Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:37]2[C:38]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3Br)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 572.0 (M+H)+.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]1=[O:14])(=O)C.C(N(CC)CC)C.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCOC(C)=O>CN(C=O)C>[C:11]([N:7]1[CH2:6][C:5](=[O:14])[NH:4][C:9](=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]1=[O:10])(=[O:13])[CH3:12]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(=O)NC(=Cc2ccccc2)C1=O
Temperature: 25 °C
Yield: 38.3 %

Procedure:
1,4-Diacetyl-2,5-piperazinedione (25.0 g, 126 mmol), which is compound (8) mentioned in Reference Example 1, was heated at 120°-130° C. in DMF (200 ml) with triethylamine (17.6 ml, 126 mmol) and benzaldehyde (13.0 ml, 126 mmol). After 4 h the mixture was cooled to room temperature and poured into EtOAc (1000 ml), and washed three times with brine. Any solid formed at this stage was filtered off. The filtrate was dried (MgSO4) and the solvent removed in vacuo. The residue was recrystallised from EtOAc:Hexane to give 11.78 g (38%) of the title compound as a yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]2[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[N:10][N:9]2[C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[N:25][CH:26]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>>[OH:3][CH2:4][CH2:5][C:6]1[N:7]=[C:8]2[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[N:10][N:9]2[C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[N:25][CH:26]=1
Reactant: CCOC(=O)Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CCO)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Compound 28e (260 mg, 0.471 mmol) was placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry THF (4 mL) was added and then the solution was cooled to 0° C. in an ice bath. 1 M LiAlH4 in THF (0.471 mL, 0.471 mmol) was added and then the ice bath was removed and the reaction was allowed to warm to rt. The reaction was stirred at rt for 20 min and then poured into saturated NH4Cl solution (20 mL). DCM (20 mL) was added and then the mixture was filtered. The filter cake was washed with DCM (2×10 mL) and then the organic phase was separated. The aqueous layer was extracted with DCM (3×10 mL) and then the organic extracts were combined, dried over Na2SO4, and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-100% ACN/DCM to afford compound 28f. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.38 (d, J=2.2 Hz, 1H), 8.00 (d, J=5.4 Hz, 1H), 7.81 (dd, J=8.8, 2.4 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 6.10 (d, J=5.6 Hz, 1H), 3.97-4.07 (m, 3H), 3.92 (s, 8H), 3.52-3.65 (m, 8H), 3.05 (t, J=4.6 Hz, 2H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H35N7O4: 510.3 (M+H). Found: 510.2.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[CH2:7][NH:8][CH3:9])([CH3:3])[CH3:2].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:32].[N:33]1([CH2:39][CH2:40][N:41]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53]([OH:55])=O)[CH:49]=[N:50][C:44]=3[NH:43][C:42]2=[O:56])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[ClH:32].[CH:1]([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[CH2:7][N:8]([CH3:9])[C:53](=[O:55])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[N:41]([CH2:40][CH2:39][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[CH2:46][C:45]=2[CH:47]=1)([CH3:3])[CH3:2]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Reactant: CNCc1cccc(OC)c1OC(C)C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: COc1cccc(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)C(=O)N3)c1OC(C)C
Yield: 47 %

Procedure:
According to the procedure of Example 1, except substituting 2-isopropoxy-3-methoxy-benzyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.15 g, 47%) was prepared as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.41-10.21 (m, 1H), 10.13 (br s, 1H), 8.41-8.31 (m, 1H), 8.01-7.93 (m, 1H), 7.51-7.43 (m, 1H), 7.31-7.11 (m, 1H), 7.01-6.91 (m, 2H), 6.70-6.59 (m, 1H), 4.76-4.52 (m, 5H), 4.11-3.85 (m, 7H), 3.84-3.60 (m, 3H), 3.59-3.51 (m, 2H), 3.40-3.31 (m, 2H), 3.07-2.86 (m, 4H), 1.23 (m, 6H); MS (ESI) m/e 524 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=4)[C:12](=[O:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=4)[C:12](=[O:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: CC(C)c1ccc(NN2C(=O)c3[nH]c4cc(Cl)ccc4c(=O)c3C2=O)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: CC(C)c1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Yield: 35.5 %

Procedure:
A stirred suspension of 6-chloro-2-(4-isopropylanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.13 g, 2.98 mM) in a solution of methanol (90 mL) and methanesulfonic acid (23 mL) was refluxed for 7 hours and cooled to room temperature. The mixture was filtered (the filtrate was saved for use in Example 21), and the collected yellow solids were washed with methanol and ether to give the title compound (0.401 g, 35%) as a yellow powder, mp 93-394° C.; MS(CI): 382 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[CH:26]=[C:27]([CH3:29])[CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:16])[C:12]=2[F:15])[CH2:7]1)=[O:5])C.[OH-].[K+]>CCO.O>[F:15][C:12]1[C:11]([F:16])=[CH:10][CH:9]=[C:8]2[C:13]=1[CH2:14][C:6]([NH:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[CH:26]=[C:27]([CH3:28])[CH3:29])([C:4]([OH:5])=[O:3])[CH2:7]2
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2ccc(F)c(F)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccc(F)c(F)c2C1
Temperature: 25 °C

Procedure:
4,5-Difluoro-2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (387) (650 mg, 1.57 mmol) is dissolved in EtOH (50 mL) and set to stir at RT. To this solution is added 5M KOH (4 mL). The reaction mixture is stirred at RT overnight. After concentration in vacuo, the residue obtained is dissolved in water (20 mL) and washed with EtOAc (20 mL). The phases are separated and the aqueous phase is acidified with concentrated HCl to pH 2. The solid precipitate is collected via filtration, dried under vacuum, and then purified on an HPLC. The desired product (388) is obtained as white solid (440.0 mg, 73%).
Reaction SMILES: [CH3:1][N:2]1[CH2:13][C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[C:3]1=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O1CCOCC1>O>[CH3:1][N:2]1[CH2:13][C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH2:3]1
Reactant: CN1Cc2c([nH]c3ccccc23)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CN1Cc2[nH]c3ccccc3c2C1
Reaction time: 5 h

Procedure:
2-Methyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one, 1.7 g., and LiAlH4, 2.3 g., are heated in refluxing dioxane, 300 ml., for five hours. The mixture is cooled and carefully hydrolyzed with excess water. Solids are filtered away and washed with dioxane, after which the filtrate is concentrated to dryness giving 1.4 g. of a crude brown product, m.p. 110°-120° C. Since the crude product is sensitive to air oxidation (darkens rapidly on standing), it is not further purified before methiodide preparation.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccc(Cl)cc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3ccc(Cl)cc3Cl)c2O1

Procedure:
The title compound was prepared (0.059 g, 57%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.135 g, 0.28 mmol) and methylamine (0.086 g, 2.8 mmol). mp 202-204° C.
Reaction SMILES: [C:1]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=O)[CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[NH2:20][CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.C(N(CC)CC)C>N1C=CC=CC=1>[CH2:4]([O:3][C:1]([NH:11][C@H:12]1[CH2:13][C:14](=[O:16])[N:20]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=2)[C:17]1=[O:18])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(N[C@H]1CC(=O)N(Cc2ccc(C(=O)O)cc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 9 h
Yield: 56.2 %

Procedure:
A mixture of N-carbobenzyloxy-L-aspartic anhydride (236) (546 mg, 2.19 mmol) and 4-(aminomethyl)benzoic acid hydrochloride (237) (383 mg, 2.53 mmol) was suspended in pyridine (8 mL) and treated with triethylamine (1 mL). The white suspension was stirred at room temperature for 9 h then concentrated under reduced pressure. The residue was dissolved in acetic acid and stirred at 83° C. for 24 h, concentrated, diluted with DCM, washed with an aqueous solution of KHSO4 and H2O then concentrated. The residue was diluted once again with benzene, concentrated and the remaining yellow solid was triturated with MeOH/H2O (1:1) to give title compound 238 (471 mg, 56% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:16]=O)=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:7]=1.[O:18]=[C:19]1[CH2:23][CH2:22][S:21][CH2:20]1>>[Br:1][C:2]1[C:3]([CH:16]=[C:20]2[C:19](=[O:18])[CH2:23][CH2:22][S:21]2)=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH:7]=1
Reactant: COC(=O)C(C)c1cc(Br)c(C=O)cc1OC
Reactant: O=C1CCSC1
Product: COC(=O)C(C)c1cc(Br)c(C=C2SCCC2=O)cc1OC
Yield: 33.3 %

Procedure:
By using methyl 2-(5-bromo-4-formyl-2-methoxyphenyl)propionate (540 mg) obtained in Example 48 and 3-oxothiolane (370 mg), the title compound (230 mg, 35%) was obtained in the same manner as that of Example 1.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[CH3:7].[Cl:15][C:16]1[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].[Cl-].[NH4+]>CCCCCC.O1CCCC1.O>[CH2:6]([O:8][CH2:9][N:10]1[C:14]([CH:18]([OH:19])[C:17]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[C:23]([Cl:24])[C:16]=2[Cl:15])=[CH:13][CH:12]=[N:11]1)[CH3:7]
Reactant: COc1ccc(C=O)c(Cl)c1Cl
Reactant: CCOCn1cccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOCn1nccc1C(O)c1ccc(OC)c(Cl)c1Cl
Reaction time: 1 h
Yield: 81.5 %

Procedure:
4.13 ml of 1.6M n-butyl lithium in hexane are added dropwise to a tetrahydrfuran solution of 0.76 g of 1-ethoxymethylpyrazole at -60° C. under argon gas atmosphere. the mixture is stirred at -63° to -50° C. for 1 hour. A solution of 1.23 g of 2,3-dichloro-4-methoxybenzaldehyde in tetrahydrofuran is added to the mixture, and the mixture is stirred at -50° C. to room temperature for 1 hour. An aqueous saturated ammonium chloride solution and water are added to the mixture under ice-cooling and the mixture is concentrated to remove tetrahydrofuran. The residual aqueous layer is extracted with ethyl acetate and the extract is washed with water, dried and evaporated to give colorless crystals, which are then washed with isopropyl ether and dried to give 1.62 g of α-(1-ethoxymethyl-5-pyrazolyl)-2,3-dichloro-4-methoxy-benzylalcohol.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=2)[CH:8]=[C:7]([N:18]2[CH2:23][C@@H:22]3[CH2:24][C@H:19]2[CH2:20][O:21]3)[N:6]=1)(=O)=O.Cl.[NH:26]1[CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[N:26]1([C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][C:14]([NH2:17])=[N:15][CH:16]=3)[CH:8]=[C:7]([N:18]3[CH2:23][C@@H:22]4[CH2:24][C@H:19]3[CH2:20][O:21]4)[N:6]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)c1nc(-c2cnc(N)nc2)cc(N2C[C@@H]3C[C@H]2CO3)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nc1ncc(-c2cc(N3C[C@@H]4C[C@H]3CO4)nc(N3CCC3)n2)cn1
Temperature: 130 °C

Procedure:
5-[2-methylsulfonyl-6-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrimidin-4-yl]pyrimidin-2-amine (30.0 mg, 0.861 mmol), azetidine hydrochloride (24.7 mg, 0.258 mmol), potassium carbonate (71.4 mg, 0.517 mmol), and 1-methyl-2-pyrrolidinone (0.861 mL) were combined in a reaction flask and heated to 130° C. for 16 hrs. The reaction was filtered and purified by reverse phase column chromatography using a gradient of 20% to 60% acetonitrile in 0.1% ammonium hydroxide in water. The combined fractions containing product were concentrated under reduced pressure to provide 2-(azetidin-1-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-[4,5′-bipyrimidin]-2′-amine 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 6.97 (s, 2H), 4.95 (s, 1H), 4.66 (s, 1H), 3.99 (t, J=7.5 Hz, 4H), 3.77 (dd, J=7.3, 1.5 Hz, 1H), 3.64 (d, J=7.3 Hz, 1H), 3.43 (dd, J=10.5, 1.5 Hz, 1H), 3.40-3.32 (m, 1H), 3.17 (s, 1H), 2.24 (p, J=7.5 Hz, 2H), 1.85 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][C:9](=O)[CH2:10][CH:3]1[CH2:4][S:5][CH2:6]2.Cl.[NH2:13][OH:14]>C(O)C>[CH3:1][N:2]1[CH:7]2[CH2:8][C:9](=[N:13][OH:14])[CH2:10][CH:3]1[CH2:4][S:5][CH2:6]2
Reactant: NO
Reactant: CN1C2CSCC1CC(=O)C2
Agent: Cl
Solvent: CCO
Product: CN1C2CSCC1CC(=NO)C2
Temperature: 23 °C

Procedure:
A mixture of 9-Methyl-3-thia-9-aza-bicyclo[3.3.1]nonan-7-one (CAS no: 99709-31-6) (3.0 g, 17.5 mmol) in ethanol (100 mL) and hydroxylamine hydrochloride (1.58 g, 22.8 mmol) was refluxed for 16 h. Cooled to 23° C., the precipitate was filtered off, washed with ethanol and diethyl ether and dried in vacuum to give a light brown solid (2.5 g), which was partitioned between dichloromethane and sodium carbonate solution, the organic layers dried over Na2SO4, filtered and the solvents evaporated to give the title compound as a white solid. (1.3 g, 40%); MS: m/e=187.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[C:8]([F:18])[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].CO>O>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]#[C:12][C:10]1[CH:9]=[C:8]([F:18])[C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1c(F)cc(C#CC(C)(C)C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)C#Cc1cc(F)c(C(=O)O)c(F)c1
Yield: 82.9 %

Procedure:
Methyl 2,6-difluoro-4-(3,3-dimethylbut-1-ynyl)benzoate (1.0 g, 0.004 mol) and lithium hydroxide (0.57 g, 0.012 mol) were placed in a 3:1 mixture of methanol:water (60 mL) and heated at 60° C. for 3.5 h. The reaction was cooled and concentrated in vacuo to a volume of 20 mL. The mixture was placed in an ice-water bath and acidified to pH 5 with coc. HCl. A white solid crashed out which was filtered and washed thoroughly with water. The solid was dried in the vacuum oven to give the product (0.79 g, 84%) as a solid. m/z=237.1 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2.CO.[CH2:22](P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:22][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2
Reactant: CC(C)(C)OC(=O)Cc1ccc2ncc(O)cc2c1
Reactant: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CO
Solvent: c1ccccc1
Product: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (0.1 g, 0.4 mmol) in benzene (5 mL) was added methanol (0.05 ml, 1 mmol) and tributylphosphine (0.1 ml, 0.6 mmol). The resulting mixture was cooled to 0° C. followed by adding 1.1′-(azodicarbonyl)dipiperidine (0.1 g, 0.6 mmol). After 10 min, ice bath was removed; the reaction mixture was warmed up to rt. The reaction mixture was continued to stir for 20 h. TLC showed about 80% conversion. More MeOH (1 ml), tibutylphosphine (0.05 mL), and ADDP (50 mg) were added and allowed to stir for 3 h. Hexane was added to the reaction mixture and dihydro-ADDP separated out and was filtered off. The filtrate was concentrated. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2) to afford the desired product as colorless liquid. MS m/z: 274.3 (M+H). Calc'd. for C16H19NO3—273.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].I[CH2:19][CH2:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:19][CH2:20][CH3:21])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:15])=[O:16]
Reactant: CCCI
Reactant: CS(=O)(=O)c1cc(N2CCNCC2)ccc1Cl
Product: CCCN1CCN(c2ccc(Cl)c(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 1-(4-Chloro-3-methanesulfonyl-phenyl)-piperazine and 1-iodopropane, the titled compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV)) 316 (M+, 25), 289 (41), 287 (bp), 70 (59), 56 (23)
Reaction SMILES: [S:1]([N:10]1[CH2:14][CH2:13][O:12]C1=O)([N:4]1[CH2:8][CH2:7][O:6]C1=O)(=[O:3])=[O:2].C(=O)=O>[OH-].[Na+]>[OH:12][CH2:13][CH2:14][NH:10][S:1]([NH:4][CH2:8][CH2:7][OH:6])(=[O:3])=[O:2]
Reactant: O=C1OCCN1S(=O)(=O)N1CCOC1=O
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)(NCCO)NCCO
Yield: 87 %

Procedure:
17 g of sulfonylbisoxazolidinone are added to 2N sodium hydroxide solution (170 ml of water for 13.6 g of NaOH) and placed under stirring. After a strong evolution of CO2, the reaction medium is stirred for 3 days at room temperature. The reaction medium is then passed through Dowex® 50WX8-200 resin (sold by Aldrich). The resin is filtered through a sinter funnel and the filtrate is concentrated under vacuum. The residue is purified by flash chromatography on silica (eluent: 8/2 EtOAc/MeOH). The volatile materials are evaporated off under vacuum to give a colourless oil (87% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][C:15]([Cl:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([Cl:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)Cc2cc3ccc(Cl)nc3n21
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Cl)nc3N21
Yield: 65.7 %

Procedure:
To a solution of 0.65 g (2.0 mmol) (R)-6-chloro-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 10 ml acetic acid was added 0.64 g (10.1 mmol) sodium cyano borohydride. After 3 h the reaction mixture was poured into 10% aqueous sodium carbonate solution and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography over silica gel (0.032–0.063 mm) with n-hexane:ethyl acetate (4:1) as eluant to afford the desired compound as a colorless oil (65.7%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[F:9])[CH3:2].[OH:10]O>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:10])=[CH:5][C:4]=1[F:9])[CH3:2]
Reactant: CCc1ccncc1F
Reactant: OO
Solvent: CC(=O)O
Product: CCc1cc[n+]([O-])cc1F
Temperature: 25 °C
Yield: 100 %

Procedure:
To a mixture of 4-ethyl-3-fluoropyridine (R. P. Dikinson et al., Bioorg. Med. Chem. Lett., 1996, 6, 2031, 28.51 g, 205.9 mmol) and 30% hydrogen peroxide (30 ml) in acetic acid (300 ml) was heated at reflux temperature for 3 h. After cooling to room temperature, the resulting mixture was concentrated. The residue was diluted in dichloromethane (300 ml) and dried (MgSO4). Removal of solvent gave 32.30 g (100%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[C:3](=[O:16])[N:4]([CH3:15])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=1[F:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:3](=[O:16])[N:4]([CH3:15])[C:5]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:27][C:26]=1[F:34])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cn1c(Nc2ccccc2)ncc(Br)c1=O
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
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: [Cl-]
Solvent: C1COCCO1
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(OCc3ccccc3)c(F)c2)c1=O
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
A suspension of 5-bromo-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.145 g, 0.518 mmol), 4-(benzyloxy)-3-fluorophenylboronic acid (0.153 g, 0.621 mmol), Pd(PPh3)4 (0.030 g, 0.026 mmol) and lithium chloride (0.110 g, 2.59 mmol) in dioxane (1.5 mL) and 2M aqueous Na2CO3 (1.5 mL) was stirred at 100° C. for 20 minutes. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude black solid. The crude product was purified by flash column chromatography, eluting with 10:1 dichloromethane/EtOAc. The desired product (0.133 g, 64%) was obtained as an off-white waxy solid. 1H NMR (400 MHz, DMSO-d6) δ 8.90 (br s, 1H), 7.93 (s, 1H), 7.59 (dd, J=1.95, 13.7 Hz, 1H), 7.55-7.31 (m, 10H), 7.22 (t, J=9.0 Hz, 1H), 7.14 (t, J=7.4 Hz, 1H), 5.20 (s, 2H), 3.55 (s, 3H). LRMS (ESI pos) m/e 402 (M+1).