Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([O:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[NH:25]1[CH2:30][CH:29]=[C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:27][CH2:26]1>CS(C)=O.C(OCC)(=O)C>[CH3:24][O:23][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C@@H:13]([CH2:12][N:25]1[CH2:26][CH:27]=[C:28]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[CH2:29][CH2:30]1)[CH:22]=[CH:21]2
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: COc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)C=C2
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cccc2c1O[C@@H](CN1CC=C(c3c[nH]c4ccccc34)CC1)C=C2
Temperature: 80 °C
Yield: 58 %

Procedure:
To a solution of [(2R)-8-methoxy-2H-chromen-2-yl]methyl 4-methyl-benzenesulfonate (0.350 g, 1.01 mmol) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.601 g, 3.03 mmol) and the reaction mixture was heated to 80° C. for 12 h. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (200 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.218 g (58%, >97% ee) of 3-(1-{[(2R)-8-methoxy-2H-chromen-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole as a yellow solid. [α]D25=+0.588 (c 10.21 in chloroform, >97% ee); Rf=0.43 (silica, methanol:ethyl acetate 1:9); mp 198-200° C. dec; Anal. Calcd. for C24H24N2O2.0.3 H2O: C, 76.29; H, 6.56; N, 7.41. Found: C, 76.02; H, 6.63; N, 7.43.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+]>CO.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:10])[CH3:11])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)c(=O)n1C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1c(Cl)cc(C(=O)NCC2CCNCC2)c(=O)n1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A mixture or tert-butyl 4-({[(5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbonyl]amino}methyl)piperidine-1-carboxylate as prepared in 6(1) (4.77 g, 11.2 mmol) in 10% hydrochloric acid methanol solution (30 mL) was stirred at room temperature for 18 h. The mixture was concentrated in vacuo. The residue was dissolved in methanol (15 mL) and tetrahydrofuran (15 mL). To the resulting solution was added potassium carbonate (3.0 g, 21.7 mmol) at room temperature, and the mixture was stirred at room temperature for 18 h. Then, the mixture was filtered through a pad of Celite, washed with methanol/tetrahydrofuran (v/v=1/1, 200 mL). The filtrate was concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% ammonium hydroxide (v/v/v=10/1/0.2) to give 3.43 g (94%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:30]([Cu])#[N:31]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3c(C)cc(C)cc3C)cc2c1O
Reactant: N#C[Cu]
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cc(C)cc3C)cc2c1O

Procedure:
The title compound was synthesized from 1-bromo-4-hydroxy-6-(2,4,6-trimethyl-phenoxy)-isoquinoline-3-carboxylic acid butyl ester and CuCN in analogy to example 3a; MS-(−)-ion: M−1=403.4.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(=O)C.[Br:16]Br.C([O-])(O)=O.[Na+]>CCOCC>[Br:16][C:9]1[CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(O)c(Br)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of 4-(methylsulfonyl)phenol (5 g, 29.1 mmol) in ether (100 mL) at −15° C. was slowly added acetic acid (5 mL). To this cold solution was slowly added Br2 (5.1 g, 32.0 mmol) and the reaction was stirred at −10° C. for 1 h and then warmed to r.t. and stirred for further 10 h. After the reaction was completed, 100 mL of sat. NaHCO3 aq. was added and the mixture was extracted with EA (50 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, 2-bromo-4-(methylsulfonyl)phenol (3.2 g, 43.6%) was obtained as a white solid.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19]([Cl:23])=[N:18][N:17]=[C:16]3Cl)=[O:12])[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].[O:28]1CCOCC1.Cl>O>[F:1][CH:2]([F:25])[O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:19]([Cl:23])=[N:18][NH:17][C:16]3=[O:28])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: C1COCCO1
Reactant: O=C(Nc1cccc(OC(F)F)c1)c1ccc2c(Cl)nnc(Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cccc(OC(F)F)c1)c1ccc2c(Cl)n[nH]c(=O)c2c1
Temperature: 50 °C

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid (3-difluoromethoxy-phenyl)-amide (0.26 g, 0.68 mmol), 2N NaOH (3.4 mL, 6.8 mmol) and dioxane (4 mL) was heated to 50° C. for 2 hours. The reaction was diluted with water, acidified with conc. HCl to ˜pH 4 and extracted with EtOAc (×3). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated. Chromatography (Hex/EtOAc) afforded 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (3-difluoromethoxy-phenyl)-amide (60 mg), 1H-NMR (DMSO-d6) δ: 13.02 (s, 1H), 10.88 (s, 1H), 8.88 (d, 1H), 8.52 (dd, 1H), 8.14 (d, 1H), 7.75 (m, 1H), 7.69 (m, 1H), 7.43 (m, 1H), 7.23 (t, 1H), 6.96 (dd, 1H). m/z (M+H)=366; and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (3-difluoromethoxy-phenyl)-amide (39 mg), 1H-NMR (DMSO-d6) δ: 12.85 (s, 1H), 10.87 (s, 1H), 8.47 (m, 1H), 8.42 (m, 2H), 7.73 (m, 1H), 7.65 (m, 1H), 7.44 (m, 1H), 7.23 (t, 1H), 6.96 (dd, 1H). m/z (M+H)=366.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)CCl.[Pd]>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2=NNC(c3ccccc3)C2)cc1
Agent: [Pd]
Solvent: ClCCCl
Product: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Yield: 79.3 %

Procedure:
3,5-Diphenyl-2-pyrazoline (21.9 parts) is dissolved in ethylene dichloride (75 parts by volume). There is next added 5% palladium on carbon catalyst (4 parts containing 40% water) is added and the mixture is heated at reflux for 8 hours. There is obtained 3,5-diphenylpyrazole in a 79.3% yield whose melting point ranges from 196°C. to 200°C.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([C:40]([CH:42]2[CH2:44][CH2:43]2)=[O:41])[C:36]([O:38]C)=O)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:28]=[C:29]2[C:30](=[CH:31][CH:32]=1)[N:33]=[CH:34][C:35]([C:40]([CH:42]1[CH2:44][CH2:43]1)=[O:41])=[C:36]2[OH:38]
Reactant: COC(=O)C(=CNc1ccc(Br)cc1)C(=O)C1CC1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(c1cnc2ccc(Br)cc2c1O)C1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
Dowtherm was heated to 250° C., methyl 3-(4-bromophenylamino)-2-(cyclopropanecarbonyl)acrylate (24 g, 74.1 mmol) was added portionwise and upon complete addition the reaction mixture was stirred for 20 min. The reaction mixture was cooled to room temperature, diluted with 2:1 hexanes/diethyl ether and filtered to afford the desired product (9.71 g, 45%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.51 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 7.89 (dd, J=8.8, 2.3 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 3.73-3.49 (m, J=7.5, 5.0 Hz, 1H), 1.15-0.76 (m, 4H).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][Br:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][Br:36])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCCBr)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCCBr)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Yield: 80.2 %

Procedure:
N.M.R. δ(DMSO-d6, ppm): 3.3-3.9 (4H, m), 4.1-4.8 (4H, m), 5.23 (1H, d, J=5Hz), 5.84 (1H, dd, J=5 Hz, 9 Hz), 7.63 (1H, s), 8.72 (1H, s), 9.57 (1H, s), 9.71 (1H, d, J=9 Hz), 12.71 (1H, broad s). (2) A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-bromoethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.5 g.), conc. hydrochloric acid (0.99 g.), tetrahydrofuran (10 ml.) and methanol (22 ml.) was treated in similar manner to that of Example 9 (2), to give 7-[2-(2-aminothiazol-4-yl)-2-(2-bromoethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.15 g.).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:23].[C:24](OC)(OC)(OC)[CH2:25][CH2:26][CH2:27][CH3:28].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:25]([C:24]1[N:6]([CH2:5][CH2:4][CH2:3][S:2][CH3:1])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:23]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CSCCCNc1c(N)cnc2cc(-c3ccccc3)ccc12
Reactant: CCCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3cc(-c4ccccc4)ccc3c2n1CCCSC
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
N4-(3-Methylsulfanylpropyl)-7-phenylquinoline-3,4-diamine (2.75 g, 8.49 mmol), trimethyl orthovalerate (1.7 g, 10 mmol), and pyridine hydrochloride (0.3 g) were dissolved in toluene (28 mL) and heated to reflux for 1.5 h, collecting the volatiles in a Dean—Stark trap. Upon cooling to room temperature, the solvent was removed under vacuum. The resulting solid was slurried in hexanes (100 mL) for 1 h and then collected by filtration to afford 3.0 g of 2-butyl-1-(3-methylsulfanylpropyl)-7-phenyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: C[C:2]([CH3:5])([O-])[CH3:3].[Li+].[C:7]([O:11][C:12]([N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[C@H:15]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[CH2:16]/[C:17](=[CH:12]\[N:14]([CH:15]([CH3:20])[CH3:16])[CH:2]([CH3:5])[CH3:3])/[C:18]1=[O:19])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of lithium tert-butoxide (2.8 eq, 2.8 mmol, 1 M solution in THF) and N,N,N′N′-tetramethylformamidinium hexafluorophosphate (18, R6=Me, R7=Me) (3 eq, 3 mmol) is stirred at 60° C. for 1 h. The mixture is then cooled to room temperature. The mixture is then diluted with tetrahydrofuran to a total volume of 5 ml. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (8-a, R1=Boc) (1 eq, 1 mmol) is then added to the mixture. The mixture is then stirred at room temperature for 3 h. The volatiles are removed under reduced pressure. Ethyl acetate (20 ml) is added to the mixture. The phases are separated and the organic phase washed with saturated sodium carbonate solution (2×20 ml) and brine (20 ml). The organic phase is dried (Na2SO4) and concentrated under reduced pressure to afford (R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) or a salt thereof. The solutions are analysed by TLC (50% ethyl acetate in hexane). RF 0.21 (salt of 7-a, R1=Boc, R6=Me, R7=Me); RF 0.27 (7-a, R1=Boc, R6=Me, R7=Me); RF 0.68 (8-a, R1=Boc).
Reaction SMILES: [OH:1][CH:2]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([O:5]CC)=[O:4].[OH-].[K+].O1CC[CH2:28][CH2:27]1.CO>O>[CH2:27]([O:1][CH:2]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:3]([OH:5])=[O:4])[CH3:28]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(O)c1c(-c2ccccc2)n(C)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(C(=O)O)c1c(-c2ccccc2)n(C)c2ccccc12
Temperature: 60 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
A solution of ethyl hydroxy-(1-methyl-2-phenyl-1H-indol-3-yl)-acetate (8b) (20 mg, 0.055 mmol) and potassium hydroxide (50 mg, 0.89 mmol) in a mixture of water (2 mL), tetrahydrofuran (2 mL) and methanol (0.5 mL) was stirred at 60° C. for 12 hours. Water (10 mL) was added to the reaction mixture which was washed with diethyl ether (10 mL). The aqueous layer was acidified to pH 2 with an aqueous solution of hydrochloric acid 0.5N and extracted with dichloromethane. The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (dichloromethane/ethanol) to afford unexpected ethoxy-(1-methyl-2-phenyl-1H-indol-3-yl)-acetic acid (example 8) (5.3 mg, 0.017 mmol, 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:9]=[C:8]([O:17][CH3:18])[C:4]=1[C:5]([NH2:7])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:18][O:17][C:8]1[CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:5][NH2:7]
Reactant: CCCCCc1cc(OC)c(C(N)=O)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCc1cc(OC)c(CN)c(OC)c1

Procedure:
Using the procedure of Example 1, 2,6-dimethoxy-4-pentyl benzamide is reduced with lithium aluminum hydride to obtain 2,6-dimethoxy-4-pentyl-benzylamine.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([Cl:15])[C:9]=2[NH:8][CH:7]=1)=[O:5])C.O[Li].O>C1COCC1.O>[Cl:15][C:14]1[C:9]2[NH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c[nH]c2c(Cl)ncnc12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 7-chloro-4,6-diazaindole 5 (4.0 g, 18 mmol) in THF (90 mL) was added a solution of LiOH.H2O (2.5 g, 59 mmol) in H2O (60 mL). The reaction mixture was stirred at 100° C. for 1 d, concentrated and recrystallized from H2O (20 mL). The crystals were collected by filtration, washed with H2O and dried under high vacuum. The off-white solid was shown to be the lithium salt of the diazaindole carboxylic acid 6 (quantitative), which was used without further purification. 1H NMR: (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.14 (s, 1H); LC/MS: (ES+) m/z (M+H)+=198; HPLC Rt=0.47 min., column G.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>C(Cl)(Cl)Cl>[Br:1][C:11]1[C:12]([CH3:14])=[CH:13][C:4]([OH:3])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)cc1O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(C)cc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Bromine (0.47 ml, 9.03 mmol) was added dropwise to a solution of methyl 2-hydroxy-4-methylbenzoate (may be prepared as described in Description 1; 1.5 g, 9.03 mmol) in chloroform (20 ml) at 0° C. The solution was stirred for 1 hour at 0° C. The reaction was quenched with saturated sodium sulphite (10 ml), then extracted with dichloromethane (2×10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a white solid. 2.24 g.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].CCOCC>C(O)C.[Pd]>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccccc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccccc2)cc1
Reaction time: 6 h

Procedure:
A mixture of 2-hydroxy-2-phenylethanamine (17.7 g) and 1-(4-carbomethoxyphenyl) propan-2-one (24.8 g) in ethanol (300 ml) was refluxed for one hour. When cooled, 10% Pd/C (1.0 g) was added and the mixture was hydrogenated on a Parr Hydrogenator at 60° and 60 psi for six hours. The mixture was filtered and the filtrate was evaporated to an oil which was taken up in methanol (75 ml). The solution was allowed to stand at 4° to give crystals (Batch 1). Ether (75 ml) was added to the mother liquors to obtain subsequent crops (Batches 2 & 3). The mother liquors were evaporated to an oil, which was crystallised from ether (Batch 4).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][C@@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Si:17]([O:16][CH2:15][C@H:14]([CH3:24])[CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19]
Reactant: O=C1COc2ccccc2N1
Reactant: C[C@H](CBr)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccccc21
Temperature: 25 °C
Reaction time: 168 h
Yield: 84.6 %

Procedure:
A reaction flask was charged with 4H-Benzo[1,4]oxazin-3-one (1.49 g, 10.0 mmol), (S)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (2.67 g, 10.0 mmol), and Cs2CO3 (4.89 g, 15.0 mmol) in MeCN (15 mL) and stirred at rt for 7 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (2.84 g, 85%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28]C(OC(C)(C)C)=O)=[CH:24][CH:23]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10]>C1(C)C=CC=CC=1>[CH3:8][S:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=2)=[CH:17][CH:18]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Oc1ccc(OCCc2ccc(N)cc2)cc1
Temperature: 60 °C

Procedure:
Trifluoroacetic acid (7.95 mL, 11.8 g, 102 mmol) was added over 5 minutes to a slurry of 4-{2-[4-(tert-butoxycarbonylamino)phenyl]ethoxy}phenyl methanesulfonate (17.6 g @ 95%, 40.8 mmol) in toluene (176 mL) at 20° C., and then heated to 60° C. to form a dark brown solution. A seed of pure product (0.05% by weight) was added and the reaction mixture heated at 60° C. for 17 hours during which period a dense solid crystallized. The reaction mixture was cooled to 20° C. and the solid isolated by filtration, washed by displacement with toluene (26 mL) and dried in a vacuum oven at 40° C. to yield the title compound as a dense, buff-coloured solid (16.1 g, 94%). HPLC (Rt 6.0 mins); m.p. 131-133° C.; 1H NMR (400 MHz, d6-DMSO) δ 7.35 (2H, d, J=8.4 Hz), 7.26 (2H, dt, J=10.8, 3.0 Hz), 7.13 (2H, d, 8.0 Hz), 7.05 (2H, dt, J=10.8, 3.0 Hz), 4.19 (2H, t, J=6.6 Hz), 3.31 (3H, s), 3.02 (2H, t, J=6.6 Hz), 2.9-4.7 (br); 13C NMR (100.6 MHz, d6-DMSO) δ 157.12, 142.46, 135.56, 133.65, 130.04, 123.31, 121.02, 115.45, 68.43, 36.92 and 34.14; MS (ES+) 308 (M+H+, 100%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:39]([NH2:41])[CH3:40]>C1COCC1>[CH2:39]([NH:41][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[N:10]([C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1)[CH3:40]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(-c1ccnc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc([N+](=O)[O-])cc23)ccn1
Temperature: 80 °C
Yield: 36 %

Procedure:
A mixture of 3-(2-fluoro-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole (800 mg, 1.6 mmol) and 2M ethyl amine in THF (20 mL) was heated in a sealed tube at 80° C. for four days. Cooled to room temperature and concentrated. The crude product was purified by column chromatography on silica get eluting with a solution of ethyl acetate in hexane (1:1) to give the title compound (300 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].Cl[C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)C(=O)Cl
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Solvent: ClCCl
Product: COC(=O)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in hexane) afforded the title compound as a solid (0.12 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.60 (d, J=4.4 Hz, 2H), 4.18 (m, 1H), 3.85 (s, 3H); ESIMS m/z 512.22 ([M−H]−); IR (thin film) 1740, 1701, 1114, 808 cm−1.