Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8](=[O:46])[NH:9][C:10]2[CH:44]=[CH:43][C:13]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:39][CH2:40][O:41][CH3:42])C(=O)OC(C)(C)C)=[CH:26][CH:25]=5)[S:23][C:16]=34)=[C:12]([F:45])[CH:11]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:45][C:12]1[CH:11]=[C:10]([NH:9][C:8]([NH:7][S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:5])=[O:6])=[O:46])[CH:44]=[CH:43][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][NH:31][CH2:39][CH2:40][O:41][CH3:42])=[CH:28][N:29]=3)[S:23][C:16]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NS(=O)(=O)C5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NS(=O)(=O)C5CC5)cc4F)c3s2)nc1
Reaction time: 4 h

Procedure:
To a solution of the 375 (140 mg, 0.208 mmol) in DCM (5 ml) was added HCl in dioxane (0.5 ml, 2 mmol, 9.6 eq, 4M in dioxane) and the reaction mixture was stirred for 4 hours. The mixture was diluted with EtOAc, made basic with NaHCO3 solution and extracted with EtOAc/acetone. The organic phase was collected and discarded. The aqueous phase was concentrated and the residue was suspended in a mixture of DCM and acetone. The solution phase was collected, dried with Na2SO4, filtered and concentrated to afford 376 as a beige solid after further trituration with Et2O (yield 8 mg, 7%). 1H NMR (DMSO-d6): 8.67 (s, 1H), 8.56 (s, 1H), 8.47 (d, J=5.28, 1H), 8.27 (s, 1H), 8.19 (d, J=8.02 Hz, 1H), 7.85 (m, 2H), 7.80 (s, 1H), 7.22 (m, 2H), 6.59 (d, J=5.28 Hz, 1H), 3.76 (s, 2H), 3.40 (m, 2H), 3.20 (s, 3H), 2.76 (m, 1H), 2.60 (m, 2H), 0.75 (m, 2H), 0.65 (m, 2H). LRMS (ESI): (calc.) 571.64 (found) 572.58 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O>[ClH:1].[N:20]1([C:2]2[C:13]3=[C:14]4[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]3)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]4=[CH:4][CH:3]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: CC1CCc2c(Cl)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: CC1CCc2c(N3CCNCC3)ccc3c(=O)c(C(=O)O)cn1c23
Product: Cl
Yield: 20.7 %

Procedure:
19.5 g of 8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 35.5 g of piperazine were added to 350 ml of anhydrous dimethyl sulfoxide and the mixture was heated on an oil bath at 170° to 180° C. for 6 hours while stirring. Treatment of the reaction mixture in the same manner as in Reference Example 25 gave 5.3 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrochloride as white amorphous crystals having a melting point of 300° C. or more.
Reaction SMILES: I[CH2:2][CH2:3][C@H:4]1[CH2:6][C@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[OH:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][NH:26][C:27]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([C:34]#[N:35])[CH:28]=2)=[CH:23][CH:22]=1.[H-].[Na+].[CH3:40]N(C=O)C>>[C:34]([C:29]1[N:30]=[C:31]([CH3:33])[N:32]=[C:27]([N:26]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:40])=[CH:37][CH:36]=2)[CH2:2][CH2:3][C@H:4]2[CH2:6][C@H:5]2[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:28]=1)#[N:35]
Reactant: Cc1nc(C#N)cc(NCc2ccc(O)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCC([C@@H]2C[C@@H]2CCI)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN(CC[C@H]2C[C@H]2C2CCN(C(=O)OC(C)(C)C)CC2)c2cc(C#N)nc(C)n2)cc1
Reaction time: 0.17 h

Procedure:
Rac-cis-tert-butyl 4-[2-(2-iodoethyl)cyclopropyl]piperidine-1-carboxylate (86 mg, 0.23 mmol) from Step 3 of this example and 6-[(4-hydroxybenzyl)amino]-2-methylpyrimidine-4-carbonitrile (63.4 mg, 0.25 mmol) from Step 2 of this example were dissolved in DMF (2.3 mL), sodium hydride (18 mg, 0.45 mmol) was added. After 10 minutes, the reaction was quenched with saturated ammonia chloride solution (5 mL), extracted with ethyl acetate (10 mL), second washed with brine (5 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by preparative-TLC (Analtech Silica Gel GF 1500 μM, 20×20 cm) using 30% ethyl acetate/hexane to give the title compound as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22].O>C(Cl)(Cl)Cl>[C:21]([NH:2][CH2:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](CNC(C)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl trans-4-(aminomethyl)cyclohexanecarboxylate hydrochloride (5.86 g) and triethylamine (12 mL) in chloroform (100 mL) is added dropwise acetyl chloride (2.69 g) under ice-cooling and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into water and the mixture is extracted with chloroform (×2). The combined extracts are washed successively with 10% HCl, saturated brine, a saturated sodium hydrogencarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=1:1→0:1) to give methyl trans-4-(acetylaminomethyl)cyclohexanecarboxylate (5.92 g, yield; 98%) as an amorphous powder. MS (APCI) m/z; 214 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([OH:6])=O.[C:15](Cl)(=[O:19])[C:16](Cl)=O.Cl.[CH3:22][NH2:23]>C(Cl)Cl>[OH:19][C:15]1[CH:16]=[CH:4][C:3]([C:22]2[NH:23][C:4](=[O:6])[C:3]3[C:2]([CH:1]=2)=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])=[CH:2][CH:1]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN
Reactant: COc1cc(C)c(C(=O)O)c(OC)c1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)cc3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.8 g, 14.3 mmol) in CH2Cl2 (30 mL), oxalyl chloride (3.62 g, 28.5 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent and excess oxalyl chloride were removed at reduced pressure. The solid was dissolved in CH2Cl2 (10 mL) and methyl amine hydrochloride (1.33 g, 42.81 mmol) was added on cooling and the mixture was stirred at room temperature for 4 h. The solvent was removed and the crude product was purified by chromatography using 5% methanol in CH2Cl2, to give 1.3 g of the amide intermediate (43% yield). To a solution of the amide intermediate (1.29 g, 6.16 mmol) in THF (30 mL), n-butyl lithium (5.6 mL, 14.18 mmol, 2.5 M solution in hexane) was added slowly under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C. The mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-O-TBDMS-benzonitrile (1.58 g, 6.78 mmol) in THF (10 mL) was added quickly. The cooling bath was removed and the mixture was stirred at room temperature for 16 h. Saturated aqueous NH4Cl solution was added with cooling, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give the crude intermediate, which was purified by chromatography using 5% methanol in CH2Cl2, to give two products (1) 678 mg of isoquinoline in 26% yield and (2) 780 mg of quinalone product in 27% yield. To a suspension of the above quinalone product (780 mg, 1.65 mmol) in ethanol (20 mL), conc. HCl (2 mL) was added and the mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed and purified by chromatography to give 3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (215 mg, 44%). Selected data: MS (ES) m/z: 297.93; MP 245-247° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8].[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=3)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1cccc(OC(F)(F)F)c1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1cccc(OC(F)(F)F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3-(trifluoromethoxy)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 375 (M+H)+; MS (ESI−) m/z 373 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.28 (d, J 6.1, 2H), 4.50 (q, J 7.1, 1H), 7.05 (s, 1H), 7.20 (m, 2H), 7.40 (m, 1H), 7.81 (t, J 7.8, 1H), 7.96 (d, J 7.2, 1H), 8.21 (d, J 8.1, 1H), 8.32 (d, J 6.2, 1H), 8.61 (d, J 6.8, 1H), 8.70 (t, J 5.8, 1H), 9.57 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11]O)[C:6]=1[CH3:13])(=[O:4])=[O:3].S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:11][C:7]1[C:6]([CH3:13])=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(S(C)(=O)=O)ccnc1CO
Solvent: ClC(Cl)Cl
Product: Cc1c(S(C)(=O)=O)ccnc1CCl
Temperature: 62.5 °C

Procedure:
To a mixture of (4-Methanesulfonyl-3-methyl-pyridin-2-yl)-methanol (13 g) and chloroform (130 ml) was added thionylchloride (7.5 ml) at 25-30° C. The reaction mixture was then heated to 60-65° C. and maintained at the same temperature for about 30 min. The solvent was distilled off completely under vacuum at 50-55° C. Ethylacetate (52 ml) was added to the crude followed by cooling to 0-10° C. and maintaining the same temperature for about 2 hrs. The compound is then filtered and washed the solid with ethylacetate (10 ml). The compound at 50-55° C. to obtain 12.2 gm of the title compound characterized by 1HNMR data (300 MHz): δ 2.75 (s, 3H), 3.38 (s, 3H), 4.95 (s, 2H), 7.82 (d, 1H), 8.70 (d, 1H) and mass [M]+: 220.06.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)[CH2:10][CH2:9]1.[CH:36](=O)[CH:37]([CH3:39])[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:36]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:33])=[O:34])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)[CH2:12][CH2:13]1)[CH:37]([CH3:39])[CH3:38]
Reactant: NS(=O)(=O)c1ccc(Nc2ncc3cccc(OC4CCNCC4)c3n2)cc1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN1CCC(Oc2cccc3cnc(Nc4ccc(S(N)(=O)=O)cc4)nc23)CC1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a solution of the TFA salt of 4-(8-(piperidin-4-yloxy)quinazolin-2-ylamino)benzenesulfonamide in DCM was added isobutyraldehyde (2 eq) and a few drops of acetic acid. The mixture was stirred for 10 mins and to it was added sodiumtriacetoxyborohydride (1.5 eq) and the mixture was stirred for 1 h. The reductive amination went to completion, by LC/MS. The crude mixture was concentrated and purified on prep HPLC to give the product 4-(8-(1-isobutylpiperidine-4-yloxy)quinazolin-2-ylamino)benzenesulfonamide in 80% yield. ES/MS m/z 456.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C@H:10]([C:12]([OH:14])=[O:13])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:15](O)[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:13][C:12](=[O:14])[C@H:10]([CH3:11])[NH:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: C[C@H](Nc1cc(F)cc(F)c1)C(=O)O
Reactant: CC(C)CO
Product: CC(C)COC(=O)[C@H](C)Nc1cc(F)cc(F)c1

Procedure:
Following General Procedure H above and using N-(3,5-difluorophenyl)alanine (from Example C above) and iso-butanol, the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.9 in 3% methanol/methylene chloride) and purification was by preparative plate chromatography (silica gel using 3% methanol/methylene chloride as the eluant).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].[C:30]([C:32]1[N:33]=[C:34]([C:45]([O-])=[O:46])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=1)#[N:31].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:45]([C:34]3[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=[C:32]([C:30]#[N:31])[N:33]=3)=[O:46])=[C:16]([C:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Yield: 87.1 %

Procedure:
A solution of 150 mg (0.389 mmol) 5-amino-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (as prepared in the previous step) in 15 mL of CH2Cl2 was treated with 131 mg (0.428 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 3, step (b)), 272 mg (0.584 mmol) PyBroP, and 203 μL (1.17 mmol) DIEA at room temperature for 3 h. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. Chromatography of the residue on a 50-g silica Varian MegaBond Elut column with 50% EtOAc-hexanes afforded 215 mg (87%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C34H50N6O4Si, 635.4 (M+H), found 635.3.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:2]1[S:6][C:5]([N:7]2[CH2:11][C:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[N:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C1OC2(CN3CCC2CC3)CN1c1ncc(Br)s1
Product: O=C1OC2(CN3CCC2CC3)CN1c1ncc(-c2ccccn2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from 3′-(5-bromothiazol-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)pyridine. The title compound (35 mg) was obtained as a pale solid, m/z 343 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.C([Li])CCC.Cl[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=1>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynylchroman in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-butyl lithium in hexane. Stirring was commenced at 0° C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0° C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0° C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 6-chloronicotinate in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and mixture stirred at room temperature for 15 minutes and then treated by double ended needle with the solution of alkynylzinc prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was extracted with 3×75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl and then dried (MgSO4). Solvent was removed in vacuo and the residue further purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=2[F:19])[CH:3]=1>C(O)C.[Pd]>[F:19][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:12]=1[O:11][C:4]1[CH:3]=[CH:2][N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]=12)[NH2:18]
Reactant: Nc1ccc(Oc2cc(Cl)nc3[nH]ccc23)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.2 g (11.5 mmol) of {4-[(6-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3-fluoro-phenyl}amine (from example XXXI) are dissolved in ethanol at 50° C. The solution is then allowed to cool to RT, and 2.45 g (2.30 mmol) of 10% palladium on activated carbon are added. The mixture is hydrogenated overnight under a hydrogen pressure of 2 bar. The palladium is then filtered off with suction through kieselguhr and washed with ethanol, and the filtrate is concentrated.
Reaction SMILES: [N:1]1([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[K+].[F:16][CH:17]([F:21])[C:18](F)=[O:19]>C1(C)C=CC=CC=1>[F:16][CH:17]([F:21])[C:18](=[O:19])[C:8](=[CH:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C=CN1CCCCC1
Reactant: O=C(F)C(F)F
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN1CCCCC1)C(=O)C(F)F
Temperature: -30 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Ethyl 3-piperidin-1-ylacrylate (99%, 8.7 g, 50 mmol) and KF (spray dried) (4.44 g, 76.3 mmol) were initially charged in 100 ml of toluene and cooled to −30° C. At this temperature, difluoroacetyl fluoride (98%, 6.10 g, 61 mmol) was then introduced. The reaction mixture was stirred at −30° C. for 3 h and then, over a period of 1 h, warmed to room temperature. The reaction mixture was washed with deionized water (50 ml). After separation of the phases, the aqueous phase was extracted once with toluene (100 ml). The toluene phases were combined and washed with an aqueous saturated NaCl solution (100 ml), and the solvent was then removed under reduced pressure. This gave ethyl 4,4-difluoro-3-oxo-2-(1-piperidin-1-ylmethylidene)butyrate as an orange oil (amount: 13.0 g; purity according to GC: 91.2%; yield: 94%). 1H-NMR (CDCl3): δ=1.3 (t, 3H), 1.75 (m, 6H), 3.3 (m, 2H), 3.6 (m, 2H), 4.25 (q, 2H), 6.6 (t, 1H), 7.85 ppm (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]([OH:16])=O)=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:38]1[C:46]2[C:41](=[C:42]([CH2:47][NH2:48])[CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14](=[O:16])[NH:48][CH2:47][C:42]2[CH:43]=[CH:44][CH:45]=[C:46]3[C:41]=2[CH:40]=[CH:39][NH:38]3)=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4]
Reactant: NCc1cccc2[nH]ccc12
Reactant: COC(=O)c1sc(C(=O)O)cc1C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
To a solution of 3-Trifluoromethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (570 mg, 2.24 mmol) in anhydrous DMF (10 mL) was added triethylamine (1.25 mL, 8.96 mmol), EDC (520 mg, 2.69 mmol), HOBT (360 mg, 2.69 mmol), and C-(1H-Indol-4-yl)-methylamine (390 mg, 2.69 mmol). The mixture was stirred at room temperature 3 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-70% EtOAc in hexane to afford the desired product (0.27 g, 31% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[N+]=[N-])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.ClCCl.[O:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh].O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)[O:25][CH:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Reactant: OC1CCOCC1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(OC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
In a dry 25 mL round bottom flask under argon was placed diazo-(3,4-dichloro-phenyl)-acetic acid methyl ester (from Example 1, 614 mg, 2.51 mmol), dichloromethane (10 mL) and tetrahydro-4H-pyran-4-ol (0.50 mL, 5.01 mmol). The solution was stirred at 25° C. and then rhodium (II) acetate dimer (22 mg, 0.05 mmol) was added. Gas evolution began immediately and the color changed from bright yellow to an aquagreen color. After the solution was stirred at 25° C. for 1 h, it was poured into water (10 mL) and the layers were separated. The aqueous layer was washed with dichloromethane (3×15 mL) and the combined organic layers were dried over sodium sulfate and in vacuo. The residual material was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate) to furnish rac-(3,4-dichloro-phenyl)-[(tetrahydro-pyran-4-yl)oxy]-acetic acid methyl ester (598 mg, 75% yield) as a clear colorless oil: EI-HRMS m/e calcd for C14H16Cl2O4 (M+) 318.0426, found 318.0412.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1cccc(F)c1
Product: COC(=O)c1c(O)c2ccc(-c3cccc(F)c3)cc2sc1=O

Procedure:
7-(3-Fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 3-fluoro-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.41 (d, 1H), 7.625-7.114 (m, 6H), 4.02 (s, 3H).