Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[CH:13]>C(N(CC)CC)C.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][C:11]([OH:15])([CH3:14])[C:12]#[C:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
4-Bromobenzonitrile (30 g), 3-methyl-1-butyne-3-ol (13.4 g), triphenylphosphine (0.7 g) and bis(triphenylphosphine)palladium(II) chloride (0.3 g) were dissolved in triethylamine (140 ml) under nitrogen atmosphere, and then copper(I) iodide (0.1 g) was added thereto. After stirring at room temperature for 1 hour, the reaction mixture was further stirred at 90° C. for 5 hours. The resulting precipitated crystals were filtered, and then triethylamine was distilled off therefrom, followed by extracting with chloroform. The resultant was washed twice with 10% hydrochloric acid, and further with water twice, and then chloroform was distilled off therefrom. The residue was distilled under reduced pressure (140° to 160° C./5 mmHg) to give 3-methyl-1-(4'-cyanophenyl)-1-butyne-3-ol (23.5 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][C:10]([C:14]([OH:17])([CH3:16])[CH3:15])=[CH:9][C:8]=2[F:18])=[N:4][C:3]=1[C:19]([NH2:21])=[O:20].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][CH:24]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:13][C:12]1[CH:11]=[C:10]([C:14]([OH:17])([CH3:16])[CH3:15])[CH:9]=[C:8]([F:18])[C:7]=1[C:5]1[S:6][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]([OH:33])([CH3:31])[CH3:32])=[C:27]([CH3:29])[N:28]=2)=[C:3]([C:19]([NH2:21])=[O:20])[N:4]=1
Reactant: Cc1nc(Cl)ccc1C(C)(C)O
Reactant: CC(C)(O)c1cc(F)c(-c2nc(C(N)=O)c(N)s2)c(F)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)nc2C(N)=O)ccc1C(C)(C)O

Procedure:
The title compound was prepared as described in Example 15, Step 7 using 5-amino-2-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 15, Step 5) (150 mg, 0.48 mmol), 2-(6-chloro-2-methylpyridin-3-yl)propan-2-ol (Example 13, Step 1) (89 mg, 0.48 mmol), Pd2(dba)3 (44 mg, 0.048 mmol), X-PHOS (114 mg, 0.24 mmol), potassium carbonate (66 mg, 0.48 mmol), and tert-amyl alcohol (0.96 ml) as starting materials. 1H NMR (500 MHz, d6-DMSO) δ 11.23 (s, 1H), 7.75 (d, 1H), 7.62 (s, 1H), 7.47 (s, 1H), 7.32 (d, 2H), 7.00 (d, 1H), 5.37 (s, 1H), 5.02 (s, 1H), 2.69 (s, 3H), 1.49 (s, 6H), 1.44 (s, 6H). LRMS (APCI) calc'd for C22H25F2N4O3S [M+H]+ 463.2, found 463.0.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25].[OH-].[Li+].Cl>CO.O>[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Br:25])[C:9]=1[CH3:26])=[O:31]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1Br)CCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1Br)CCC3
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(2-bromobenzyl)-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (106 mg, 0.21 mmol) in methanol (3 mL) was treated with 1 N lithium hydroxide solution (1 mL). The solution was heated to reflux then allowed to cool to room temperature. The mixture was diluted with water and acidified with 1 N hydrochloric acid. The resulting precipitate was collected via vacuum filtration and washed carefully with ethyl acetate to provide 36 mg (35%) of the title compound as a tan solid: mp 261-262° C. (dec). 1H NMR (DMSO-d6) δ 12.88 (bs, 1H), 7.72 (m, 2H), 7.43 (bs, 1H), 7.26 (m, 2H), 6.46 (s, 1H), 6.18 (m, 1H), 5.48 (s, 2H), 4.62 (s, 2H), 2.80 (m, 4H), 2.43 (s, 3H), 1.93 (quintet, J=7.3 Hz, 2H); IR (KBr, cm−1) 3431, 1735, 1628, 1213.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N:6][NH:5][C:4]=1[NH2:8])#[N:2].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH2:31][CH3:32])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:7]=[N:6][N:5]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH2:31][CH3:32])[S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:8][C:4]=12)#[N:2]
Reactant: N#Cc1cn[nH]c1N
Reactant: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN(c1cccc(-c2ccnc3c(C#N)cnn23)c1)S(=O)(=O)c1ccccc1
Yield: 46.7 %

Procedure:
A mixture of 0.15 g (1.38 mmol) of 4-cyano-2H-pyrazol-3-ylamine and 0.50 g (1.38 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-benzenesulfonamide in 10 ml of glacial acetic acid was refluxed for 8 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 10 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 260 mg of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)-phenyl]-N-ethyl-benzenesulfonamide as a yellow solid (yield 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([O:18]C)=[O:17])[N:13]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[N:13]=1
Reactant: COC(=O)/C=C/c1csc(-c2c(F)cccc2Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/c1csc(-c2c(F)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.2 %

Procedure:
To a stirred solution of (E)-methyl 3-(2-(2-chloro-6-fluorophenyl)thiazol-4-yl)acrylate (6.0 g, 20 mmol) in MeOH (100 mL) and H2O (20 mL) was added lithium hydroxide (1.5 g, 61 mmol). The resulting mixture was stirred at room temperature for 24 hours and then partially concentrated under reduced pressure. The pH of the residue was adjusted to 5 by the addition of 2N HCl and the aqueous phase extracted with EtOAc (3×100 mL). The combined organic extract was washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a 0-20% gradient of MeOH in DCM to give the desired product as a white solid (5.4 g, 94% yield). LCMS (ESI) m/z: 284.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]([C:22]1[O:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1)([CH3:21])[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]([CH3:21])[CH3:20])[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: CC(C)c1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C(C)C)oc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-isopropyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.05 min; [M+H]+=418.95.
Reaction SMILES: [C:1]([C:4]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-])=O)[C:5]=1[O:6][CH2:7][C:8](=O)[CH3:9])(=[O:3])[CH3:2].[H][H]>[Ni].C(O)C>[F:15][C:14]1[CH:13]=[CH:12][C:11]2[NH:16][CH:8]([CH3:9])[CH2:7][O:6][C:5]=2[C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)COc1c([N+](=O)[O-])ccc(F)c1C(C)=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(=O)c1c(F)ccc2c1OCC(C)N2
Yield: 67.7 %

Procedure:
A mixture of 4.98 g (19.5 mmole) of 1-(2-acetyl-3-fluoro-6-nitrophenoxy)-2-propanone, 100 ml of 95% ethanol and 1 g of Raney nickel was shaken in an atmosphere of hydrogen at 4.5×105Pa at room temperature for 18 hours. The reaction was filtered and the solvent removed at reduced pressure. The residue was chromatographed on silica, with hexane:ether (1:1) to give 2.76 g of 1-(7-fluoro-3,4-dihydro-3-methyl-2H-1,4-benzoxazin-8-yl)ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:27]=1)([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:28]2[CH:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[O:30][N:29]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)on4)c3)c2cc1OC
Yield: 59 %

Procedure:
The title compound was prepared as described in Example 113C using 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3 mmol) and phenyl 5-isopropylisoxazol-3-ylcarbamate from the previous step (110 mg, 0.45 mmol) to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (79 mg, 59%) as a white solid after purification by preparative HPLC (phenylhexyl reverse phase column). 1H NMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.01 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.41 (t, 2H) 7.27 (d, 1H), 6.99 (d, 1H), 6.49 (s, 1H), 4.00 (s, 6H), 3.01-2.99 (m, 1H), 1.22 (d, 6H); LC-MS (ESI) m/z 450 (M+H)+.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.Cl[C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:15]=2)[CH:10]=[C:9]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[N:8]=1>>[CH3:23][O:22][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]([O:5][CH:3]1[CH2:4][O:1][CH2:2]1)=[N:8][C:9]([NH:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1)=[CH:10]2
Reactant: OC1COC1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Product: COCCOc1cc2c(OC3COC3)nc(Nc3cc(C)[nH]n3)cc2cc1OC

Procedure:
Similar procedure as described in example 400 was used, starting from oxetan-3-ol and [1-Chloro-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine to give [6-Methoxy-7-(2-methoxy-ethoxy)-1-(oxetan-3-yloxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 401 (MH+).
Reaction SMILES: BO[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([CH3:16])([CH3:15])[O:13][C:12]([NH:17][C@H:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[N:11][S:10]2(=[O:37])=[O:36])=[CH:5][CH:4]=1.[C:38]([O-])(=[O:40])[CH3:39].[K+].C(Cl)(=O)C>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Si:22]([O:21][CH2:20][CH2:19][C@H:18]([NH:17][C:12]1[O:13][C:14]([CH3:15])([CH3:16])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:38](=[O:40])[CH3:39])=[CH:8][CH:7]=2)[S:10](=[O:37])(=[O:36])[N:11]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:24])[CH3:23]
Reactant: BOc1ccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3F)=NS2(=O)=O)cc1
Reactant: CC(=O)[O-]
Agent: Cl[Pd]Cl
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CC(=O)Cl
Product: CC(=O)c1ccc(C2C(C)(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c3ccccc3F)=NS2(=O)=O)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a suspension of [5-(4-boroxyphenyl)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propyl]amine (400 mg) and potassium acetate (140 mg) in dioxane (6 ml) were added bis(triphenylphosphine)palladium(II)dichloride (60 mg) and acetyl chloride (120 μl), and the mixture was stirred at 50° C. overnight. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (172 mg) with a molecular weight of 562.8 g/mol (C28H39FN2O5SSi).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10](Br)[CH:11]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[C:20]=2[Cl:21])[CH:11]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: COC(=O)CCc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCc1cncc(-c2cccc(Cl)c2Cl)c1
Reaction time: 0.67 h
Yield: 51.3 %

Procedure:
A mixture of 3-(5-bromo-pyridin-3-yl)-propionic acid methyl ester (155 mg), 2,3-dichlorobenzeneboronic acid (142 mg, 0.744 mmol), PdCl2(dppf).CH2Cl2 adduct (48.6 mg, 0.059 mmol) and Na2CO3 (2 M, 0.929 ml, 1.859 mmol) in DMF (5 ml) was heated at 100° C. After 40 min, solvent was removed in vacuo. The residue was purified via flash column (EtOAc/Heptane=0-20-25%, v/v) to give 3-[5-(2,3-Dichloro-phenyl)-pyridin-3-yl]-propionic acid methyl ester (101 mg, 0.326 mmol, 43% yield). ESI-MS m/z: 310[M+1]+; 1H NMR (CDCl3, 400 MHz) δ 2.71 (t, J=7.6 Hz, 2H), 3.05 (t, J=7.6 Hz, 2H), 3.70 (s, 3H), 7.23 (dd, J=7.6, 1.6 Hz, 1H), 7.30 (t, J=7.6 Hz, 1H), 7.53 (dd, J=7.6, 1.6 Hz, 1H), 7.63 (s, 1H), 8.52 (s, 2H).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25](=[O:28])[CH:26]=[CH2:27])[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[BrH:29].C(OC(C)C)(C)C>C(O)(=O)C>[Br:29][CH2:27][CH2:26][C:25]([C:23]1[N:22]=[CH:21][NH:20][CH:24]=1)=[O:28]
Reactant: C=CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Br
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: O=C(CCBr)c1c[nH]cn1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
1-(1-Trityl-1H-imidazol-4-yl)-2-propen-1-one (29.0 g) was dissolved in acetic acid (130 ml) and the mixture was cooled to 10° C. A 25% solution of hydrogen bromide in acetic acid (100 ml) was added and the mixture was stirred at room temperature for 2 h. Isopropyl ether was added to the reaction mixture and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give the title compound (22.3 g) as a pale yellow powder.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Cl.[CH3:13][CH:14]([N:16]1[CH:20]=[C:19]([CH2:21][C:22]([NH2:24])=[S:23])[N:18]=[CH:17]1)[CH3:15]>>[CH3:15][CH:14]([N:16]1[CH:20]=[C:19]([CH2:21][C:22]2[S:23][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:24]=2)[N:18]=[CH:17]1)[CH3:13]
Reactant: CC(C)n1cnc(CC(N)=S)c1
Reactant: O=C1c2ccccc2CC1Br
Agent: Cl
Product: CC(C)n1cnc(Cc2nc3c(s2)Cc2ccccc2-3)c1

Procedure:
Starting compounds: 2-bromo-1-indanone, [1-(2-propyl)-4-imidazolyl]thioacetamide hydrochloride
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[CH:10][C:9]([CH:12]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:13])=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1
Reactant: CC(=O)c1cnc(OCC2CC2)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC1CC1
Yield: 85 %

Procedure:
The title compound is prepared in 85% yield (4.10 g, colorless oil) from 1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethanone (3.18 g, 15.5 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (2.82 g, 23.3 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:8]2([CH3:20])[NH:13][C:12](=S)[C@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH4+:21].[OH-].C(OO)(C)(C)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH3:20])[CH2:9][O:10][C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:21])=[N:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@]1(c2cccc(Br)c2)CO[C@@](C)(C(F)(F)F)C(=S)N1
Reactant: [NH4+]
Agent: CC(C)(C)OO
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@]1(c2cccc(Br)c2)CO[C@@](C)(C(F)(F)F)C(N)=N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S*,5R*)-5-(3-bromo-phenyl)-2,5-dimethyl-2-trifluoromethyl-morpholine-3-thione (2.5 g, 6.79 mmol) in THF (25 ml) was added concentrated aqueous NH4OH (10.7 ml, 170 mmol) and 80% tert-butylhydroperoxide in H2O (4.25 ml, 33.9 mmol) and the reaction mixture was stirred for 3 h at 25° C. After addition of another 4.25 ml of 80% tert-butyl-hydroperoxide in H2O the reaction mixture was stirred overnight at 25° C. The reaction mixture was slowly added to concentrated sodium metabisulfite solution at 0-10° C., and after addition of 20% aqueous K2CO3 solution the product was extracted with EtOAc. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude title product was used as such for the next transformation. A small amount was purified by flash-chromatography and transferred into the hydrochloride salt with 1N HCl in Et2O to provide the title compound as a white solid: TLC (EtOAc/MeOH 9:1): Rf=0.60; HPLC RtH5=1.024 min; 1H NMR (600 MHz, DMSO-d6): δ 11.55 (s, 1H), 9.54 (d, 2H), 7.74 (s, 1H), 7.60 (d, 1H), 7.51 (d, 1H), 7.42 (t, 1H), 4.15 (d, 1H), 4.06 (d, 1H), 1.75 (s, 3H), 1.66 (s, 3H); ESIMS: 351, 353 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)([O-])=O.[H][H]>C(OCC)(=O)C.CO.[C].[Pd]>[F:14][C:13]([F:15])([F:16])[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[C:8]([NH2:10])[CH:7]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(N)cc(C(F)(F)F)c1
Yield: 101.8 %

Procedure:
In a mixed solvent of 10 mL of ethyl acetate and 1 mL of methanol, 500 mg (2.12 mmol) of 3,5-dinitrobenzotrifluoride was dissolved, and 20 mg of 10% palladium carbon was added thereto, and the mixture solution was stirred at room temperature for 20 hours in a hydrogen atmosphere at normal pressures. The catalyst was removed by filtration, and the filtrate was concentrated and dried to obtain 380 mg (100%) of a brown oily target product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]([S:21]Cl)=[O:20]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][C:19](=[O:20])[S:21][N:15]=2)=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)SCl
Solvent: c1ccccc1
Product: O=c1oc(-c2ccc(OCc3ccccc3)cc2)ns1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
4-benzyloxybenzamide (0.66 g, 2.98 mmol) and 0.26 ml of chlorocarbonyl sulfenyl chloride were dissolved in 10 ml of benzene, refluxed for 3 hours, and stirred at 50° C. for 12 hours. The organic solvent was distilled off under reduced pressure, and the resulting solid was washed with n-hexane to obtain 0.78 g of 5-(4-benzyloxy-phenyl)-[1,3,4]oxathiazol-2-one.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[N:14][CH:13]=[C:12](Cl)[N:11]=1.CCN(C(C)C)C(C)C>>[CH2:1]([NH:8][C:12]1[CH:13]=[N:14][CH:15]=[C:10]([Cl:9])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Clc1cncc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cncc(NCc2ccccc2)n1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-20, benzyl-amine was reacted with 2,6-dichloropyrazine in presence of Hunig's base to give the title compound as a light yellow foam. MS: 220.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[CH2:10].C[Li].CI.O1CC[CH2:25][CH2:24]1>CCOCC>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH2:24][CH3:25])[CH3:10]
Reactant: C=C(c1ccccc1OC)c1ccccc1OC
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CCOCC
Solvent: CI
Product: CCC(C)(c1ccccc1OC)c1ccccc1OC
Reaction time: 2 h

Procedure:
1,1-Bis(2-methoxyphenyl)ethene (5.6 g) was dissolved in 25 ml of tetrahydrofuran and 25 ml of a 1.3M solution of methyl lithium in ether was added dropwise with stirring. The solution became dark red and exothermed. After 2 hours, 5.0 ml of methyl iodide was added slowly with stirring. The solution again exothermed. When all of the methyl iodide had been added the starting material was found to be completely consumed and replaced by a single product by gas-liquid chromatography. About 300 ml of ether was added and the resulting solution was extracted with 100 ml of water and then 100 ml of brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 5.46 g (88 percent of theory) of the title compound as a pale yellow crystalline solid melting at 49-52° C. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH:10]2NS(C1C(C)=CC(OC)=CC=1C)(=O)=O)=[O:6]>CO.O1CCCC1.O.CC(C)=O>[CH2:12]1[C:13]2[C:9](=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)c1ccc2c(c1)C(NS(=O)(=O)c1c(C)cc(OC)cc1C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
LiOH (5 equiv.) was added to a suspension of 3-[[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]amino]-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (C-01) (11.75 mmol) in methanol (40 ml), tetrahydrofuran (40 ml) and water (30 ml) and the reaction mixture was stirred at 25° C. overnight. Methanol and THF were distilled off, the aqueous residue was acidified with 1N HCl and the mixture was filtered. The white solid obtained was taken up in a mixture of 350 ml of acetone and 50 ml of methanol and the mixture was stirred for 1 h. After filtration, the white solid was dried in vacuo to obtain 3-[[(4-methoxy-2,6-dimethyl-phenyl))sulfonyl]amino]-2,3-dihydro-1H-indene-5-carboxylic acid (F-01). Yield: 90%