Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[OH:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[CH2:24][OH:23])=[O:6]
Reactant: OCC1CCCCN1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)N1CCCCC1CO
Yield: 93.2 %

Procedure:
The procedure of Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 3.5 g of 2-hydroxymethylpiperidine were used as starting materials. 7.5 g (yield 94%) of the title compound was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH:24]3[CH2:26][CH2:25]3)=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:27][N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH:24]4[CH2:26][CH2:25]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:2]([N:30]2[CH2:31][CH2:32][N:28]([CH3:27])[C:29]2=[O:33])[CH:7]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2Br)CC1
Reactant: CN1CCNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)cc2N2CCN(C)C2=O)CC1
Yield: 28.2 %

Procedure:
Using (2-bromo-4-chlorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (848 mg) described in Preparation Example 235 and 1-methylimidazolidin-2-one (293 mg) and by the reaction and treatment in the same manner as in Preparation Example 241, the title compound (250 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][C:7]([CH3:19])([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=1)[CH3:8].[C:21](O)(=[O:24])[CH:22]=[O:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)CCl>[CH:16]([C:11]1[C:12]2[O:15][C:22](=[O:23])[CH:21]([OH:24])[C:13]=2[CH:14]=[C:9]([C:7]([CH3:19])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:20])[CH:10]=1)([CH3:17])[CH3:18]
Reactant: O=CC(=O)O
Reactant: COC(=O)CCCC(C)(C)c1ccc(O)c(C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: COC(=O)CCCC(C)(C)c1cc(C(C)C)c2c(c1)C(O)C(=O)O2
Temperature: 25 °C

Procedure:
5-Methyl-5-(4-hydroxy-3-isopropyl phenyl)-hexanoic acid methyl ester (10.0 g), glyoxylic acid (6.4 g of the 50% solution in water) and p-toluene sulphonic acid (40 mg) are heated in 40 ml of ethylene chloride under nitrogen at reflux in an apparatus designed for the removal of water. After 5 hours the reaction mixture is cooled to room temperature, washed two times with 25 ml water, dried over magnesium sulphate and evaporated under reduced pressure to give 13 g of 7-isopropyl-5-(4-methoxycarbonyl-1,1-dimethylbutyl)-3-hydroxy-3H-benzofuran-2-one as a yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]1[C:55]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)=[CH:54][CH:53]=[N:52]1>CN(C=O)C>[CH3:50][N:51]1[C:55]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)=[CH:54][CH:53]=[N:52]1
Reactant: Cn1nccc1-c1cccc(N)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccnn4C)c3)c(=O)oc12
Temperature: 25 °C
Yield: 73.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 77% yield: LCMS (ESI) m/z 376 (MH+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[CH:14]=[CH2:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC#N>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:12]=3[CH:14]=[CH2:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: C=Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CC#N
Product: C=Cc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 54.4 %

Procedure:
A mixture of 1-cyclopropyl-8-ethenyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.40 g, 1.44 mmol), piperazine (0.80 g, 7.8 mmol), and CH3CN (3 mL) was refluxed for 16 hours. Workup was identical to that described in Example 1 to provide 0.28 g (54%) of the desired product; mp 213°-218° dec.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.S(=O)(=O)(O)O.[C:18](=O)([O-])O.[Na+]>CO>[CH3:18][O:11][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2[nH]ccc2c1

Procedure:
A methanol (200 ml) solution of indole-5-carboxylic acid (5.15 g) was refluxed in the presence of concentrated sulfuric acid (3 ml) at 85° C. for 4.5 hours. After the reaction, saturated aqueous sodium hydrogencarbonate solution was added at 0° C. and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulfate, then the solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to obtain indole-5-carboxylic acid methyl ester (4.8 g).
Reaction SMILES: [OH-:1].[K+].[F:3][C:4]([F:16])([F:15])[CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.OO.Cl>CO>[F:3][C:4]([F:15])([F:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:1])=[O:12])=[CH:13][CH:14]=1
Reactant: [OH-]
Reactant: O=Cc1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: O=C(O)c1ccc(OCC(F)(F)F)cc1
Temperature: 65 °C
Yield: 91 %

Procedure:
To a stirred solution of 50% w/v KOH (1.2 ml) and 4-(2,2,2-trifluoroethoxy)-benzaldehyde (0.6 g, 2.94 mmol) in MeOH (5 ml) at 65° C. was added dropwise over 20 min aqueous hydrogen peroxide (30 wt. % in water, 2.4 ml). On completion of the addition the reaction mixture was heated at 65° C. for a further 10 min. On cooling to room temperature, the reaction mixture was acidified with 1 M HCl and extracted with Et2O (3×30 ml). The combined organic extracts were washed with brine (20 ml), dried (Na2SO4) and the solvent removed under reduced pressure to give the title compound (0.59 g, 91%) as a pale yellow solid which was used without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Si]([O:26][C@H:27]([CH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(C(C)(C)C)(C)C>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.C1(C)C=CC=CC=1>[OH:26][C@H:27]([CH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(B(O)O)cc1
Reactant: Cn1cc(I)ccc1=O
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: Cc1ccccc1
Solvent: CCO
Product: Cn1cc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)ccc1=O

Procedure:
Prepared according to the method described in Example 7c) from 5-iodo-N-methylpyridin-2-one (Example 13a), 0.276 g), ethanol (4 ml), toluene (10 ml), 2M aqueous sodium carbonate (0.58 ml), (2R)-4-[2-(tert-butyldimethylsilanyloxy)-4-pyridin-3-yl-butoxy]benzeneboronic acid (Example 7b), 0.471 g), and tetrakis(triphenylphosphine)palladium(0) (0.03 g). After work up, the residue was purified by column chromatography over silica eluting dichloromethane:methanol (95:5) to give the title compound as a foam (0.191 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorophenol and 4-fluorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:19]([C:20]3[C:21](=O)[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH:25]=3)[C:10]3[N:11]=[C:12]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:29]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:19]([C:20]3[C:21](=[S:39])[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH:25]=3)[C:10]3[N:11]=[C:12]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:29]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(N4CCCC4)nc32)c(=O)[nH]c1=O
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(N4CCCC4)nc32)c(=S)[nH]c1=O

Procedure:
The product from step (i) (0.04 g) was treated with Lawesson's reagent (0.037 g) according to the method of example 34 step (iv). Purification was by chromatography eluting with 1:1 ethyl acetate/isohexane to give the title product as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: C1COCCN1
Product: O=S(=O)(CCCCl)N1CCOCC1

Procedure:
The procedure used for the preparation of Intermediate D was used to prepare the title compound from 3-chloropropanesulfonyl chloride and morpholine. High vacuum drying gave the title compound (1.3 g, 104%): 1H NMR (CDCl3) δ: 2.20-2.29 (2H, m), 3.02 (2H, dd), 3.20-3.23 (4H, m), 3.64 (2H, t), 3.68-3.72 (4H, m).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1.S(=O)(=O)(O)O>O>[OH:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cnc(O)c([N+](=O)[O-])c1
Temperature: 45 °C

Procedure:
Fuming nitric acid (10.4 mL) was added dropwise to a mixture of 6-hydroxynicotinic acid (15 g) and concentrated sulfuric acid(45 mL) at 0° C. The reaction mixture was slowly heated to 45° C. and maintained at the same temperature for 3 hours. The mixture was poured into a mixture of ice and water. The resultant precipitate was collected by suction filtration, washed with water, and air-dried to give 6-hydroxy-5-nitronicotinic acid (8.63 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: Cc1ccc2cc(F)ccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2nc(CBr)ccc2c1
Temperature: 25 °C

Procedure:
To a solution of 6-fluoro-2-methylquinoline (see C. M. Leir, J. Org. Chem., vol 42, pp 911-913, 1977) (21.67 g) in carbon tetrachloride (700 mL) were added N-bromosuccinimide (26.32 g) and benzoyl peroxide (1.62 g). The mixture was brought to reflux with two spot lights of 150 Watts. The mixture was irradiated for 24 hours at reflux. The mixture was then cooled to room temperature, evaporated to dryness and chromatographed on flash silica gel using pure toluene as eluant to give, as the slower running compound, a beige solid (11.9 g); m.p. 90°-92° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:26][CH2:25]2)=[C:20]([C:34]([F:37])([F:36])[F:35])[CH:19]=1.B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:30]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:6]5[CH:7]=[N:8][C:9]6[C:4]([CH:5]=5)=[CH:3][CH:2]=[CH:11][CH:10]=6)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:19][C:20]=2[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]1)(=[O:33])[CH2:31][CH3:32]
Reactant: CCOC(=O)c1cnc2ccc(Cl)cc2c1Nc1ccc(N2CCN(C(=O)CC)CC2)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2ccc(-c3cnc4ccccc4c3)cc2c1Nc1ccc(N2CCN(C(=O)CC)CC2)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 71.7 %

Procedure:
To a solution of compound 5.2 ethyl 6-chloro-4-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)quinoline-3-carboxylate (1 g, 1.6 mmol, 1 equiv.) in dioxane (5 mL) at room temperature was sequentially added 3-qunionline boronic acid 5.3 (350 mg, 2 mmol, 1.1 equiv.), PdCl2(Ph3P)2 (130 mg, 0.19 mmol, 0.1 equiv.), t-Bu-Xphos (78 mg, 0.19 mmol, 0.1 equiv.) and Na2CO3 (1N, 5.5 mL, 5.5 mmol, 3 equiv.). The mixture was degassed, sealed under argon, and heated overnight at 100° C. Upon cooling to room temperature, the mixture was diluted with EtOAc (20 mL), filtered through celite, and washed with EtOAc (20 mL×2). The resulting solution was concentrated and the residue was purified via flash chromagraphy (CH2Cl2: MeOH=30:1) to afford the desired product 5.4 ethyl 4′-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)-3,6′-biquinoline-3′-carboxylate (360 mg; 31%). LC-MS: (M+H): 535.20
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][CH3:15])[CH2:9][CH2:10][NH:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:27]>O1CCCC1>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:26](=[O:27])[N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][CH3:15])=[CH:30][CH:31]=1
Reactant: CCNCCN(CC)C(=O)OC(C)(C)C
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(CCN(CC)C(=O)OC(C)(C)C)C(=O)Oc1ccc(OC)cc1
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A solution of N-tert.-butoxycarbonyl-N,N'-diethylethylenediamine (3.22 g, 15 mmol) and N,N-diisopropylethylamine (2.6 mL, 15 mmol) in tetrahydrofuran (100 mL) was added over 1 hour to a stirred, cooled solution of 4-methoxyphenyl chloroformate (2.78 g, 15 mmol) in tetrahydrofuran (50 mL). After stirring at 20°-25° overnight, solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic extract was washed with brine, dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue over silica gel and elution with 10-20% ethyl acetate-90-80% n-butylchloride gave 3.53 g of the carbamate as an oil.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[H-].[Na+].[CH3:15]I>C1COCC1>[CH3:15][O:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccccc1)C(=O)O
Temperature: 65 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
(S)-2-Hydroxy-3-phenylpropanoic acid (1.0 g, 6.02 mmol) was dissolved in THF (100 ml), sodium hydride (0.48 g, 12.00 mmol) and methyl iodide (1.71 g, 12.04 mmol) were added, and the mixture was stirred at 65° C. for one hour. After leaving to cool, the reaction solution was concentrated under reduced pressure and adjusted to pH 4 by adding a 6 M aqueous hydrochloric acid solution thereto. The aqueous layer was extracted with ethyl acetate, the organic layer was concentrated, and the resulting residue was purified by column chromatography (dichloromethane:methanol=10:1) to afford the title compound (0.71 g, 59%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[O:34][C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>O1CCCC1>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[O:34][C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4o3)CC2)c2ccccc2-c2ccccc21

Procedure:
A solution of 0.3 g (0.7 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide, 0.2 g (0.98 mmol) of 2-(piperazin-1-yl)-benzoxazole and 1 ml of triethylamine in 10 ml of tetrahydrofuran is refluxed for 48 hours. The reaction mixture is then poured onto water, extracted twice with dichloromethane and the combined organic phases are dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:14][CH2:15][CH2:16][Cl:17])[CH:3]=1
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(N)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N)cc1OCCCCl
Temperature: 60 °C
Reaction time: 6 h
Yield: 94.2 %

Procedure:
To a solution of methyl 4-amino-2-hydroxybenzoate (500 mg, 2.99 mmol) and 1-bromo-3-chloropropane (0.294 mL, 2.99 mmol) in DMF (3 mL) was added CESIUM CARBONATE (1462 mg, 4.49 mmol). The resulting mixture was stirred at 60° C. for 6 hrs. The reaction mixture was poured into water, extracted with ethyl acetate, washed with brine, dried over MgSO4, concentrated. The crude product was purified by silica gel chromatography using a gradient of 20-50% EtOAc/Hexanes to give 686 mg (94%) methyl 4-amino-2-(3-chloropropoxy)benzoate.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][C:14]1[N:19]=[C:18]([O:20][CH:21]([F:23])[F:22])[CH:17]=[C:16]([CH3:24])[N:15]=1>C(Cl)Cl>[CH3:12][S:13]([C:14]1[N:19]=[C:18]([O:20][CH:21]([F:23])[F:22])[CH:17]=[C:16]([CH3:24])[N:15]=1)=[O:6]
Reactant: CSc1nc(C)cc(OC(F)F)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(OC(F)F)nc(S(C)=O)n1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A suspension of 20.6 g (0.1 mol) of 3-chloroperoxybenzoic acid in 100 ml of methylene chloride is cooled to a temperature of between -15° C. and -20° C., and there is then added dropwise a solution of 20.6 g (0.1 mol) of 2-methylthio-4-difluoromethoxy-6-methylpyrimidine in 50 ml of methylene chloride. After the reaction mixture has been stirred for 1 hour at the same temperature, it is diluted with methylene chloride; it is subsequently washed with a sodium hydrogen carbonate solution and water, dried over sodium sulfate and concentrated by evaporation. Crystallisation of the residue from a methylene chloride/petroleum ether mixture yields 21.6 g (97% of theory) of 2-methylsulfinyl-4-difluoromethoxy-6-methylpyrimidine, m.p. 105°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[C:4]([F:16])[CH:3]=1.[Br-].[Cl-].[NH4+].O.[CH2:21]1[CH2:25]OC[CH2:22]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:9][S@:10]([C:12]([CH3:13])([CH3:15])[CH3:14])=[O:11])[CH:22]2[CH2:21][CH2:25]2)=[C:4]([F:16])[CH:3]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccc(Cl)cc1F
Reactant: C1CCOC1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(Cl)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step 1 To a solution of (S)-2-methyl-propane-2-sulfinic acid 1-(4-chloro-2-fluoro-phenyl)-meth-(E)-ylideneamide (26.2 g, 0.1 mol, 1.0 eq) in anhydrous THF (700 ml) at −75° C. was added 0.5M cyclopropylmagensium bromide in THF (400 ml, 0.2 mol, 2.0 eq) dropwise at <−65° C. over 30 min. The reaction was stirred for 2 hours at <−65° C. then allowed to warm to room temperature and stirred for 4 hours. Saturated ammonium chloride solution (300 ml), was added, followed by water (150 ml). The layers were separated and the aqueous extracted with EtOAc (3×200 ml). The combined organic layers were washed with sat. brine (300 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by column chromatography on silica (500 g), eluting with 10% EtOAc/heptanesup to 80% EtOAc. (S)-2-Methyl-propane-2-sulfinic acid [(R)-(4-chloro-2-fluoro-phenyl)cyclopropyl-methyl]-amide was isolated in two batches (combined yield 26.4 g, 86.9 mmol, 87%): 1st batch; 18.4 g 1H NMR 4:1 mixture of diastereomers in favour of desired isomer, 2nd batch; 8 g 1H NMR 19:1 mixture of diastereomers in favour of desired isomer. The 2nd batch was repurified by column chromatography on silica (500 g), eluting with 10% EtOAc/heptanesup to 80% EtOAc, to give 6.6 g of pure (S)-2-methyl-propane-2-sulfinic acid [(R)-(4-chloro-2-fluoro-phenyl)-cyclopropyl-methyl]-amide. 1H NMR (270 MHz, CDCl3): 7.33 (1H, t), 7.11 (1H, dd), 7.08 (1H, dd), 3.86 (1H, dd), 3.56 (1H, d), 1.28-1.22 (1H, m), 1.18 (9H, s), 0.90-0.80 (1H, m), 0.74-0.64 (1H, m), 0.56-0.35 (2H, m).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([Cl:10])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.O1CCOC[CH2:16]1>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]>[Cl:10][C:5]1[N:6]([CH3:9])[C:7](=[O:8])[C:2]([CH3:16])=[CH:3][C:4]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C1COCCO1
Reactant: COC(=O)c1cc(Br)c(=O)n(C)c1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COC(=O)c1cc(C)c(=O)n(C)c1Cl
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 73 %

Procedure:
An oven dried two-necked flask was charged with methyl 5-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (5.79 g, 20.64 mmol), Pd(dppf)2Cl2 (0.82 g, 1.0 mmol) and dioxane (60 mL). The resulting red suspension was purged with argon for 10 min and ZnMe2 (2.0M, 10.3 mL, toluene) was added. The reaction mixture was stirred at 70° C. for 50 min, cooled at room temperature and quenched with MeOH (50 mL) and diluted with EtOAc (100 mL). The mixture was washed with a sat NH4Cl aq. solution, the organic layer was dried (Na2SO4) and concentrated under reduced pressure yielding to a brown residue. The residue was purified by flash chromatography (Biotage system) using a gradient of EtOAc (0-30%) in hexane to afford the title product (3.23 g, 73%).