Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[N:22]=1.[C:28]1([C@@H:34]([NH:36][C:37](=[O:40])[CH:38]=[CH2:39])[CH3:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:27][C:23]1[N:22]=[C:21](/[CH:39]=[CH:38]/[C:37]([NH:36][C@H:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:35])=[O:40])[CH:26]=[CH:25][CH:24]=1
Reactant: Brc1cccc(Br)n1
Reactant: C=CC(=O)N[C@@H](C)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)/C=C/c1cccc(Br)n1)c1ccccc1
Reaction time: 0.08 h

Procedure:
To the solution of triphenylphosphine (0.496 mmol) in DMF (10 mL), a palladium acetate (0.245 mmol) was added at room temperature under argon atmosphere. The mixture was stirred for 5 min then 2,6-dibromopyridine (12.7 mmol) followed by N-((S)-1-phenylethyl)acrylamide (14.0 mmol) and triethylamine (35.9 mmol) were added and the reaction mixture was stirred at 140° C. for 7 hr. The majority of the solvent was removed under diminished pressure. Diluted HCl was added and the product was extracted with ethyl acetate. Organic layers were combined, washed with brine, dried over sodium sulfate. Drying agent and solvent was removed and product was purified by column chromatography using hexanes and hexanes:ethyl acetate 2:1 as eluents, to give pure product with a good yield.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:17][C@H:16]2[C@H:12]([CH2:13][C:14](=[O:18])[O:15]2)[C@H:11]1[CH2:19][OH:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27].S(=O)(=O)(O)O>CN(C)C=O.CCOCC.[Cl-].[Na+].O>[C:1]([O:9][C@@H:10]1[CH2:17][C@H:16]2[C@H:12]([CH2:13][C:14](=[O:18])[O:15]2)[C@H:11]1[CH2:19][O:20][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C[C@@H]2[C@@H](CO)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A solution of 16.58 g of (1S,5R,6S,7R)-7-benzoyloxy-6-hydroxymethyl-2-oxabicyclo[3.3.0]octan-3-one in 18 ml of dimethylformamide is combined at 0° C. with 10.21 g of imidazole and 10.85 g of tert.-butyldimethylsilyl chloride. The mixture is stirred for 24 hours at 20° C., diluted with 1.5 l of ether, shaken in succession with 5% sulfuric acid and brine, dried over magnesium sulfate, and evaporated under vacuum. The residue is recrystallized from hexane.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C([O-])=O.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](O)=O.[OH-].[Na+]>O>[N:11]1([CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]=3)=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: c1ccc(OCCCN2CCCCC2)cc1
Reactant: NCCCCC(=O)O
Agent: O=C([O-])C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cc(C2=NCCCC2)ccc1OCCCN1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 1-(3-phenoxypropyl)piperidine, oxalate (0.2 g), 5-aminopentanoic acid (0.076 g) and polyphosphoric acid (2 g) is stirred at a temperature close to 100° C. for one hour. The mixture is cooled to room temperature, diluted with water (25 mL), made alkaline through addition of concentrated aqueous sodium hydroxide solution with external cooling and extracted twice with ethyl acetate (25 mL). The organic layers are pooled, washed with a saturated aqueous solution of sodium chloride (25 mL), dried over magnesium sulphate and purified by chromatography over silica gel. Fractions containing the expected product are pooled, concentrated under reduced pressure to give 0.172 g of 6-[4-(3-piperidinopropoxy)phenyl]-2,3,4,5-tetrahydropyridine which is dissolved in ethanol (2 mL). A solution of oxalic acid (0.104 g) in ethanol (0.5 mL) is added. The precipitate that appears on standing is filtered, rinsed with ethanol and dried to afford 200 mg of 6-[4-(3-piperidinopropoxy)phenyl]-2,3,4,5-tetrahydropyridine, oxalate as a white powder melting at 104° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:22])[CH2:11][C:12]2[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:13]=2[O:20][CH3:21])=[CH:5][CH:4]=1.P([CH:29]([CH2:35][CH3:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])(O)(O)=O>>[CH2:35]([C:29](=[CH:18][C:16]1[CH:15]=[CH:14][C:13]([O:20][CH3:21])=[C:12]([CH2:11][C:10](=[O:22])[NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:23])[F:24])=[CH:4][CH:5]=2)[CH:17]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:36]
Reactant: COc1ccc(C=O)cc1CC(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CC)P(=O)(O)O
Product: CCOC(=O)C(=Cc1ccc(OC)c(CC(=O)Nc2ccc(C(F)(F)F)cc2)c1)CC
Yield: 88.5 %

Procedure:
0.7 g of N-[4-(trifluoromethyl)phenyl]-2-(5-formyl-2-methoxyphenyl)acetamide and 1.6 g of ethyl 2-phosphonobutanoate were treated in the same manner as in Production Example 1a), to give 0.8 g of ethyl 2-ethyl-3-(4-methoxy-3-{2-oxo-2-[4-(trifluoromethyl)anilino]ethyl}phenyl)-2-propenoate as a colorless oil.
Reaction SMILES: CCCCCC.[CH3:7][P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10].[CH3:14][C:15]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])[C:16](OC)=[O:17].C(O)(=O)C>C1COCC1.O>[CH3:20][C:15]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:14])[C:16](=[O:17])[CH2:7][P:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C(C)(C)Oc1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COP(=O)(CC(=O)C(C)(C)Oc1ccccc1)OC
Reaction time: 0.5 h
Yield: 100 %

Procedure:
N-butyl lithium in hexane (1.62N, 38.1 ml, 0.0617 mol) was added dropwise under argon atmosphere to a solution of dimethyl methylphosphonate (7.0 ml, 0.0643 mol) in anhydrous THF (100 ml) at -78° C. The reaction mixture was stirred for 30 min. To the mixture was added dropwise methyl 2-methyl-2-phenoxypropionate (5.00 g, 0.0257 mol), and the mixture was stirred for 20 min. at -78° C. and further stirred for 30 min. at room temperature. To the resulting mixture were added 10 ml of water and acetic acid (3.2 ml, 0.0559 mol), and then the mixture was concentrated. The residue was extracted with ethyl acetate (50 ml×4). The combined ethyl acetate layers were washed with 50 ml of water and with 50 ml of brine, dried over anhydrous sodium sulfate, and concentrated. The residue thus obtained was purified by column chromatography (silica gel, ethyl acetate/cyclohexane: 3/1) to give a purified dimethyl 3-methyl-2-oxo-3-phenoxybutylphosphonate (6.5867 g, 0.0257 mol, 100%). The product was assigned the structure by the following data.
Reaction SMILES: C(OC[N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:32][C:33]#[N:34])[CH2:26][N:25]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=O)C(C)(C)C.O.[OH-].[Li+].Cl>C(#N)C.C(O)(C)C>[N:14]1[C:13]2[NH:9][CH:10]=[CH:11][C:12]=2[C:17]([C:18]2[CH:19]=[N:20][N:21]([C:23]3([CH2:32][C:33]#[N:34])[CH2:24][N:25]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])[CH2:26]3)[CH:22]=2)=[N:16][CH:15]=1
Reactant: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COC(=O)C(C)(C)C)cn2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CC(C)O
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 47.5 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Alternatively, a suspension of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 10.0 g, 20.6 mmol) and lithium hydroxide monohydrate (2.59 g, 61.8 mmol) in acetonitrile (CH3CN 40 mL) and isopropyl alcohol (10 mL) was heated at 45-50° C. for 6 hours. When HPLC showed that the reaction was deemed complete, the reaction mixture was cooled to room temperature and 1M hydrochloric acid aqueous solution (41 mL) as added to adjust the pH to 6-7 at temperature below 25° C. After the acid addition, the mixture was stirred at room temperature for 1 h and the precipitates were isolated by filtration. The wet cake was washed with water (50 mL) and dried in vacuum oven at 50° C. to give crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (14, 6.0 g, 7.65 g theoretical, 78% yield) as off-white solids, which was found to be identical to the material prepared by Method A.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:13]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:15])[CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1cc(C(=O)N2CCOCC2)cc(Cl)c1F

Procedure:
was prepared according to Scheme C3 (step A) from 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (125 mg, 0.41 mmol), HATU (235 mg, 0.62 mmol), morpholine (43 mg, 0.49 mmol) and DIPEA (0.22 mL, 1.2 mmol) in DMF (2 mL). MS (LC-MS): 317.0 [M−55]+; tR (HPLC conditions c): 4.65 min.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6]([CH3:12])=[N:5]1)[CH3:3].[CH3:13][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:3][CH:2]([N:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:13])=[O:10])[C:6]([CH3:12])=[N:5]1)[CH3:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1nn(C(C)C)cc1C(=O)O
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cn(C(C)C)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 1-(1-methylethyl)-3-methyl-1H-pyrazole-4-carboxylic acid (2.00 g, 11.9 mmol) in benzene (15.9 mL) and methanol (7.93 mL) at room temperature was added 2M trimethylsilyldiazomethane (23.8 mL). The resulting solution was stirred at room temperature for 3 hours. Solvent was removed at reduced pressure on a rotary evaporator to yield the title compound (2.17 g, 111.89 mmol, 100% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].[OH-].[Li+]>CS(C)=O.O>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[C:3]([CH:6]=1)[C:4]#[N:5])([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)c1ccc(N)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1ccc(Nc2ccccc2[N+](=O)[O-])c(C#N)c1
Temperature: 25 °C

Procedure:
Combine 2-amino-5-isopropyl-benzonitrile (3.19 g, 20 mmol), 1-fluoro-2-nitro benzene (2.1 mL, 20 mmol) and lithium hydroxide (1.68 g, 40 mmol) in DMSO (40.0 mL) and heat at 55° C. for 19 hours. Cool to ambient temperature and dilute with water (200 mL). The title compound precipitates as 4.56 g of an orange solid: mp 91-96° C.; mass spectrum (ion spray): m/z=280 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13](I)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[Br-].[CH:23]1([Zn+])[CH2:25][CH2:24]1.[Cl-].[NH4+]>CC(N(C)C)=O.O.[Zn]>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:23]4[CH2:25][CH2:24]4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: NC(=O)c1nc2n(c1I)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: [Zn+]C1CC1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1nc2n(c1C1CC1)C1CC(C1)c1cc(F)c(Br)cc1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 10-bromo-9-fluoro-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide (2.0 g, 4.3 mmol) in 15 mL dry DMA with PdCl2-[P(o-Tol)3]2 (210 mg, 0.26 mmol) was sparged with nitrogen gas then treated with a solution of cyclopropylzinc bromide (19 mL, 9.5 mmol, 0.5 M in THF) over 10 min. The mixture was heated at 50° C. for 40 min at which time 10 mL of additional zinc reagent (5 mmols, 1.16 eq) was added at 50° C. with sparging nitrogen. After 15 min, an additional 6 mL of zinc reagent was added. The mixture was cooled to room temp and treated with ˜5 mL of ammonium chloride. The mixture was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. The mixture was dissolved in DMF and purified by RPHPLC. The resultant solid was used in subsequent operations without further purification.
Reaction SMILES: C(C1CCC2C(=C(C(=O)C)C=CC=2[C:14]#[N:15])C1=O)(=O)C.[C:20]([NH:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27]([NH:34]C(=O)C)[CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:38])(=[O:22])[CH3:21]>>[C:20]([NH:23][CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[C:27]([NH2:34])[CH:28]=[CH:29][C:30]=2[C:14]#[N:15])[C:25]1=[O:38])(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Reactant: CC(=O)c1ccc(C#N)c2c1C(=O)C(C(C)=O)CC2
Product: CC(=O)NC1CCc2c(C#N)ccc(N)c2C1=O

Procedure:
The reaction was carried out in the same manner as in Example 1-(4), except that 250 mg of the compound prepared in (1) above was used instead of 2,8-diacetylamino-1-tetralone of Example 1-(4), and post-treated to produce 182 mg of the title compound. IRνmaxKBr cm-1 : 3428, 3336, 2216, 1652, 1614, 1542; NMR(CDCl3)δ: 1.6-2.0(1H, m), 2.09(3H, s), 2.56-3.39(3H, m), 4.51-4.71(1H, m), 6.59(1H, d, J=9.0 Hz), 7.40(1H, d, J=9.0 Hz); MASS m/z: 243(M+)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([SH:18])[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.[CH2:19](N(CC)CC)C.IC.O>CS(C)=O>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[S:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([S:18][CH3:19])[C:5]=3[N:10]=2)=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: Nc1nc(S)c2nc(-c3ccc(F)cc3)sc2n1
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: CSc1nc(N)nc2sc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
To a solution of 5-amino-2-(4-fluorophenyl)thiazolo[5,4-d]pyrimidine-7-thiol (1.2 g, 4.31 mmol) and triethylamine (1.50 ml, 10.8 mmol) in DMSO (25 ml) was added iodomethane (0.54 ml, 8.62 mmol). The reaction mixture was stirred for 12 h under N2 at 25° C. The mixture was poured into water and extracted with EtOAc. The organic extracts were dried over Na2SO4 and the solvents were removed under reduced pressure. The crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 80:1), yielding the title compound as a light yellow solid (0.76 g, 60%).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])C.[Li]N.[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:13]C#C)[CH3:11].C(I)C>CCCCCC>[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:13][C:5]#[C:3][CH2:2][CH3:1])[CH3:11]
Reactant: C#CCOC(C)(C)OC
Reactant: C=CC(=C)C
Agent: [Li]N
Solvent: CCCCCC
Solvent: CCI
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 120.6 %

Procedure:
0.89 g (127 mmol) of granulated lithium were added within 15 minutes to 100 ml (4 mol) of liquid ammonia at −37° C. The mixture was stirred until no more lithium floated (after approximately 15 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 5.94 g (86.3 mmol) of isoprene were added portion wise within 30 minutes. The end of the formation of LiNH2 could be recognized by the de-coloration of the reaction mixture and 10.69 g (70.1 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne were added to the reaction mixture at −37° C. within 30 minutes. The reaction mixture was held at −37° C. for about 1 hour. Ethyl iodide (20.05 g, 126 mmol) was added with a dropping funnel to the reaction mixture within 30 minutes. The reaction mixture was subsequently stirred for 1 hour. n-Hexane (100 ml) was added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1.5 hours. Water (50 ml) was added to the reaction mixture at 22° C., and the mixture was vigorously stirred until all salt was dissolved. The water layer was extracted twice with 50 ml n-hexane. The organic layer was dried over 5 g of anhydrous sodium sulfate. The solution was concentrated under reduced pressure (40° C., 60 mbar) and the crude product was analyzed by GC. Crude 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne (13.21 g) were obtained with a purity of 72.95% (88.0% yield based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: Cl([O-])=O.[Na+].S(=O)(=O)(O)N.[F:10][C:11]1[CH:18]=[C:17]([N:19]([CH:23]2[C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][C:26]=3[CH2:25][CH2:24]2)[N:33]=[C:32]([CH3:36])[N:31]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C:30]4=[O:45])[CH2:20][C:21]#[CH:22])[CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].C([O-])(=[O:48])C.[Na+]>C(O)(=O)C.C(O)(C)(C)C>[F:10][C:11]1[CH:18]=[C:17]([N:19]([CH:23]2[C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][C:26]=3[CH2:25][CH2:24]2)[N:33]=[C:32]([CH3:36])[N:31]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:43])[CH3:42])[C:30]4=[O:45])[CH2:20][C:21]#[CH:22])[CH:16]=[CH:15][C:12]=1[C:13]([OH:48])=[O:14]
Reactant: C#CCN(c1ccc(C=O)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Reactant: CC(=O)[O-]
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: C#CCN(c1ccc(C(=O)O)c(F)c1)C1CCc2cc3nc(C)n(COC(=O)C(C)(C)C)c(=O)c3cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium chlorite (0.28 g) and sulphamic acid (0.24 g) were added portionwise to a stirred mixture of o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzaldehyde (0.47 g), 0.2M sodium acetate in acetic acid buffer (pH 4, 70 ml) and tert-butanol (70 ml). The mixture was stirred at ambient temperature for 24 hours. The mixture was partitioned between methylene chloride and a saturated aqueous sodium dihydrogen phosphate solution. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography to give o-fluoro-p-[N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid (0.41 g);
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[C:18]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)(=[O:29])=[O:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([NH:26][S:27]([C:30]1[CH:31]=[CH:32][C:33]([NH:36][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:34][CH:35]=1)(=[O:29])=[O:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Nc1ccc(S(=O)(=O)NC(=O)c2ccccc2)cc1
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)NC(=O)c2ccccc2)cc1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and N-benzoyl-4-aminobenzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 12.5 (br s, 1H), 11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 8.0 (d, 2H), 7.9 (t, 3H), 7.65 (t, 3H), 7.5 (t, 2H), 7.2 (d, 1H); ESI-MS m/z 475 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](O)[CH2:13][C@H:12]1[C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Na+].C(N(/C(/F)=C(\F)/C(F)(F)[F:31])CC)C.C(N(C(F)(F)C(F)C(F)(F)F)CC)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:31])[CH2:13][C@H:12]1[C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)/C(F)=C(\F)C(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CCN(CC)C(F)(F)C(F)C(F)(F)F
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
Methyl(2S,4R)-1-benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylate (306 mg, 0.00108 mol) and sodium fluoride (55 mg, 0.00131 mol) were suspended in dichloromethane (1.8 mL), followed by addition of Ishikawa reagent (293 mg, 0.00131 mol) under ice cooling. The reaction mixture was slowly warmed to room temperature and then stirred for 20 hours. After the reaction, the reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate (5 mL) and then separated into organic and aqueous layers. The aqueous layer was extracted with ethyl acetate. This extracted solution was combined with the organic layer obtained above, washed sequentially with 10% aqueous potassium bisulfate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. After drying, the solvent and the decomposition product of Ishikawa reagent (N,N-diethyl-2,3,3,3-tetrafluoropropionamide) were distilled off under reduced pressure, and the residue was applied to silica gel column chromatography (developing solvent; hexane:ethyl acetate=5:1 to 0:1) to give the titled compound (227 mg, colorless oil).
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:47]1([NH2:54])[CH:52]=[CH:51][CH:50]=[C:49]([NH2:53])[CH:48]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH2:53][C:49]1[CH:48]=[C:47]([NH:54][C:11](=[O:13])[C@@H:9]([N:8]([CH3:14])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH3:10])[CH:52]=[CH:51][CH:50]=1
Reactant: Nc1cccc(N)c1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)Nc1cccc(N)c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To N-Boc-N-methyl-L-alanine (1.02 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.92 g) and 1-hydroxybenzotriazole monohydrate (1.35 g), N,N-dimethylformamide (15 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a solution of N,N-diisopropylethylamine (2.6 mL) and 1,3-phenylenediamine (1.35 g) in N,N-dimethylformamide (4 mL) was added at room temperature, and the mixture was stirred at 40° C. for 3 hours. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 60 to 25% hexane in ethyl acetate) to obtain amorphous (S)-tert-butyl (1-((3-aminophenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (B9, 967 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[N:6][C:7]=1[N+:8]([O-])=O.O.Cl[Sn]Cl>CCO.C(Cl)Cl>[Br:1][C:2]1[C:7]([NH2:8])=[N:6][CH:5]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ncc(N2CCOCC2)cc1Br
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Nc1ncc(N2CCOCC2)cc1Br
Temperature: 80 °C
Yield: 83.9 %

Procedure:
4-(5-Bromo-6-nitropyridin-3-yl)morpholine (95 mg, 0.33 mmol) was dissolved in EtOH (12 mL) and water (3.0 mL) was added, followed by SnCl2 (313 mg, 1.65 mmol). The reaction mixture was heated to 80° C. for 2 h, cooled to room temperature and diluted with DCM. The two phases were separated, the organic phase was washed with water. The water phase was back extracted with DCM. The pH was adjusted to 12 with 6N NaOH and the mixture was further extracted with DCM. The organic extracts were combined, dried (Na2SO4) and evaporated under reduced pressure obtaining the desired 3-bromo-5-morpholinopyridin-2-amine (71.5 mg, 84%). LCMS (m/z): 260.0 (MH+), 0.37 min.