Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:17]=[CH:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.C(O[C:34]1(O[Si](C)(C)C)[CH2:36][CH2:35]1)C.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[ClH:27].[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[S:20][C:14]3[C:13](=[O:28])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH:3]5[CH2:4][N:1]([CH:34]6[CH2:36][CH2:35]6)[CH2:2]5)=[C:7]([O:29][CH3:30])[CH:8]=4)[CH:17]=[CH:16][C:15]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CNC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CN(C2CC2)C1
Product: Cl
Yield: 69.6 %

Procedure:
Mix molecular sieves (100 mg, type 3A), 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (1.00 g, 2.27 mmol), and [(1-ethoxycyclopropyl)oxy]trimethylsilane (688.3 μL, 3.41 mmol), and acetic acid (651.3 μL, 11.37 mmoles) in dry methanol (11 mL) and reflux the mixture for 3 h. Cool the reaction to room temperature, then add sodium cyanoborohydride (376 mg, 5.68 mmoles) and slowly warm to 40° C. for one hour. Cool the mixture and add 1 N NaOH solution, then extract the aqueous layer with CHCl3 (3×25 mL). Dry the organic layer with Na2SO4, filter, and concentrate. Purify the crude material on silica gel chromatography using a gradient of 0-10% 2 N NH3/MeOH in CHCl3. Collect the desired fractions and remove the solvent via reduced pressure. Re-dissolve the resulting material in CHCl3 and add 1 N HCl/Et2O solution (2.27 mL). Remove the solvent and dry under vacuum to give 408 mg (35%) of the title compound. ES/MS m/z (35Cl) 480.0 [M+1]+.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:37][CH2:38][C:39]1[CH:46]=[CH:45][C:42](C#N)=[C:41](F)[CH:40]=1>CN(C=O)C>[N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([NH:37][CH2:38][C:39]1[CH:46]=[CH:45][CH:42]=[CH:41][CH:40]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: N#Cc1ccc(CN)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To an ice cooled solution of Boc-Aze-OH (0.194 g, 0.96 mmol) in 5 mL of DMF was added TBTU (0.50 g, 9.6 mmol). After 30 min another solution, comprising 4-aminomethyl-2-fluorobenzonitrile (0.17 g, 0.81 mmol; see step (v) above) and diiisopropylethyl amine (0.326 g, 2.53 mmol) in 7 mL of DMF was added. The resulting solution was stirred overnight at room temperature. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN: 0.1M NH4OAc (50:50). Freeze-drying gave 0.237 g (74%) of the desired sub-title compound.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Si:9].C(CC(=O)C)(=O)C>>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Si+4:9].[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2]
Reactant: Oc1ccccc1O
Reactant: [Si]
Solvent: CC(=O)CC(C)=O
Product: [O-]c1ccccc1[O-]
Product: [Si+4]

Procedure:
A solution of catechol (22.0 g, 0.20 mmol) and toluene (220 mL) was dehydrated by distilling 20 mL of the solution. Thereafter, 20.8 g (0.10 mmol) of tetraethoxysilane (TEOS) was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled at a liquid flow rate of 15 mL/h until the amount of the solution became 100 mL. As a result, catechol-silicon complex toluene was obtained. To 2 mL of catechol-silicon complex toluene, 2 mL of acetylacetone was added to produce a coating liquid.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Cl:23][C:24]1[N:29]=[C:28]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[Cl:23][C:24]1[N:29]=[C:28]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[CH:27]=[CH:26][CH:25]=1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cccc(Cl)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(Cl)n2)c2c(N)ncnc21
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (150 mg, 0.443 mmol), (6-chloro-2-pyridinyl)acetic acid (76 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), DIEA (0.310 mL, 1.774 mmol) was stirred at room temperature overnight. The resulting suspension was poured into water (10 mL) and stirred for 30 min. The resulting precipitate was collected by filtration, and the residue was washed with water (10 mL), dried at the pump for ca. 1 hour. The solid residue was dissolved in acetone and adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtOAc) to afford 5-{1-[(6-chloro-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (99.8 mg, 53.7% yield) as a beige solid. LC-MS (ES) m/z=419 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.25 (t, J=8.34 Hz, 2H), 3.74 (s, 3H), 4.08 (s, 2H), 4.27 (t, J=8.46 Hz, 2H), 5.92-6.22 (m, 2H), 7.20-7.28 (m, 2H), 7.33 (s, 1H), 7.38-7.46 (m, 2H), 7.87 (t, J=7.83 Hz, 1H), 8.10 (d, J=8.34 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[N:3]1[C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:6]2[CH2:5][CH:4]([CH3:8])[N:3]([C:9]3[S:10][C:11]4[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:2]([CH3:1])[CH2:7]2)[CH:27]=1
Reactant: CC1CNCC(C)N1c1nc2ccc(C(F)(F)F)cc2s1
Reactant: COC(=O)Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(CN2CC(C)N(c3nc4ccc(C(F)(F)F)cc4s3)C(C)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
A mixture of 2-(2,6-dimethyl piperazine-1-yl)-6-trifluoromethyl benzothiazole (163 mg), (3-bromomethylphenyl)acetic acid methyl ester (126 mg), potassium carbonate (75 mg) and dimethylformamide (4 mL) was stirred at room temperature for 18 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (171 mg). Yield: 65%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]([O:23]C)=[O:22])=[C:19]([O:25][CH3:26])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.CO.O.[OH-].[Li+].Cl>O.CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([O:25][CH3:26])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COC(=O)c1c(OC)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2c(c1C(=O)O)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 30 °C
Reaction time: 10 h
Yield: 66.9 %

Procedure:
Methyl (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylate (0.070 g, 0.20 mmol) was added with methanol (3.0 mL), dimethyl sulfoxide (1.0 mL), and water (0.50 mL), and then added with lithium hydroxide monohydrate (0.025 g, 0.60 mmol), and the mixture was stirred at 30° C. for 10 hours. The reaction mixture was made acidic with 3 N hydrochloric acid, and the solid formed was collected by filtration. The solid was suspended in chloroform/methanol (95:5), then collected by filtration and dried to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylic acid (0.045 g, 67%).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:39]([CH2:38][CH2:37][C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:13])=[O:14]
Reactant: NCCc1ccc(F)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(CCc2ccc(F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(4-Fluoro-phenyl)-ethylamine. MS (ESI): 451.3 (MH+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)[CH:20]=1.[NH2:34][CH2:35][C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[OH:37][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:33][CH:32]=1)=[O:18]
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: NC[C@@H](O)c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3cccnc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (1S)-2-amino-1-phenylethanol, the title compound was obtained in 73% purity by HPLC. MS(ESI+): m/z=459.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].Br[C:18]1[C:19]([Cl:30])=[CH:20][N:21]=[C:22]2[C:27]=1[N:26]=[C:25]([O:28][CH3:29])[CH:24]=[CH:23]2.[Cl-].[Li+].C(OCC)(=O)C>CN(C)C=O.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>[CH2:3]([C:18]1[C:19]([Cl:30])=[CH:20][N:21]=[C:22]2[C:27]=1[N:26]=[C:25]([O:28][CH3:29])[CH:24]=[CH:23]2)[CH:2]=[CH2:1]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc2ncc(Cl)c(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1c(Cl)cnc2ccc(OC)nc12
Temperature: 105 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
Allyltributylstannane (7.3 g, 21.9 mmol, 1.2 eq) is added at room temperature to a stirred solution of 8-bromo-7-chloro-2-methoxy-[1,5]naphthyridine (5.0 g, 18.3 mmol, 1.0 eq) in N,N-dimethylformamide (100 mL), followed by tetrakis(triphenylphosphine)palladium(0) (0.63 g, 0.55 mmol, 0.03 eq) and lithium chloride (2.9 g, 67.6 mmol, 3.7 eq). After 1 hour stirring at 105° C., the reaction mixture is cooled down to room temperature and filtered through decalite. The filtrate is concentrated to give a crude product that is extracted with ethyl acetate (3×100 mL) and a 10% ammonium hydroxide aqueous solution (100 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 30:1, v/v) to afford 8-allyl-7-chloro-2-methoxy-[1,5]naphthyridine as a colorless oil (2.5 g, 58% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12](O)[CH3:13])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(O)c1cc(Br)cc(C(=O)O)c1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(Br)cc(C(=O)O)c1O
Temperature: 90 °C
Yield: 61.7 %

Procedure:
974 mg (3.73 mmol) of 5-bromo-2-hydroxy-3-(1-hydroxy-ethyl)-benzoic acid was dissolved in trifluoroacetic acid under nitrogen. 715 μL (521 mg, 4.48 mmol) of triethyl silane was added and the resulting mixture was heated to 90° C. for 2 h. The mixture was evaporated and the residue purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 563 mg (2.30 mmol, 62%) of 5-bromo-3-ethyl-2-hydroxy-benzoic acid as a colorless solid. 1H-NMR (500 MHz, d6-DMSO): δ 7.73 (d, 1H), 7.57 (d, 1H), 2.61 (q, 2H), 1.15 (t, 3H); MS: m/z 243.0+244.9 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH:21]([CH3:26])[C:22](OC)=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].O.[NH2:28][NH2:29]>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH:21]([CH3:26])[C:22]([NH:28][NH2:29])=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)N(c2ccc(C)cc2)C(C)C(=O)OC)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: CCOc1ccc(S(=O)(=O)N(c2ccc(C)cc2)C(C)C(=O)NN)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
The crude carboxylic acid methyl ester, e.g. methyl 2-{[(4-ethoxyphenyl)sulfonyl]-4-methylanilino}propanoate (264 mg, 0.70 mmol), was dissolved in MeOH (2 mL). Hydrazine hydrate was added (0.44 mL). The reaction mixture was stirred overnight at 60° C. Solvents were evaporated. The crude mass was redissolved in MeOH and solvents were evaporated again. This process was repeated three times. The desired product, e.g. 4-ethoxy-N-(2-hydrazino-1-methyl-2-oxoethyl)-N-(4-methylphenyl)benzenesulfonamide (138.4 mg, 52%) was isolated as a colorless solid in 91.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([C:24]([OH:26])=O)[CH:22]=[CH:23][C:17]=4[N:16]4[CH:27]=[CH:28][CH:29]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2].[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([N:9]2[CH2:14][CH2:13][C:12]3([O:19][C:18]4[CH:20]=[C:21]([C:24]([NH:35][CH3:34])=[O:26])[CH:22]=[CH:23][C:17]=4[N:16]4[CH:27]=[CH:28][CH:29]=[C:15]34)[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[O:32][CH3:33])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)O)ccc2-n2cccc23)cc1OC
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)N2CCC3(CC2)Oc2cc(C(=O)NC)ccc2-n2cccc23)cc1OC

Procedure:
A solution of 1′-(4-ethyl-3-methoxybenzoyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylic acid (40 mg, 0.090 mmol), HATU (34 mg, 0.090 mmol), N-methylamine hydrochloride (6.0 mg, 0.090 mmol) and iPr2NEt (62 μL, 0.36 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was filtered and purified by reverse phase LC-MS (10-99% CH3CN/H2O). Pure fractions were combined and evaporated to yield 1′-(4-ethyl-3-methoxybenzoyl)-N-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxamide. ESI-MS m/z calc. 459.5. found 460.5 (M+1)+; Retention time: 1.73 minutes (3 min run).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[S:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2].C([O-])([O-])=[O:18].[K+].[K+].O>CS(C)=O>[CH:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[S:12][C:11]([C:13]([NH2:14])=[O:18])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)s1
Reaction time: 1 h

Procedure:
Dissolve 5-(4-formylphenoxy)thiophene-2-carbonitrile (0.818 g, 3.57 mmol) in DMSO (18 mL) in a round bottom flask, then add K2CO3 (0.247 g, 1.78 mmol). Cool the reaction flask in a water bath and add 30% H2O, (0.81 mL, 7.14 mmol) solution. After one hour, add water (25 mL). Filter the resulting precipitate and wash the filter cake with water (25 mL). Collect the filter cake as the title compound: HRMS calcd for C12H10NO3S 248.0381 (M+H)+, found 248.0396, time 0.36 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=13.0 min, 100% purity.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:45])[C@H:19]([NH:31][C:32](=[O:44])[C:33]([NH:36]C(=O)OC(C)(C)C)([CH3:35])[CH3:34])[CH2:20][C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]([CH3:30])[CH:22]=4)[CH2:13]3)[C:11](=[O:46])[N:10]([CH:47]([CH3:49])[CH3:48])[CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[NH2:36][C:33]([CH3:35])([CH3:34])[C:32]([NH:31][C@H:19]([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([CH3:30])[CH:22]=1)[C:18]([N:14]1[CH2:15][CH2:16][CH2:17][C:12]2([C:11](=[O:46])[N:10]([CH:47]([CH3:48])[CH3:49])[CH2:9][CH:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13]1)=[O:45])=[O:44]
Reactant: CC(C)N1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](Cc3cn(C)c4ccccc34)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](Cc3cn(C)c4ccccc34)NC(=O)C(C)(C)N)C2)C1=O

Procedure:
A mixture comprising tert-butyl 1-((2R)-1-(4-(4-fluorophenyl)-2-isopropyl-1-oxo-2,7-diazaspiro[4.5]decan-7-yl)-3-(1-methyl-1H-indol-3-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (378 mg, 0.559 mmol) (step 1) and TFA (0.431 ml, 5.59 mmol) in DCM (3 ml) was stirred at room temperature for 4 hours. The solvent was removed in vacuo to afford a colourless oil. The oil was dissolved with methanol (3 ml) and passed through a 10 g SCX-2 cartridge eluting with 2M NH3 in methanol (70 ml). The solvent was removed in vacuo to yield the title compound as diastereomeric mixture.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:11][C:10]2=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH:29]1([NH:32][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[CH3:28])[CH:8]=3)[N:13]=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:11]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: Cc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)nc(NC3CC3)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropylamine in step E. MS (ESI/CI): predicted mass C22H19N5O2, 385.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.C1(=O)[O:13][CH2:12][CH2:11][O:10]1.C(=O)=O>[F-].[K+]>[OH:10][CH2:11][CH2:12][O:13][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C1OCCO1
Agent: O=C=O
Agent: [F-]
Agent: [K+]
Product: OCCOCc1ccccc1
Yield: 93.4 %

Procedure:
The reaction apparatus used in Example 1 was charged with 4-methylphenol (54 grams), ethylene carbonate (45 grams) and a small amount of KF (0.5 grams, 0.5 percent). After thorough mixing the flask was immersed in an oil bath and the temperature adjusted to 160° C.±2°. After a reaction time of 1.1 hours, CO2 evolution ceased and the product, 4-(2-hydroxyethoxy)methylbenzene (71 grams, 94 percent yield) was recovered and purified by recrystallization from acetone.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:16][CH:17]([CH3:19])[CH3:18])=[C:7]([C:10]([CH3:15])=[C:11]([C:13]#[CH:14])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:14]#[C:13][C:11]2[CH:12]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([O:16][CH:17]([CH3:19])[CH3:18])=[C:7]([CH:8]=[O:9])[C:10]=2[CH3:15])=[CH:28][CH:29]=1
Reactant: C#Cc1cc(C(C)(C)C)c(OC(C)C)c(C=O)c1C
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(C=O)c2C)cc1

Procedure:
Following General Procedure B and using 3-tert-butyl-5-ethynyl-2-isopropoxy-6-methyl-benzaldehyde (Intermediate 143, 0.35 g, 1.35 mmol), 4-iodo phenyl acetic acid methyl ester (0.374 g, 1.35 mmol), triethyl amine (8 mL), copper(I)iodide (0.02 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.072 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 3-5% ethyl acetate in hexane as the eluent, the title compound was obtained as a white solid (0.37 g, 75%).
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[N:49])[CH:43]=1.C(=O)(O)[O-].[Na+]>C1COCC1.N1C=CC=CC=1>[C:39]([C:33]1[CH:34]=[N:35][C:36]2[C:31]([C:32]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[N:49])[CH:43]=1)=[CH:30][C:29]([NH:28][C:10](=[O:12])[C:9]#[C:8][CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[CH:38][CH:37]=2)#[N:40]
Reactant: N#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reactant: O=C(O)C#CCN1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: N#Cc1cccc(Nc2c(C#N)cnc3ccc(NC(=O)C#CCN4CCCCC4)cc23)c1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
Partially dissolved 1.46 g (8.75 mmol) 4-piperidino-2-butynoic acid in 100 ml THF and chilled to 0° C. under N2. Added 1.16 ml (10.5 mmol) N-methylmorpholine and 911 μl (7.00 mmol) isobutyl chloroformate and stirred for 30 minutes. Added a solution of 1.00 g (3.50 mmol) 6-amino-4-[(3-cyanophenyl)amino]-3-quinolinecarbonitrile in 8 ml pyridine. At 3.5 hours poured onto ice bath and made basic with saturated sodium bicarbonate. Extracted with ethyl acetate, dried organic layers with magnesium sulfate, filtered, and reduced solvent to a small volume. Loaded compound onto a column of silica gel and eluted with 7% methanol/ethyl acetate. Stripped solvent from desired fractions and dried in vacuo, giving 1.008 g of off-white solid: mass spectrum (electrospray m/e): 435.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl>>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][S:23][C:21]1[O:22][C:18]([C:15]2[CH:16]=[CH:17][C:12]3[N:11]=[CH:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:13]=3[CH:14]=2)=[N:19][N:20]=1
Reactant: COc1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Reactant: Fc1cccc(CCl)c1
Product: COc1ccc(-n2cnc3ccc(-c4nnc(SCc5cccc(F)c5)o4)cc32)cc1
Yield: 26 %

Procedure:
In the same manner as in Example 1 and using 5-[1-(4-methoxyphenyl)-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 26%) was obtained as colorless crystals.