Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:4]=1.[H-].[Na+].[CH:22](OC)=[O:23]>CN(C=O)C>[OH:23][CH:22]=[C:15]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:4]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CN(C)c1cccc(-c2ccccc2)c1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)N(C)c1cccc(-c2ccccc2)c1
Yield: 12.5 %

Procedure:
Methyl (N-methyl-3-phenylanilino)acetate (4.33 g) was formylated as described in Example 1 by treatment with sodium hydride (0.94 g) and methyl formate (21.01 g) in DMF (50 ml) to give methyl 3-hydroxy-2-(N-methyl-3'-phenylanilino)propenoate (0.60 g) as a brown viscous liquid. Methylation with dimethyl sulphate (0.59 g) and potassium carbonate (0.62 g) in DMF (25 ml) for 5 hours afforded on work-up and HPLC (eluent petroleum ether - ether, 70:30) on silica gel a pure sample of the title compound (260 mg) as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][C@@H:7]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]3[CH:19]=[CH:20][S:21][C:11]=23)[CH2:6][CH2:5][C@@H:4]1[CH2:22][C:23]#[N:24]>[Pd].CO>[NH2:16][C:15]1[C:10]([NH:9][C@H:7]2[CH2:6][CH2:5][C@H:4]([CH2:22][C:23]#[N:24])[C@@H:3]([O:2][CH3:1])[CH2:8]2)=[C:11]2[S:21][CH:20]=[CH:19][C:12]2=[N:13][CH:14]=1
Reactant: CO[C@H]1C[C@@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC[C@@H]1CC#N
Agent: [Pd]
Solvent: CO
Product: CO[C@H]1C[C@@H](Nc2c(N)cnc3ccsc23)CC[C@@H]1CC#N
Yield: 93.2 %

Procedure:
A mixture of {(1R,2S,4S)-2-methoxy-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (racemic) (401 mg, 1.16 mmol) and 10% palladium on carbon (0.20 g) in methanol (7.7 mL) was subjected to balloon pressure of H2 at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated and purified with flash chromatography (eluting with 15% methanol in dichloromethane) to give the desired product (342 mg, 93%). LCMS calculated for C16H21N4OS (M+H)+: m/z=317.1. Found: 317.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[O:10])=[CH:3][CH:2]=1.[BH4-].[Na+]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][OH:10])=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1-c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Product: OCc1ccccc1-c1ccncc1

Procedure:
2-pyridin-4-yl-benzaldehyde was treated with NaBH4 according to the method of Example 119A to provide the title compound. MS (ESI+) m/z 185 (M+H)+;
Reaction SMILES: C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1.[N:24]1([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([OH:28])=O.[NH2:42][C@H:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH:44]([CH3:46])[CH3:45].Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[N:24]1([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([NH:42][C@H:43]([C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:28]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
1.3 ml of N-ethylmorpholine and 2.2 g of DCC are added, at 0° C., to a solution of 2.49 g of Z-Pro-OH, 2.1 g of H-Val-OtBu.HCl and 1.35 g of HOBt in 20 ml of dimethylformamide. The subsequent procedure is as in Example 8a. The residue is triturated with petroleum ether, filtered off with suction and dried.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:22]([F:23])=[CH:21][C:9]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=3[OH:20])=O)=[CH:8][C:7]=2[F:24])[CH2:3][CH2:2]1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:22]([F:23])=[CH:21][C:9]([C:10]3[O:20][C:14]4[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=4[N:12]=3)=[CH:8][C:7]=2[F:24])[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(O)cc1O)c1cc(F)c(OCC2CC2)c(F)c1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Oc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.7 %

Procedure:
To a solution of 4-(cyclopropylmethoxy)-N-(2,4-dihydroxyphenyl)-3,5-difluorobenzamide (3.78 g), hexachloroethane (6.67 g) and triphenylphosphine (7.39 g) in acetonitrile (50 mL) was added triethylamine (3.42 mL), and the mixture was stirred at room temperature for 15 min, and then with heating at 80° C. for 1 hr. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.92 g).
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9]2)[CH2:5][CH2:4]1)#N.Cl>>[C:17]1([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]3([CH2:5][CH2:4][NH:3][CH2:8][CH2:7]3)[CH2:9]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CN1CCC2(CC1)CN(c1ccccc1)c1ccccc12
Agent: Cl
Product: c1ccc(N2CC3(CCNCC3)c3ccccc32)cc1

Procedure:
A mixture of 1'-cyano-1-phenylspiro[indoline-3,4'-piperidine] (Example 8), is treated with 3N hydrochloric acid under reflux to provide 1-phenylspiro[indoline-3,4'-piperidine].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:19]([O-:21])=[O:20])[C:13]([C:16](N)=[O:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:22][OH:23]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:19]([O-:21])=[O:20])[C:13]([C:16]([O:23][CH3:22])=[O:17])=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CO
Reactant: NC(=O)c1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Product: COC(=O)c1ncc(Cc2ccc(F)c(F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-[(3,4-difluorophenyl)methyl]-3-nitro-2-pyridinecarboxamide (2.7 g, 9.21 mmol) and MeOH (100 ml), was added dimethylformamidedimethylacetal (3.29 g, 27.62 mmol). After stirring at room temperature overnight, the solvent was evaporated using no heat, EtOAc was added and the organic layer was washed three times with brine, dried and concentrated in vacuo. The product was purified by chromatography on silica gel, eluting with 20-60% EtOAc/hexanes to afford a dark brown oil. 1H NMR (CDCl3) δ 8.71 (1H, s), 8.05 (1H, s), 7.20-7.15 (1H, m), 7.00-6.80 (2H, m), 4.10 (2H, s), 4.01 (3H, s); HRMS calcd for C14H10F2N2O4+H+: 309.0687. Found 309.0681.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C:10]1([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[C:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][Si](C(C)(C)C)(C)C)=[CH:51][CH:50]=2)[CH:42]=1)[OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](C(C)C)C(C)C)(C)C.B(F)(F)F.CCOCC.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][C@@:10]1([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[C:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[CH:42]=1)[OH:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: Cc1ccc([C@@]2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.48 g (approx. 88% pure) 1-(2,3,4,6-tetra-O-benzyl-1-hydroxy-D-glucopyranosyl)-3-[4-(tert-butyl-dimethyl-silyloxy)-benzyl]-4-methyl-benzene in 3.5 mL dry acetonitrile is cooled to −40° C. under argon. 0.13 mL triisopropylsilane and 0.08 mL boron trifluoride etherate are added dropwise. The solution is stirred for 3 h at −35° C., before another 0.02 mL of triisopropylsilane and 0.01 mL of boron trifluoride etherate are added. After a further 2 h at −40° C. aqueous potassium carbonate solution is added, and the resulting mixture is stirred for 1 h at ambient temperature. Then water is added and the mixture is extracted four times with ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and chromatographed on silica gel (cyclohexane/ethyl acetate 10:1->4:1).
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]([CH:13]=O)[C:7]3[CH:8]=[N:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].[N+:20]([CH2:23][CH3:24])([O-:22])=[O:21]>>[N+:20]([C:23]([CH3:24])=[CH:13][C:6]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[N:4]2[CH2:3][CH2:2][CH2:1][C:5]=12)([O-:22])=[O:21]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1c2n(c3ccncc13)CCC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1c2n(c3ccncc13)CCC2)[N+](=O)[O-]
Temperature: 100 °C
Yield: 77 %

Procedure:
To a solution of 2,3-dihydro-1H-3a,6-diaza-cyclopenta[a]indene-8-carbaldehyde (0.30 g 1.6 mMol) in nitroethane (3.00 ml) was added ammonium acetate (0.30 g 3.9 mMol) and the mixture was heated to 100° C. for 4 h with stirring under argon. The mixture was cooled to room temperature and purified by chromatography on silicagel gel (ca 30 g) eluting first with ethyl acetate (ca 100 ml) then with a mixture of ethyl acetate (9 parts) and methanol (1 part). The product fraction were combined, concentrated and the residue was recrystallised from ethyl acetate to yield the title compound (0.30 g, 77%) as yellow crystals. mp 141-142° C. Found C, 64.05; H, 5.51; N, 17.14%; C13H13N3O2 requires C, 64.19; H, 5.39; N, 17.27%.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([O-:21])(=[O:20])=[O:19].[N+:22]([O-])([OH:24])=[O:23]>>[OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6]([N+:22]([O-:24])=[O:23])[C:3]=1[CH:4]=[O:5].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([O-:21])(=[O:20])=[O:19]
Reactant: COc1cccc(C=O)c1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)([O-])c1ccccc1
Product: COc1ccc([N+](=O)[O-])c(C=O)c1O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-Hydroxy-3-methoxybenzaldehyde-2-benzenesulfonate (50 g, 171 mM) is added to nitric acid (500 ml) at 0° C.-5° C. The solution is kept five minutes at 5° C. and then poured into ice-water (1.5 L). The crude product, a tan solid, is filtered, washed with cold water, alcohol, and then recrystallized from acetic acid (650 ml) to afford the product as a white solid; yield 30.3 g (52.6%); m.p. 152°-154° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[Br:19][CH:20]([CH:23]=O)[CH:21]=O>CCO>[Br:19][C:20]1[CH:21]=[N:7][C:5]2[N:4]([N:3]=[C:2]([CH3:1])[CH:6]=2)[CH:23]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: O=CC(Br)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1cc2ncc(Br)cn2n1
Temperature: 80 °C
Yield: 30 %

Procedure:
To a solution of 3-methyl-1H-pyrazol-5-amine a12 (64.8 mmol, 1 eq, 6.3 g) in EtOH (100 ml), in the presence of PTSA, is added bromomalonaldehyde x9 (64.8 mmol, 1 eq, 9.79 g). The mixture is heated at 80° C. for 12 hours. The solvent is evaporated under reduce pressure and the residue purified by chromatography on silicagel (hexane/AcOEt: 93/7 (v/v)). 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine x14 is obtained as a white solid (4.04 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[C:10]([C@@H:13]3[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]3[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C@@H:13]3[CH2:18][CH2:17][N:16]([CH2:27][C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:29])[CH2:15][C@H:14]3[C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[NH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Fc1ccc([C@@H]2CNCC[C@H]2c2cc(-c3ccc(Cl)cc3)[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CC[C@@H](c2cc(-c3ccc(Cl)cc3)n[nH]2)[C@H](c2ccc(F)cc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3R,4R)-4-[5-(4-chlorophenyl)-1H-pyrazol-3-yl]-3-(4-fluorophenyl)piperidine (100 mg, 0.213 mmol, prepared in a similar manner to Examples 7 and 8), 2-bromoaceto-phenone (50.8 mg, 0.255 mmol) and potassium carbonate (147 mg, 1.064 mmol) in acetonitrile (1.0 ml) was stirred at rt for 4 h. Direct purification of the crude reaction mixture by RP-HPLC (C18, acetonitrile, water, 0.1% TFA) afforded the title compound. HPLC/MS: 474.3, 476.3 (M+1); Rt=1.74 min (LC-4 HPLC conditions).
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[O:29])[CH2:24][CH:23]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:46].O1CCOCC1>O1CCOCC1>[ClH:46].[C:11]1([C@H:9]([NH:8][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]3[CH:32]=[CH:33][C:34]([C:35]([OH:37])=[O:36])=[CH:38][CH:39]=3)=[O:29])[CH2:24][CH:23]2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)Oc2ccc(C(=O)O)cc2)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(C(=O)Oc2ccc(C(=O)O)cc2)CC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 193 mg of 4-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}oxy)benzoic acid was added 2.0 mL of a 1,4-dioxane, and 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was heated in isopropanol under reflux, and the mixture was left to be cooled at room temperature. The precipitate was collected by filtration, and dried under reduced pressure to obtain 117 mg of 4-({[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}oxy)benzoic acid hydrochloride as a white solid.
Reaction SMILES: I[C:2]1[S:6][C:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[N:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][C:26]([CH:28]=[CH2:29])=[O:27]>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)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>[CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:5]2[S:6][C:2](/[CH:29]=[CH:28]/[C:26](=[O:27])[CH3:25])=[CH:3][N:4]=2)=[CH:9][CH:10]=1)([CH3:17])[CH3:16]
Reactant: C=CC(C)=O
Reactant: CC(C)Oc1ccc(Oc2ncc(I)s2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1
Temperature: 75 °C
Yield: 85.6 %

Procedure:
To a solution of the product from Example 7B (1.6 g, 4.43 mmole) in N,N-dimethylformamide (25 mL) was consecutively added triethylamine (8 mL), tetrabutyl ammonium chloride (1.2 g, 4.3 mmole), methylvinylketone (2 g, 28.5 mmole) and dichlorobis(triphenylphosphine)palladium(II) (155 mg, 0.22 mmole). The reaction mixture was heated at 75° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with 0.5N aqueous HCl, followed by brine. The reaction mixture was dried over magnesium sulfate filtered and evaporated. The product was purified via silica column, using a gradient of 5-25% ethyl acetate in hexane, to yield 1.15 g (85%) of orange solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.50 (d, J=15.44 Hz, 1H) 7.42 (s, 1H) 7.13-7.24 (m, 2 H) 6.84-7.00 (m, 2H) 6.23 (d, J=15.81 Hz, 1H) 4.38-4.63 (m, 1H) 2.30 (s, 3H) 1.35 (t, J=5.52 Hz, 6H). Mass spectrum DCI 304 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.ClC1C=C(I)C=C2C=1O[CH:20]([C:23]([F:26])([F:25])[F:24])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=C2>>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[C:4]([Cl:11])[CH:3]=1)[O:10][CH:20]([C:23]([F:24])([F:26])[F:25])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7]2
Reactant: O=Cc1cc(Br)cc(Cl)c1O
Reactant: CCOC(=O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Product: CCOC(=O)C1=Cc2cc(Br)cc(Cl)c2OC1C(F)(F)F

Procedure:
The ethyl 6-bromo-8-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate was prepared from 5-bromo-3-chloro-2-hydroxybenzaldehyde in an analogous manner to step 2, preparation of ethyl 8-chloro-6-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1.Br[CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)Cc2ccc3c(c2)OCO3)cc1
Product: COC(=O)c1ccc(CC(C(=O)NS(=O)(=O)c2ccc(C(C)C)cc2)c2ccc3c(c2)OCO3)cc1
Yield: 84 %

Procedure:
Using the general procedure described in Example 6 the dianion derived from the product of Example 1 (2.503 g; 6.93 mmol) was alkylated with methyl 4-bromomethylbenzoate. The crude reaction mixture was partitioned between EtOAc and 10% aqueous NaHSO4, separated dried and evaporated. The residue was purified on a silica gel flash chromatography eluted with CHCl3 -MeOH--NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 2.987 g (84%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12>>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13](=[O:14])[C:12]3[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]2=[O:15])[CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1cc(O)cc(N)n1
Product: Cc1cc(O)cc(N2C(=O)c3ccccc3C2=O)n1
Temperature: 190 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
The title compound from Example 31 (2.5 g, 20.0 mmol) and phthalic anhydride (3.0 g, 20.0 mmol) were ground in a mortor. This mixture was added to a flask which was flushed with N2 and immersed in an oil bath maintained at 190° C. Heating was continued for 2 h while a gentle flow of N2 was passed through the flask to removed the water by-product. The reaction was cooled to room temperature and the product solid was filtered and washed extensively with 100 mL aliquotes of CH2Cl2, MeOH, EtOAc, and Et2O. After drying, 4.63 g (92%) of the title material was obtained.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[F:36])=O)(C)(C)C.Cl>C(Cl)Cl.CCOCC>[F:36][C:18]1[CH:19]=[CH:20][C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:22][C:17]=1[C:9]1[NH:8][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(F)c(-c3nc4ccccc4n3C(=O)OC(C)(C)C)c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Fc1ccc(N2CCNCC2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a solution of 2-[5-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-fluoro-phenyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (0.45 g, 0.91 mmol) in DCM (1.0 mL) 2M HCl in Et2O (8.0 mL) was added and the resulting suspension was stirred at room temperature overnight. 2M HCl in Et2O (5.0 mL) more were added and reaction was left stirring for 24 h. The precipitate was filtered off and tritured with Et2O (3×15 mL) to afford 0.21 g of the title compound (55%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[C:13]([S:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=2)=[CH:14][C:15]2[C:16]([CH3:25])([CH3:24])[CH2:17][CH2:18][C:19]([CH3:23])([CH3:22])[C:20]=2[CH:21]=1.C(N(CC)CC)C>ClCCl.O>[CH3:11][C:12]1[C:13]([S:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][CH:28]=2)=[CH:14][C:15]2[C:16]([CH3:25])([CH3:24])[CH2:17][CH2:18][C:19]([CH3:22])([CH3:23])[C:20]=2[CH:21]=1
Reactant: Cc1cc2c(cc1Sc1ccc(CO)cc1)C(C)(C)CCC2(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cc2c(cc1Sc1ccc(C=O)cc1)C(C)(C)CCC2(C)C
Reaction time: 0.17 h

Procedure:
60 μl (0.7 mmol) of oxalyl chloride and 5 ml of dichloromethane were introduced into a three-necked flask and under a nitrogen stream. 100 μl (1.4 mmol) of DMSO were added at -60° C. and the mixture was stirred for 10 min and then a solution of 200 mg (0.6 mmol) of 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylthio)benzenemethanol in 5 ml of dichloromethane and 400 μl (3 mmol) of triethylamine was added. The mixture was stirred at room temperature for one hour, the reaction medium poured into water, extracted with dichloromethane, the organic phase decanted off, dried over magnesium sulfate and evaporated.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](Cl)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1.C([O-])(O)=O.[Na+]>COCCOC.[Zn]>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][C:3](=[O:14])[N:2]([CH3:1])[C:6]=3[CH:7]=2)=[O:12])=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:17]=1
Reactant: FC(F)(F)c1cc(Br)ccc1CBr
Reactant: Cn1c(=O)oc2ccc(C(=O)Cl)cc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: COCCOC
Product: Cn1c(=O)oc2ccc(C(=O)Cc3ccc(Br)cc3C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carboxylic acid (935 mg, obtained in Example 116, step 5) in CH2Cl2 (15 mL) were added two drops of DMF and oxalylchloride (0.66 mL). The mixture was stirred at room temperature for 1 hour and was then concentrated to dryness. 1,2-Dimethoxyethane (20 mL) was added and the solvent was evaporated again. The resulting solid was dried at high vacuum over night to give the crude acid chloride (3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carbonyl chloride). To a suspension of zinc powder (633 mg) in 1,2-dimethoxyethane (10 mL) was added tetrakis(triphenyl-phosphine)palladium(0) (56 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (10 mL) was added. The mixture was cooled in an ice bath and a solution of 4-bromo-1-bromomethyl-2-trifluoromethyl-benzene (1.54 g, [CAS Reg. No. 335013-18-8]) in 1,2-dimethoxyethane (10 mL) was slowly added over a period of 15 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 18 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=1:1) to give the title compound as a yellow oil (944 mg, 47%). MS (neg. ion, m/e)=414.1 [(M−H)−].