Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]=2[OH:18])[CH:5]=[CH:6][CH:7]=1.CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]2[O:18][C:9]3[CH:10]=[CH:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:8]=3[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2ccccc2c1-c1cccc(Cl)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1cccc2c1oc1ccc3ccccc3c12
Yield: 104.3 %

Procedure:
In a 300-mL recovery flask were put 3.1 g (11 mmol) of 1-(3-chloro-2-fluorophenyl)-2-naphthol, 70 mL of N-methyl-2-pyrrolidone, and 4.2 g (31 mmol) of potassium carbonate, and this mixture was stirred at 150° C. in air for 7 hours. After stirring, about 50 mL of water and about 50 mL of hydrochloric acid (1.0 mol/L) were added to the resulting mixture. To the resulting solution was added about 100 mL of ethyl acetate; then, the aqueous layer was subjected to extraction with ethyl acetate three times. The solution of the extract combined with the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and magnesium sulfate was then added. The mixture was gravity-filtered, and the resulting filtrate was concentrated to give 2.9 g of a pale brown solid of a target substance in a yield of over 99%.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([N:5]([CH2:15][C@H:16]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:2]([F:1])([F:28])[C:3]([N:5]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N(C[C@H]1CCNC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)acetamido) methyl)pyrrolidine-1-carboxylate (1.28 g, 3.10 mmol) in dichloromethane (DCM) (12 mL) was added TFA (3 ml, 38.9 mmol), and the mixture was stirred at room temperature for 3 h. The mixture was concentrated and the residue was treated with saturated NaHCO3 solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dried under vacuum to give 950 mg of product as pale yellow oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([O:36][C:37]([C:39]1[O:40][C:41]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][C:42]=2[CH:43]=1)=[O:38])[CH3:35].[F:49][C:50]([F:61])([F:60])[CH:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH2:58]O)[CH2:53][CH2:52]1>C(Cl)Cl>[CH2:34]([O:36][C:37]([C:39]1[O:40][C:41]2[CH:47]=[CH:46][C:45]([O:48][CH2:58][CH2:57][N:54]3[CH2:55][CH2:56][CH:51]([C:50]([F:60])([F:49])[F:61])[CH2:52][CH2:53]3)=[CH:44][C:42]=2[CH:43]=1)=[O:38])[CH3:35]
Reactant: CCOC(=O)c1cc2cc(O)ccc2o1
Reactant: OCCN1CCC(C(F)(F)F)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(OCCN3CCC(C(F)(F)F)CC3)ccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
To a solution of 4-trifluoromethylpiperidine hydrochloride (1 g, 5.3 mmol) in THF (20 mL) was added methylbromoacetate (0.52 mL, 5.5 mmol) and triethylamine (2.2 mL, 15.8 mmol). The reaction was heated at reflux for 4 h and then diluted with water (50 mL) and the product extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester as a brown oil (1.19 g, 98%). MS 226 (M+H)+. To a solution of (4-trifluoromethylpiperidin-1-yl)acetic acid methyl ester (1.19 g, 5.3 mmol) in THF (15 mL) at 0° C. was added portion wise lithium aluminium hydride (0.4 g, 10.6 mmol). Once the effervescence had ceased the reaction was heated at 60° C. for 1.5 h. The reaction was quenched with water (10 mL) followed by sodium hydroxide solution (2N, 10 mL) then water (10 mL). The reaction was filtered and the filtrate extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with brine, dried over magnesium sulphate and concentrated in vacuo to yield 2-(4-trifluoromethylpiperidin-1-yl)-ethanol as a brown oil (1.0 g, 99%). MS 198 (M+H)+. To a solution of diisopropylazodicarboxylate (0.58 mL, 2.28 mmol) in DCM (20 mL) was added polymer supported triphenylphosphine (1.14 g, 3.4 mmol). The reaction was stirred at RT for 10 mins. 5-Hydroxybenzofuran-2-carboxylic acid ethyl ester (0.47 g, 2.3 mmol) and 2-(4-trifluoromethylpiperidin-1-yl)-ethanol (0.45 g, 2.28 mmol) were added and the reaction stirred at RT for 16 h. The reaction was filtered and the filtrate concentrated in vacuo. The product was purified on silica eluting with 50% tert-butyl methyl ether in n-heptane to yield 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester as a yellow solid (548 mg, 62%). MS 386 (M+H)+. To a solution of 5-[2-(4-trifluoromethylpiperidin-1-yl)ethoxy]benzofuran-2-carboxylic acid ethyl ester (548 mg, 1.42 mmol) in THF (5 mL) and water (1 mL) was added lithium hydroxide (45 mg, 2.84 mmol). The reaction was stirred at RT for 16 h. The THF was removed in vacuo and the remaining aqueous solution dried overnight in a freeze dryer to yield the crude title compound as a brown solid. MS 358 (M+H)+ which was used directly for coupling with H2N-Leu-P1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([F:19])[CH:13]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([F:19])[CH:13]=2)=[N:28]\[OH:29])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)cc(F)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2cccc(Br)c2)c2ccccc2C)=N/O)cc(F)n1

Procedure:
In analogy to example 74, step 7, from 3-(3-bromo-phenyl)-1-(2-fluoro-6-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI+): m/z=427.0801 ([M+H]+, 1Br).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][N:37]=1)CCC.N#N>C1COCC1.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>[CH3:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:33]4[S:34][CH:35]=[CH:36][N:37]=4)[N:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4nccs4)n3)cnc2n1
Yield: 56.6 %

Procedure:
A solution of 3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (prepared as in Example 34) (200 mg, 0.50 mmol) and 2-tributylstannylthiazole (370 mg, 1.0 mmol) in THF (10 ml) was degassed with a stream of N2 for 10 min, then tetrakis(triphenylphosphine)palladium(0) (29 mg, 5 mol %) was added and the reaction heated at reflux for 5 h. The mixture was concentrated under reduced pressure while dry loading onto silica and then purified by column chromatography on silica using 100% EtOAc as the eluent to afford 7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(thiazol-2-yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine (128 mg, 57%); m/z (ES+) 453 (M+H+).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[N:6]([CH3:26])[C:7]([C:16]2[S:17][C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH2:25])[C:23]=3[N:24]=2)=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1>CO>[CH3:1][O:2][C:5]1[N:6]([CH3:26])[C:7]([C:16]2[S:17][C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH2:25])[C:23]=3[N:24]=2)=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Yield: 78 %

Procedure:
Sodium methoxide (31 mg) was added to a solution of 2-(2-bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (22 mg) in MeOH (1 mL). The reaction was stirred and refluxed for 4 days with further sodium methoxide (31 mg) added each day. The solvent was evaporated in vacuo and water (5 mL) added. Extracted with DCM (2×5 mL) and the combined organics were dried over MgSO4, filtered and the solvent evaporated in vacuo to give a white solid (15 mg, 78%);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([NH:8][C:9]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:43]=[O:44])C>C1COCC1>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[C:5]2[C:4]=1[CH:43]([OH:44])[N:8]([C:9]([CH3:17])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])[C:6]2=[O:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:18]([CH:43]([OH:44])[N:8]([C:9]([CH3:17])([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[C:6]2=[O:7])=[CH:19][CH:20]=1
Reactant: COc1cccc(C(=O)NC(C)(C)c2ccccc2)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2c(c1)C(=O)N(C(C)(C)c1ccccc1)C2O
Product: COc1cccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 66 %
Yield: 17 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-methoxy-N-(1-methyl-1-phenylethyl)benzamide (6.00 g, 22.3 mmol) was dissolved in THF (240 mL), and the solution was treated with TMEDA (10.8 mL, 71.3 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 72.0 mL, 71.3 mmol) and DMF (3.80 mL, 49.0 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=2/1, 1/1) to obtain 4-methoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (4.36 g, yield 66%) and 6-methoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (1.12 g, yield 17%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10]O)=O)(C)(C)C.[OH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:8][CH2:9][CH2:10][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a cooled (0° C.) solution of 2-(N-tert-butoxycarbonylamino)ethanol (3.20 g, 19.9 mmol), methyl 4-hydroxybenzoate (3.02 g, 19.9 mmol) and Ph3P (6.25 g, 23.8 mmol) in THF (50 ml) was added dropwise DIAD (4.69 ml, 23.8 mmol) over for 5 min. The reaction mixture was heated under reflux for 3 hr. The mixture was evaporated and the residue was dissolved in CH2Cl2 (30 ml) and TFA (30 ml). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was dissolved in CHCl3 and H2O. The solution was made basic by sat. NaHCO3 and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (30:1, v/v) as eluent to give methyl 4-(2-aminoethoxy)benzoate (1.03 g, 34% for 2 steps) as a colorless oil. 1H-NMR (CDCl3) δ 3.10–3.13 (m, 2 H), 3.89 (s, 3 H), 4.03–4.06 (m, 2 H), 6.92–6.94 (m, 2 H), 7.98–8.00 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[F:11].[Br:12]N1C(=O)CCC1=O.Cl(O)(=O)(=O)=O.CCCCCC>C(Cl)(Cl)(Cl)Cl>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][C:8]([Br:12])=[C:3]([O:2][CH3:1])[C:4]=1[F:11]
Reactant: COc1cccc(OC)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: COc1ccc(Br)c(OC)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
2-fluoro resorcinol (prepared according to Patrick, T. B., et al., J. Org. Chem (1986), 51, 3242-4) (12.8 g, 100 mmol), potassium carbonate (42 g, 0.3 mol), and methyl iodide (25 mL, 0.4 mol) were mixed with acetone (300 mL) and refluxed for 6 hrs. The reaction was poured into ice-water (500 mL) and extracted in ethyl acetate (500 mL). The ethyl acetate was washed with water (200 mL×2), and brine (200 mL×1), dried over sodium sulfate, filtered, and solvent was removed to yield 14.2 grams (91%) of 1,3-dimethoxy 2-fluoro benzene. This fluoro-benzene intermediate (23.19 g, 148.5 mmoL), N-bromo succinimide (26.52 g, 149 mmol), and 300 uL of 70% aqueous perchloric acid (Aldrich Chemical, 3.4 mmoL) were mixed in carbon tetrachloride (100 mL) and stirred at room temperature for 1 hour. The mixture was filtered, and solvent was removed to obtain a yellow oil. The oil was subjected to silica-gel chromatography (silica gel, hexane mobile phase) to yield 33.28 grams (95%) of the 1,3-dimethoxy-4-bromo-2-fluorobenzene 12 compound as a yellow oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[C:5](=[O:7])[CH3:6]
Reactant: COc1ccc(OC)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(OC)c(C(C)=O)c1
Reaction time: 3 h
Yield: 94.8 %

Procedure:
19.3 g of AlCl3 are placed in 200 ml of CCl4 at +5° C. under nitrogen and 11.36 g of acetyl chloride are added, followed by portionwise addition of 20 g of 1,4-dimethoxybenzene. After stirring for 3 hours at +5° C., the mixture is poured into dilute ice-cold HCl solution. The organic phase is separated out and dried over MgSO4 and evaporated, and the residue is then chromatographed on silica, eluting with a DCM/heptane mixture (50/50; v/v) to give 24.71 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][C:13]([NH2:15])=[O:14])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C[O:17][C:18](=O)[C:19]([C:21]1[C:31]2=[C:32]3[C:27](=[CH:28][C:29]([F:33])=[CH:30]2)[C:26]([CH3:35])([CH3:34])[CH2:25][CH2:24][N:23]3[CH:22]=1)=O>>[CH3:34][C:26]1([CH3:35])[C:27]2[C:32]3=[C:31]([C:21]([C:19]4[C:18](=[O:17])[NH:15][C:13](=[O:14])[C:12]=4[C:7]4[C:6]5[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[NH:9][CH:8]=4)=[CH:22][N:23]3[CH2:24][CH2:25]1)[CH:30]=[C:29]([F:33])[CH:28]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cc(F)cc13)C(C)(C)CC2
Reactant: COc1ccc2c(CC(N)=O)c[nH]c2c1
Product: COc1ccc2c(C3=C(c4cn5c6c(cc(F)cc46)C(C)(C)CC5)C(=O)NC3=O)c[nH]c2c1

Procedure:
Beginning with (6-methoxyindol-3-yl)acetamide and (6,6-dimethyl-8-fluoro-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.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.COCCOC>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CSc1ccc(B(O)O)cc1
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: [Na+]
Solvent: COCCOC
Product: CSc1ccc(-c2ccc(O)cn2)cc1
Temperature: 80 °C
Yield: 69 %

Procedure:
A mixture of [4-(methylthio)phenyl]boronic acid (7.2 g, 43.1 mmol), 6-bromo-3-pyridinol (5 g, 28.7 mmol), 2M Na2CO3 (44 mL), Pd(PPh3)4 (1.7 g, 1.4 mmol) and DME (70 mL) was degassed with N2 for 30 min, and stirred and heated at 80° C. for 18 h. The mixture was charged with water and CH2Cl2 and the organic layer was washed with 1N NaOH (100 mL). The basic aqueous layer was washed with Et2O, cooled in an ice bath and the pH was adjusted to about 10 with 6N HCl. The resulting solid was collected, washed with water and air-dried to give 6-[4-(methylthio)phenyl]-3-pyridinol (4.3 g, 69%) as a yellow solid. The reaction was repeated on twice the scale (10 g of 6-bromo-3-pyridinol) to provide 9.1 g (72%) of product. The reaction was repeated on 10× the scale (101.5 g of 6-bromo-3-pyridinol) to provide 53.7 g of product. 1H NMR (400 MHz, DMSO-d6): δ 9.96 (s, 1H), 8.15 (d, 1H, J=2.6 Hz), 7.87 (d, 2H, J=8.6 Hz), 7.73 (d, 1H, J=8.7 Hz), 7.27 (d, 2H, J=8.6 Hz), 7.18 (dd, 1H, Ja=8.6 Hz, Jb=2.9 Hz), 2.46 (s, 3H); LRMS (ESI), m/z 218 (M+H).
Reaction SMILES: C([O:3][C:4]([NH:6][N:7]([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9])=O)C.[CH3:13][SH:14]>O>[CH:10]([N:7]1[C:8]([S:14][CH3:13])=[N:9][C:4]([OH:3])=[N:6]1)([CH3:12])[CH3:11]
Reactant: CS
Reactant: CCOC(=O)NN(C#N)C(C)C
Solvent: O
Product: CSc1nc(O)nn1C(C)C
Temperature: 120 °C
Reaction time: 24 h
Yield: 52.7 %

Procedure:
1370 g of 2-isopropyl-2-cyanohydrazinecarboxylic acid ethyl ester is placed into an autoclave, and 423 g of methyl mercaptan is injected. The temperature is held for 24 hours at 40° C. The resulting crystal mass is afterwards transferred to a 2.5 liter sulphonating flask, and heated in an oil bath for 2 1/2 hours at 120° C. There is then added to the reaction mixture cooled to 90° C 1.2 liters of water, whereupon the the reaction product precipitates in crystalline form. Crude 1-isopropyl-5-methylthio-3-hydroxy-1,2,4-thiazole is filtered off, and recrystallised from one liter of acetonitrile. There is obtained 730 g (52% of theory) of pure 1-isopropyl-5-methylthio-3-hydroxy-1,2,4-triazole, m.p. 88°-93° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[CH:26]=[CH:25][C:24](=[O:27])[C:23]([O:28][CH3:29])=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[CH:26]=[CH:25][C:24](=[O:27])[C:23]([O:28][CH3:29])=[CH:22][CH:21]=1)=[O:17]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: COc1ccc(N)ccc1=O
Solvent: Cc1ccccc1C
Product: COc1ccc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)ccc1=O
Reaction time: 8 h
Yield: 5.2 %

Procedure:
In a nitrogen atmosphere, a solution of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (4.0 g) and 5-amino-2-methoxy-2,4,6-cycloheptatrien-1-one (2.7 g) in xylene (100 ml) is refluxed for 6 hours. The reaction mixture is then allowed to stand at room temperature overnight. The crystals that have separated out are collected by filtration and purified by silica gel (40 g) column chromatography using methanol-dichloromethane (5:95) as the eluent. The resulting crude product is recrystallized from dioxane-methanol to give 4-hydroxy-2-methyl-N-(2-methoxy-1-oxo-2,4,6-cycloheptatrien-5-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.3 g), m.p. 215°-218° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[C:16]([F:25])[CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:4][CH2:3]1.[Li+].[OH-]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:33])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[C:16]([F:25])[CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccc(C)cc2)CCC3(C)C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
To a solution of 0.088 g (0.19 mmol) of ethyl 4-(2-(4,4-dimethyl-1,2,3,4-tetrahydro-N-(4-methylphenyl) quinolin-7-yl)ethynyl)-2-fluorobenzoate (Compound 11) in 3.0 mL of tetrahydrofuran and 0.5 mL of methanol was added 0.5 mL (0.5 mmol) of 1.0M aqueous LiOH. The resulting solution was stirred at room temperature for 72 hours. The mixture was concentrated in vacuo, water was added, and the mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by recrystallization from acetonitrile to give the title compound as a solid (77 mg, 90%). PNMR (300 MHz, d6-acetone) d 1.36 (6 H, s), 1.40 (3 H, t, J=7.1 Hz), 1.86 (2 H, t, J=5.9 Hz), 2.34 (3 H, s), 3.62 (2 H, t, J=5.9 Hz), 6.64 (1 H, d, J=1.6 Hz), 6.86 (1 H, dd, J=8.0, 1.6 Hz), ), 7.17 (2 H, d, J=8.3 Hz), 7.25-7.37 (5 H, m), 7.92 (1 H, t, J=7.8 Hz).
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH:5]1[OH:17])=[N+:2]=[N-:3].[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19].[N:1]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[OH:17])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])C(O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NC1CCNCC1O

Procedure:
Compound 201B (44 mg, 0.18 mmol) was treated with a mixture of CH2Cl2 and TFA (1:1, 2 mL) for 30 min. The volatiles were removed under reduced pressure and the residue was azeotropically evaporated with heptane-CH2Cl2 three times to give a TFA salt of Compound 201C, which was used immediately in the next reaction without step further purification.
Reaction SMILES: [CH:1]1([N:6]([C@@H:11]2[CH2:16][C:15]3[C:17]([O:22]C)=[CH:18][CH:19]=[C:20]([F:21])[C:14]=3[O:13][CH2:12]2)[CH:7]2[CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N>Br>[CH:1]1([N:6]([C@@H:11]2[CH2:16][C:15]3[C:17]([OH:22])=[CH:18][CH:19]=[C:20]([F:21])[C:14]=3[O:13][CH2:12]2)[CH:7]2[CH2:10][CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(F)c2c1C[C@@H](N(C1CCCC1)C1CCC1)CO2
Agent: Br
Agent: N
Product: Oc1ccc(F)c2c1C[C@@H](N(C1CCCC1)C1CCC1)CO2
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 102.3 %

Procedure:
(R)-3-(N-Cyclopentyl-N-cyclobutylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (0.53 g, 1.6 mmol) was dissolved in 47% HBr (15 mL) and stirred at 120° C. for 1.5 h. The solution was cooled by adding ice and alkalised by 14M ammonia. Extractive work-up gave 0.5 g of the title compound as a slightly brown oil. IR contained a typical OH-band at 3654 cm-1.