CH2:46][CH:45]([C:47]#[N:48])[CH2:44]1>>[CH3:42][C@@H:37]1[CH2:36][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:33][C:24]3[C:25]([C:28]([N:43]4[CH2:46][CH:45]([C:47]#[N:48])[CH2:44]4)=[O:29])=[N:26][O:27][C:23]=3[C:22]=2[F:34])[CH2:40][C@H:39]([CH3:41])[O:38]1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reactant: N#CC1CNC1
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)N4CC(C#N)C4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and azetidine-3-carbonitrile
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[O:49][C:48]([NH2:51])=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[C:50]3[O:49][C:48]([NH:51][C:8](=[O:10])[CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)Cc3ccccc3)nc12

Procedure:
From phenylacetic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 377 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:30])[C@@:14]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:29][C:26]([CH3:27])([CH3:28])[CH2:25][CH2:24][C@:14]1([CH3:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([OH:22])=[C:12]([C:7]2[NH:6][C:5]3[CH:31]=[CH:32][C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:3][C:4]=3[S:9](=[O:11])(=[O:10])[N:8]=2)[C:13]1=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 87.2 %

Procedure:
To a solution of the product of Example 49-6 (235.0 g, 0.518 mol) and pyridine (123.0 g, 1.55 mol) in dichloromethane (1645 mL) at 18-200C was added methane sulfonyl chloride (89.0 g, 0.777 mol) over 45 minutes. The solution was mixed at RT for 3.5 h then quenched with 1 M HCl (1500 mL). The layers were separated and the organic layer was concentrated under vacuum. The product was crystallized from ethyl acetate/heptane (1/1, 8 volumes) to give the title compound (240.01 g, 87%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH2:12])[CH:6]=1)C.[NH2:14][NH2:15]>CCO>[NH2:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[CH3:11])[C:4]([NH:14][NH2:15])=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1ccc(C)c(N)c1
Solvent: CCO
Product: Cc1ccc(C(=O)NN)cc1N
Temperature: 25 °C

Procedure:
To a solution of 3-amino-4-methyl-benzoic acid ethyl ester (10 g) in EtOH (25 mL) was added anhydrous hydrazine (20 mL) dropwise over 45 min at rt. The reaction was stirred at rt. overnight, then concentrated to afford 3-amino-4-methyl-benzoic acid hydrazide (10 g) as a yellow solid. The hydrazide (500 mg) was dissolved in THF (5 mL) and TMS-isocycanate (0.41 mL) was added. After 2-3 h, HPLC analysis indicated 50-60% conversion of the hydrazide. No further conversion was found after 3 days at rt. Evaporation of the THF was followed by addition of 1 N NaOH (2 mL) and the solution was heated to 100° C. overnight. LCMS analysis indicated the desired oxo-triazole to be present along with the carboxylic acid corresponding to hydrolysis of the hydrazide. The solution was neutralized with 1N HCl and the crude product collected by filtration. The crude 5-(3-amino-4-methyl-phenyl)-2,4-dihydro-[1,2,4]triazol-3-one (100 mg) was dissolved in DMF (1 mL) along with 4-chloro-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (119 mg), and the solution was heated to 55° C. overnight. The product was purified by reverse phase preparative HPLC to afford Example 51 as a white solid (151 mg, TFA, hydrate), HPLC ret. t. (min): 2.33, MW: 379.4, LCMS[M+H2O+H]+=398.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]2[CH2:8][CH2:9][S:10][C:6]=2[CH:5]=1)[CH:2]=[CH2:3].CCCCCC.CCOC(C)=O>C(O)C.[Pd]>[CH2:1]([C:4]1[CH:12]=[CH:11][C:7]2[CH2:8][CH2:9][S:10][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: C=CCc1ccc2c(c1)SCC2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1ccc2c(c1)SCC2
Yield: 85.8 %

Procedure:
A solution of 6-allyl-2,3-dihydrobenzothiophene (95 mg, 0.49 mmole) in 10 mL absolute ethanol was hydrogenated at 40 psi over 20 mg 10% Pd/C at room temperature overnight. TLC (90/10, hexane/EtOAc) indicated the reaction to be complete. The catalyst was filtered off through a celite pad and the filtrate concentrated down to afford 96 mg crude product as an oil. Purification by flash chromatography (90/10, hexane/EtOAc) afforded 75 mg white solids mp 58°-60° C. (78%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[S:19]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH2:28][OH:29])(=[O:21])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[S:19]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH:28]=[O:29])(=[O:21])=[O:20]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Oxalyl chloride (3.3 mmol, 2 eq.) was dissolved in methylene chloride and DMSO (4 eq) was added under argon at −78° C. and the reaction mixture was then stirred at this temperature for 15 min. (1-(2-Chloro-6-methylphenylsulfonyl)-piperidin-2-yl)methanol (1.65 mmol) was dissolved in methylene chloride (15 ml) and the solution was added dropwise to the reaction solution at −78° C. The resulting mixture was stirred for 1 h. Triethylamine (8.25 mmol, 5 eq) was then added and the reaction solution was warmed to room temperature and stirred for 1 h. It was then diluted with methylene chloride (10 ml) and washed with saturated ammonium chloride solution (10 ml), water (2×20 ml) and saturated sodium chloride solution (10 ml). The organic phase was dried over sodium sulfate and the filtrate was concentrated to dryness under reduced pressure. The crude product was employed in the next stage without further purification. Yield: 80%