Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[CH:12].N>>[C:13]1([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:12]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ON=C(Cl)c1cnccn1
Reactant: C#Cc1ccccc1
Agent: N
Product: c1ccc(-c2cc(-c3cnccn3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 1-ethynyl-benzene (Aldrich, 52 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.41 (s, 1H), 7.47-7.70 (m, 3H), 7.86-8.08 (m, 2H), 8.70 (d, J=2.4 Hz, 1H), 8.76 (dd, J=2.8, 1.6 Hz, 1H), 9.29 (d, J=1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z 224 (M+H)+.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:28][O:29][CH3:30])[C:10]([NH:12][CH:13]2[C:26](=[O:27])[N:15]3[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:31]>CO.O1CCCC1.C(OC(C)C)(C)C>[ClH:31].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:28][O:29][CH3:30])[C:10]([NH:12][CH:13]2[C:26](=[O:27])[N:15]3[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][O:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 30 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a suspension of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (0.52 g) in a mixture of methanol (3ml) and tetrahydrofuran (2 ml) was added conc. hydrochloric acid (0.18 g), and the mixture was stirred at 30° C. for 4 hours. After the reaction mixture was cooled and diluted with diisopropyl ether, the precipitated crystals were collected by filtration, washed with diisopropyl ether and then dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (0.45 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:16][NH:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[NH2:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:16][N:15]([C:30]4[N:31]=[CH:32][C:27]([F:26])=[CH:28][N:29]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc([C@]23CNC[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Reactant: Fc1cnc(Cl)nc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1cccc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Yield: 79.3 %

Procedure:
A solution of N-[(4aR,7aS)-7a-(3-aminophenyl)-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (2.49 g, 7.06 mmol), 5-fluoro-2-chloropyrimidine (3.74 g, 28.26 mmol), and diisopropylethylamine (6.16 mL, 35.32 mmol) in 1,4-dioxane (60 mL) is heated to reflux for 4 hours under nitrogen. The reaction is cooled, diluted with water and extracted with ethyl acetate (3×). The combined organic extracts are dried over sodium sulfate, filtered and the solvent is removed in vacuo to give the crude product. The crude product is purified over silica gel with a 25 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (2.51 g, 79%). ES/MS (m/e): 449 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([Cl:10])=[CH:4][C:3]=1[CH:11](C(OCC)=O)[C:12]([O:14]CC)=[O:13].[OH-].[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(Cl)c(OC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(Cl)c(CC(=O)O)cc1Cl
Temperature: 60 °C
Reaction time: 17 h
Yield: 60.7 %

Procedure:
A solution of diethyl 2-(2,5-dichloro-4-methoxyphenyl)malonate (Intermediate 4-5; 1.88 g, 5.61 mmol) in THF (55 mL) and EtOH (5 mL) was treated with 2M sodium hydroxide (11.22 mL, 22.44 mmol) in one portion and the resulting solution was stirred at 60° C. for 17 hours. The reaction mixture was evaporated and the aqueous residue was acidified with 2M HCl. The precipitate was collected by filtration, washed with water (25 mL) and dried under vacuum to afford 2-(2,5-dichloro-4-methoxyphenyl)acetic acid (0.800 g, 60.7%) as a grey solid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[CH:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])=[CH:4][CH:3]=1.[CH:29]1([Mg]Br)[CH2:31][CH2:30]1.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[CH:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([C:24]([CH:29]2[CH2:31][CH2:30]2)([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl)C1CC1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl)(C1CC1)C1CC1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a stirred solution of [10-chloro-1-(2,4-dichlorophenyl)-4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-a]benzimidazol-7-yl](cyclopropyl)methanone (67.1 mg, 0.154 mmol) in tetrahydrofuran (1 mL) was added a solution of cyclopropyl magnesium bromide in tetrahydrofuran (1.0 M, 4.62 mL, 4.62 mmol) at 0° C. After 15 min, the reaction mixture was poured into a mixture of ethyl acetate and aqueous ammonium chloride. The organic phase was washed with brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography on NH silica gel eluting with a 0-25% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (48.2 mg, 0.101 mmol, 65%).
Reaction SMILES: C([O:4][CH2:5][C:6]([C:13]#[C:14][C:15]1[C:23]2[C:22]([Cl:24])=[N:21][C:20]([NH2:25])=[N:19][C:18]=2[N:17]([CH2:26][C:27]2[C:32]([CH3:33])=[C:31]([O:34][CH3:35])[C:30]([CH3:36])=[CH:29][N:28]=2)[CH:16]=1)([OH:12])[CH2:7][O:8]C(=O)C)(=O)C.CCN(CC)CC>C1COCC1.CO>[NH2:25][C:20]1[N:21]=[C:22]([Cl:24])[C:23]2[C:15]([C:14]#[C:13][C:6]([OH:12])([CH2:7][OH:8])[CH2:5][OH:4])=[CH:16][N:17]([CH2:26][C:27]3[C:32]([CH3:33])=[C:31]([O:34][CH3:35])[C:30]([CH3:36])=[CH:29][N:28]=3)[C:18]=2[N:19]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CC(O)(COC(C)=O)COC(C)=O)c3c(Cl)nc(N)nc32)c1C
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(C)cnc(Cn2cc(C#CC(O)(CO)CO)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of 2-((2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethynyl)-2-hydroxypropane-1,3-diyl diacetate (see example 56) (60 mg) and Et3N (1 mL) in THF (1 mL) and MeOH (6 mL) was heated in a microwave oven to 150° C. for 20 min. Concentration and preparative HPLC gave the title compound, as a solid. HPLC Rt=3.90 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:20]/[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCCCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/CCCCc1ccccc1
Reaction time: 2.5 h
Yield: 77.6 %

Procedure:
A stirred solution of 5-phenylpentanal (9.96 g, Reference Example 6) in anhydrous tetrahydrofuran (100 ml) at room temperature was treated with (tert-butoxycarbonylmethylene)triphenylphosphorane (27.5 g). The resulting orange solution was stirred for 2.5 hours then evaporated. The residual crude product was subjected to flash chromatography on silica eluting with a mixture of hexane and ethyl acetate (19:1, v/v) to afford the title compound (12.4 g) as a colourless oil. NMR (CDCl3): δ1.45 (s,9H), 1.65 (m,4H), 2.18 (q,2H), 2.61 (t,2H), 5.70 (d,1H), 6.82 (dt,1H), 7.10-7.30 (m,5H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[N:21]=[CH:20]2>>[OH:29][C:27]([CH3:30])([CH3:28])[CH2:26][N:22]1[C:23]2[C:19](=[CH:18][C:17]([CH2:16][NH:15][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:25][CH:24]=2)[CH:20]=[N:21]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(O)Cn1ncc2cc(CN)ccc21
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3CC(C)(C)O)c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and 1-(5-(aminomethyl)-1H-indazol-1-yl)-2-methylpropan-2-ol (step-2 of Example 22).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:25])[O:6][CH2:7][C:8]1([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]=[C:9]1[O:18][CH3:19])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:27].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OOC(C)(C)C)(C)(C)C.O>C1C=CC=CC=1>[CH:1]([NH:4][C:5](=[O:25])[O:6][CH2:7][C:8]1([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[CH:10]=[C:9]1[O:18][CH3:19])([CH3:3])[CH3:2]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: COC1=CCc2ccccc2C1(CCC(C)C)COC(=O)NC(C)C
Agent: CC(C)(C)OOC(C)(C)C
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COC1=CC(=O)c2ccccc2C1(CCC(C)C)COC(=O)NC(C)C
Yield: 83.5 %

Procedure:
To a solution of Example 180A (39 mg, 0.11 mmol) in benzene (1 mL) was added celite (39 mg), pyridinium dichromate (0.17 g, 0.45 mmol), and a solution of 70% t-butyl peroxide in water (58 μL, 0.45 mmol). The heterogenous solution was filtered through celite. The filtrate was diluted with ethyl acetate (3 mL), washed with 5% Na2S2O5 (3 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (10%-20% ethyl acetate/hexane) afforded product as a white solid (33 mg, 83%). 1H NMR (300 MHz, CDCl3) δ ppm 0.53 (m, 1H), 0.75 (m, 7H), 0.93 (d, J=5.88 Hz, 3H), 1.03 (d, J=5.88 Hz, 3H), 1.34 (m, 1H), 1.79 (m, 1H), 2.08 (m, 1H), 3.84 (s, 3H), 4.13 (m, 1H), 4.41 (d, J=10.30 Hz, 2H), 4.57 (m, 1H), 5.96 (s, 1H), 7.43 (m, 2H), 7.59 (m, 1H), 8.19 (d, J=7.72 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(CC)CC.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:21]=[C:20]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[CH2:19][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[O:1]
Reactant: Oc1nc2ccccc2s1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Cn2c(=O)sc3ccccc32)cc1
Yield: 67 %

Procedure:
To a solution of 2-hydroxybenzothiazole (1.17 g, 7.58 mmol) in THF (10 mL) was added Et3N (1.1 mL, 7.89 mmol). A solution of 2-bromo-4′-methylacetophenone (1.67 g, 7.06 mmol) in THf (10 mL) was added dropwise. Another equivalent of Et3N was added after 24 hours. Purification by flash chromatography on silicagel (CH2Cl2) gave a white powder in 67% yield: mp 168-170° C.; 1H-NMR (DMSO-d6) 2.43 (s, 3H), 5.62 (s, 2H), 7.21 (t, 1H), 7.27 (d, 1H) 7.32 (t, 1H), 7.42 (d, 2H), 7.70 (d, 1H), 8.01 (d, 2H); Anal. (C16H13NO2S) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]=[C:31]=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13][NH:14]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1n[nH]c2cc(-c3ccc(N)cc3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1n[nH]c2cc(-c3ccc(NC(=O)Nc4ccc(Cl)c(Cl)c4)cc3)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture of ethyl 6-(4-aminophenyl)-1H-indazole-3-carboxylate (40 mg) and 3,4-dichlorophenylisocyanate in tetrahydrofuran (3 Ml; THF) was stirred at room temperature for 24 h. Ethyl acetate and saturated sodium bicarbonate solution were wadded. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated by THF/hexane to give ethyl 6-(4-(3-(3,4-dichlorophenyl)ureido)phenyl)-1H-indazole-3-carboxylate (17.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([SH:18])[CH2:16][SH:17])[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH2:10]OC.[CH3:19][O:20][C:21]1[CH:22]=[C:23](C=[C:27]([O:30][CH3:31])[C:28]=1[CH3:29])C=S.C1(C)C=CC([S:38]([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:19][O:20][C:21]1[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[S:38][C:22]=1[C@H:23]1[S:18][C@H:15]([C:5]2[CH:6]=[C:7]([O:13][CH3:14])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:16][S:17]1
Reactant: COc1cc(C=S)cc(OC)c1C
Reactant: COCOc1c(OC)cc(C(S)CS)cc1OC
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc([C@@H]2CS[C@@H](c3sc(OC)c(C)c3OC)S2)cc(OC)c1OC

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (0.148 g,0.57 mmole), 3,5-dimethoxy-4-methylthiobenzaldehyde (48) (FIG. 23) (0.11 g, 0.519 mmole) and 0.052 g of pyridinium para-toluenesulfonate was added to 40 ml dry benzene and refluxed with Dean-Stark removal of the benzene- water azeotrope for 48 hours. The benzene was removed in vacuo, and the remaining oil redissolved in dichloromethane. The organic layer was washed with 3×30 ml H2O and was dried over MgSO4, and evaporated in vacuo to an oil which was purified by flash column chromatography with 2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.0 cis/trans ratio (0.151 g, 64%). The trans isomer was isolated after two recrytallizations of this mixture from methanol.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[Cl:22][C:23]1[C:28]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:27][CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[Cl:22][C:23]1[C:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:2](=[O:1])[CH3:4])[CH2:31][CH2:30]2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Clc1nccnc1C1CCNCC1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
To an ice cooled solution of 2-chloro-3-(piperidin-4-yl)pyrazine-3TFA (150 g, 0.278 mol) in anhydrous dichloromethane (1.5 L) kept under nitrogen was added triethylamine (194 mL, 1.39 mol, 5 eq.) over a period of 15 min., followed by acetic anhydride (53 mL, 0.556 mol, 2 eq.) over a period of 10 min. The resulting mixture was allowed to stir at room temperature for 2 h and quenched with 500 mL of water. After separation, the organic phase was further washed with water (500 mL) and brine (500 mL). The aqueous phases were combined and back extracted with dichloromethane (1 L). Organic extracts were combined, dried and concentrated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=2:3 to 100% ethyl acetate) to give 70 g 1-(4-(3-chloropyrazin-2-yl)piperidin-1-yl)ethanone. Yield: 94% for two steps.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH2:5][OH:6])[CH2:2]1.C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:6][CH2:5][CH:3]2[CH2:4][O:1][CH2:2]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1COC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of oxetan-3-yl-methanol (300 mg, 3.41 mmol, CAS RN 6246-06-6) in CH2Cl2 (3 mL) was added triethylamine (517 mg, 712 μl, 5.11 mmol), DMAP (41.6 mg, 341 μmol) and p-toluenesulfonyl chloride (779 mg, 4.09 mmol) at 0° C. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured on 30 mL 1M aqueous HCl and 30 mL CH2Cl2 and the layers were separated. The aqueous layer was extracted a second time with 30 mL CH2Cl2. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Colorless liquid (595 mg, 72%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:15][CH3:16])=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1.[F:17][C:18]([F:42])([F:41])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]>>[F:17][C:18]([F:41])([F:42])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39][N:12]2[CH2:11][CH2:10][N:9]([C:7]3[CH:8]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=3[O:15][CH3:16])[CH2:14][CH2:13]2)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]
Reactant: COc1ccc(Cl)cc1N1CCNCC1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Agent: Cl
Product: COc1ccc(Cl)cc1N1CCN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1

Procedure:
Prepared analogously to Example 2 b from 1-(5-chloro-2-methoxy-phenyl)-piperazine hydrochloride and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: Cl[CH2:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1.[C:18]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[N:33]([CH2:42][C:43]#[C:44][CH3:45])[C:34]3[C:39](=[O:40])[NH:38][N:37]=[CH:36][C:35]=3[N:41]=2)[CH2:27]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:18]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[N:33]([CH2:42][C:43]#[C:44][CH3:45])[C:34]3[C:39](=[O:40])[N:38]([CH2:2][C:3]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[O:7][C:6]5[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=5[N:4]=4)[N:37]=[CH:36][C:35]=3[N:41]=2)[CH2:27]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2cn[nH]c(=O)c21
Reactant: ClCC1=Nc2ccccc2Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2cnn(CC3=Nc4ccccc4Oc4ccccc43)c(=O)c21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
317 mg 11-chloromethyl-dibenzo[b,f][1,4]oxazepin are added to 400 mg 2-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 276 mg potassium carbonate in 4 ml N,N-dimethylformamide. The reaction mixture is stirred for two hours at 80° C. For working up it is combined with water and the precipitate formed is suction filtered. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol (100:0 to 70:30) as eluant.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(C#Cc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1ccc(C#Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.6 %

Procedure:
1-(trimethylsilylethynyl)-4-(4-fluorophenylethynyl)benzene (2.2 g, 7.5 mmol) was dissolved in CH2Cl2 (30 mL) diluted with MeOH (30 mL) and then treated with powdered K2CO3 (2.1 g, 15 mmol) and allowed to stir at ambient temperature for 20 h under N2. The reaction mixture was filtered to remove solids, concentrated, redissolved in CH2Cl2, washed with water (2×), brine, dried over MgSO4, filtered and concentrated to dryness to give 1.43 g (87%) product that was used as is in the next reaction. 1H NMR, (CDCl3) δ: 7.54 (m, 2H), 7.49 (m, 4H); 7.05 (t, J=8.4 Hz, 2H); 3.20 (s, 1H). 13C {1H} NMR (CDCl3): 162.6 (J=250.3 Hz), 133.6 (J=8.0 Hz), 132.1, 131.4, 123.6, 122.0, 119.1 (J=3.6 Hz), 115.7 (J=32.0 Hz), 90.3, 88.6, 83.3, 79.0 ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:10]1([CH3:19])[C:11]([N:16]=[C:17]=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=1>C(Cl)(Cl)Cl>[CH2:7]=[CH:6][C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1.[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([NH2:1])=[O:18]
Reactant: C=Cc1ccc(N)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: ClC(Cl)Cl
Product: C=Cc1ccccc1
Product: Cc1ccccc1NC(N)=O

Procedure:
1.00 g (8.40 mmol) of p-aminostyrene (99% Tokyo Kasei) was added to a 250 ml round bottom flask containing 10 ml of chloroform. After ten minutes of mixing, 1.12 g (8.41 mmol) of o-tolyl isocyanate (99% Aldrich) was added dropwise. Within seconds, a yellow precipitate formed. The precipitate was filtered to remove the reaction liquid, then washed with 20 ml of chloroform resulting in pale yellow powder (1.45 g, 68% crude yield, mp=193° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH:19]([CH3:21])[CH3:20]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC(C)C
Temperature: 60 °C

Procedure:
A mixture of 3-hydroxy-4-methoxybenzaldehyde (20.0 g), anhydrous potassium carbonate (26.2 g) and 2-bromopropane (18.3 mL) in dry dimethylformamide (300 mL) is stirred and heated at 55-65° C. for 24 hours. The cooled mixture is poured into water and extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated in vacuo at 40° C., to give 4-methoxy-3-prop-2-yloxybenzaldehyde, in the form of an oil (24.2 g).
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C.C(OC(=O)C)(=O)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:2]2[O:1][CH2:6][C:5](=[O:7])[NH:4][C:3]=2[N:8]=1)([O-:14])=[O:13]
Reactant: O=C1COc2cccnc2N1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1COc2ccc([N+](=O)[O-])nc2N1
Reaction time: 8 h

Procedure:
2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one (2.5 g) was dissolved in acetic acid (6 mL) and acetic anhydride (30 mL). Fuming nitric acid (3 mL) was added dropwise to the reaction solution in ice-bath. The reaction solution was stirred in ice-bath overnight. Solution was poured into crashed ice. The light yellow precipitation was collected by filtration, washed with water and dried to give a mixture of nitrated products (regio-isomers). The mixture was crystallized from dichloromethane to give 6-nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (1 g) as a light yellow solid.