Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@H:13]([C:21]([OH:23])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[OH-].[Na+]>[CH2:5]([O:4][C:2]([NH:12][CH:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]([OH:23])=[O:22])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(NC(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reaction time: 1 h

Procedure:
82 mmol (13.9 g) of benzyl chloroformate and 20 ml of 4M aqueous sodium hydroxide are added over a period of 30 minutes to a solution, cooled to 0° C., of 80 mmol (13.2 g) of phenylalanine in 20 ml of 4M aqueous sodium hydroxide. The solution returns to room temperature during a period of 1 hour. The reaction mixture is extracted with ether. The aqueous phase is rendered acidic to pH=2 with a dilute hydrochloric acid solution. The precipitate that forms is filtered off and washed to yield the expected compound.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=[CH:10][CH:11]=1)=[CH:3][Cl:4].[H][H]>C(O)C.[Ni]>[Cl:1][C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[NH2:12])=[CH:3][Cl:4]
Reactant: O=[N+]([O-])c1cccc(OC(Cl)=CCl)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc(OC(Cl)=CCl)c1

Procedure:
Yield: 115 grams of 3-(1',2'-dichlorovinyloxy)-nitrobenzene 1 mole of the nitro-product was dissolved in 1liter of ethanol and was reduced by means of hydrogen in an autoclave at 60°C, after 5 grams of a Raney-nickel catalyst (R/50) had been added. The catalyst was then filtered off with suction, the ethanol was distilled off, and the residue was distilled in vacuo.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]1[S:14][CH:15]=[C:16](/[CH:18]=[CH:19]/[C:20](Cl)=[O:21])[N:17]=1>O.CC(C)=O.O1CCOCC1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]1[S:14][CH:15]=[C:16](/[CH:18]=[CH:19]/[C:20]([N:1]=[N+:2]=[N-:3])=[O:21])[N:17]=1
Reactant: O=C(Cl)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: [N-]=[N+]=NC(=O)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a cooled (0° C.) solution of sodium azide (6.2 g, 95 mmol) in water (100 mL) and acetone (100 mL) was added a solution of (E)-3-(2-(2,6-dichlorophenyl)thiazol-4-yl)acryloyl chloride (6.0 g, 19 mmol) in dioxane (100 mL) dropwise. After addition, the resulting mixture was stirred for 1 hour at 0° C. The reaction was quenched with water (50 mL) and extracted with EtOAc (3×80 mL). The combined organic extract was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The resultant residue was purified via silica gel column chromatography eluting with EtOAc/petroleum ether (1:8) to afford the desired product as a yellow solid (6.0 g, 98% yield). LCMS (ESI) m/z: 325.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[N:12]2[CH:26]=[CH:27][N:28]=[C:11]2[CH:10]=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH2:17][NH2:18])[N:12]2[CH:26]=[CH:27][N:28]=[C:11]2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.42 g (10.47 mmol) of tert-butyl (2-{[7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]amino}ethyl)carbamate are dissolved in 160 ml of dichloromethane, and 16 ml (209 mmol) of trifluoroacetic acid are added. The mixture is stirred at RT for 2 h and then removed from all volatile constituents in vacuo. 4.56 g (99% of theory) of product are obtained and are employed without further purification.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH2:18][N:19]([CH2:30][C:31]([O:33][CH3:34])=[O:32])S(C1C=CC(C)=CC=1)(=O)=O)C.C[O-].[Na+].CC(O)=O>CN(C=O)C>[CH3:34][O:33][C:31]([C:30]1[N:19]=[CH:18][C:6]2[C:5]([C:4]=1[OH:3])=[CH:10][CH:9]=[C:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH:7]=2)=[O:32]
Reactant: CCOC(=O)c1ccc(Oc2ccccn2)cc1CN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1ncc2cc(Oc3ccccn3)ccc2c1O
Temperature: 0 °C
Yield: 55.8 %

Procedure:
A mixture of 2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-4-(pyridin-2-yloxy)-benzoic acid ethyl ester (745 mg), and NaOMe (0.702 mL, 0.5 M solution in HOMe) in DMF (5 mL) was stirred with ice/water bath cooling for 4 h. HOAc (2.5 eq relative to NaOMe) was added, diluted with ice/water; then the solids were collected via filtration and washed with water to give product (247 mg). Filtrate was back extracted with EtOAc; EtOAc phase was washed with water, diluted NaCl solution and dried over anhydrous sodium sulphate, filtered, concentrated and column purified to give more product (135 mg). LC MS ESI+: 297 (M+1)+.
Reaction SMILES: O[CH2:2][C:3]1([C:6]2[C:11]([O:12][CH2:13][O:14][CH3:15])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:16][OH:17])[CH2:5][CH2:4]1.[Li]CCCC.CCCCCC.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1>[CH3:15][O:14][CH2:13][O:12][C:11]1[C:6]2[C:3]3([CH2:2][O:17][CH2:16][C:7]=2[CH:8]=[CH:9][CH:10]=1)[CH2:4][CH2:5]3
Reactant: COCOc1cccc(CO)c1C1(CO)CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1cccc2c1C1(CC1)COC2
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a solution of (2-[1-(hydroxymethyl)cyclopropyl]-3-{[(methyloxy)methyl]oxy}phenyl)methanol (Intermediate 134, 450 mg) in dry tetrahydrofuran (10 ml) at 0° C., a solution of BuLi in hexane (1.6M, 1.180 mL, 1.889 mmol) was slowly added and the reaction mixture was stirred for 15 minutes at the same temperature. A solution of tosyl chloride (360 mg, 1.889 mmol) in dry tetrahydrofuran (5 ml) was slowly added and the reaction mixture was stirred for 15 minutes at 0° C. A second equivalent of a solution of BuLi in hexane (1.6M, 1.180 mL, 1.889 mmol) was added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with an aqueous saturated solution of NaHCO3 (10 ml) diluted with water (10 ml) and extracted with ethyl acetate (2×30 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane/ethyl acetate as eluents from 100:0 to 8:2. This afforded the title compound 5-{[(methyloxy)methyl]oxy}-1H-spiro[2-benzopyran-4,1′-cyclopropane] as a colourless oil (385 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][C@H:6]1[C:12](=[CH:13][O:14]C)[CH2:11][CH2:10][N:9]([C:16]2[N:17]([CH3:24])[N:18]=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])[CH2:8][CH2:7]1)=[O:4].ClC(Cl)(Cl)C(O)=O>C(Cl)(Cl)Cl>[F:25][C:2]([F:1])([F:26])[C:3]([NH:5][C@H:6]1[CH:12]([CH:13]=[O:14])[CH2:11][CH2:10][N:9]([C:16]2[N:17]([CH3:24])[N:18]=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])[CH2:8][CH2:7]1)=[O:4]
Reactant: COC=C1CCN(c2c([N+](=O)[O-])cnn2C)CC[C@H]1NC(=O)C(F)(F)F
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(C=O)[C@H](NC(=O)C(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 87.8 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[(4R)-5-(methoxymethylene)-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]acetamide (1060 mg, 2.81 mmol) in chloroform (90 mL) was added trichloroacetic acid (1.84 g, 11.24 mmol). The mixture was heated at 70° C. overnight and another portion of trichloroacetic acid (1.84 g, 11.24 mmol) was added and heating continued for 6 h. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate and extracted with DCM 3×. The combined organic layers were concentrated and the residue was purified via silica gel column chromatography (0-100% EA/heptane) to give 2,2,2-trifluoro-N-[(4R)-5-formyl-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]acetamide (896 mg, 88%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[O:3]1.C1C(=O)N([Br:22])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:22][C:5]1[C:6](=[O:7])[C:2]([CH3:14])([CH3:1])[O:3][C:4]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(c2ccncc2)=CC1=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(c2ccncc2)=C(Br)C1=O
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.81 g, 4.28 mmol) in CHCl3 (20 mL), NBS (1.3 g, 7.28 mmol) was added portionwise at RT. The reaction mixture was then stirred for 2 h and diluted with DCM (100 mL). The organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-bromo-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (0.25 g, 21%) as a solid
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:17]=3)[CH2:13][C:12]2=[O:30])[CH:6]=1)C.[OH-].[Na+].Cl>CCO.O>[CH:25]1([O:24][C:18]2[CH:17]=[C:16]([CH:14]3[CH2:15][N:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:4]([OH:31])=[O:3])[C:12](=[O:30])[CH2:13]3)[CH:21]=[CH:20][C:19]=2[O:22][CH3:23])[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)c1cccc(N2CC(c3ccc(OC)c(OC4CCCC4)c3)CC2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2CC(=O)N(c3cccc(C(=O)O)c3)C2)cc1OC1CCCC1
Temperature: 90 °C
Yield: 89 %

Procedure:
3-[4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]benzoic acid ethyl ester (180 mg, 0.43 mmol) was mixed with EtOH:water (1:1, 20 mL) and NaOH (1N, 1.3 mL). The mixture was heated to 90° C. for 12 h and then cooled down to r.t. After neutralizing to pH=2 with HCl (1N), the mixture was extracted twice with EtOAc. The organic layer was combined, washed with brine and dried over MgSO4. After concentration 150 mg of the desired product was obtained as a light brown solid. Yield: 89%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[NH:9][C:8](=O)[NH:7][C:6]=2[CH:14]=1.Cl.[CH3:20][CH:21]([NH2:25])[CH:22]([CH3:24])[CH3:23]>>[Cl:1][C:2]1[C:3]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[N:9]=[C:8]([NH:25][CH:21]([CH3:20])[CH:22]([CH3:24])[CH3:23])[NH:7][C:6]=2[CH:14]=1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)NC(=O)NS2(=O)=O
Reactant: CC(C)C(C)N
Agent: Cl
Product: CC(C)C(C)NC1=NS(=O)(=O)c2cc(S(N)(=O)=O)c(Cl)cc2N1

Procedure:
The title compound was prepared from 6-chloro-2,3-dihydro-3-oxo-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide (4.94 g, 15.84 mmol) and 1,2-dimethylpropylamine hydrochloride (8.0 g, 65.0 mmol) by a method analogous to the method described in example 37, except that the product was purified by column chromatography affording 143 mg (2.4%) of pure product; m.p. (DSC) 244° C. (methanol); 1H-NMR (DMSO-d6): δ 0.90 (dd, 6H, CH(CH3)2), 1.11 (d, 3H, NCHCH3), 1.76 (m, 1H, CH(CH3)2), 3.71 (m, 1H, NHCH), 7.34 (br., 1H, NH), 7.41 (br.s, 1H, ArH), 7.80 (br.s, 2H, SO2NH2), 8.18 (s, 1H, ArH), 10.58 (br.s, 1H, NH); MS (FAB): m/e 381/383 (MH+); (C12H17N4Cl1O4S2) calc. C, 37.84; H, 4.50; N, 14.71; found C, 37.66; H, 4.65; N, 14.52.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:20]=[C:19]([S:27][CH3:28])[N:18]=2)[CH2:13]1)(=[O:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:35][O:36][CH2:37][CH2:38][OH:39]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:39][CH2:38][CH2:37][O:36][CH3:35])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[N:20]=[C:19]([S:27][CH3:28])[N:18]=2)[CH2:13]1)(=[O:11])=[O:10]
Reactant: CSc1nc(N2CC[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C2)cc(C(F)(F)F)n1
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc(S(=O)(=O)[C@H]2CCN(c3cc(C(F)(F)F)nc(SC)n3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-[(S)-3-(2-Chloro-4-fluoro-benzenesulfonyl)-pyrrolidin-1-yl]-2-methylsulfanyl-6-trifluoromethyl-pyrimidine (Intermediate of example 42; 300 mg) was dissolved in DMF (5.0 mL). Cs2CO3 (429 mg) and 2-methoxy-ethanol (0.10 mL) were added. The reaction mixture was stirred for 24 h at 25° C. After that, the reaction mixture was diluted with ethyl acetate (20 mL) and extracted with water (10 mL). The organic layers were dried over Na2SO4, filtrated and evaporated to dryness. The crude material was purified by flash chromatography (50 g silica gel; ethyl acetate/n-heptane) to yield a colorless waxy solid (170 mg; 50%) MS: m/z=512.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:43][NH:44][C@@H:45]([CH2:52][CH2:53][CH3:54])[CH2:46][N:47]1[CH2:50][CH:49]([OH:51])[CH2:48]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:44]([C@@H:45]([CH2:52][CH2:53][CH3:54])[CH2:46][N:47]1[CH2:48][CH:49]([OH:51])[CH2:50]1)[CH3:43])=[O:7]
Reactant: CCC[C@@H](CN1CC(O)C1)NC
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.3 %

Procedure:
3,4-Difluorobenzoic acid (0.184 g, 1.16 mmol), TBTU (0.373 g, 1.16 mmol) and DIPEA (0.303 mL, 1.74 mmol) was stirred in DCM (2 mL) for 40 min before (S)-1-(2-(methylamino)pentyl)azetidin-3-ol (Compound J4) (0.1 g, 0.58 mmol) was added. The resultant mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue dissolved in a mixture of MeOH (3 mL) and NaOH (aq. 1 mL, 1M). The resultant mixture was stirred at rt for 90 min before the MeOH was removed on a vacuum centrifuge. The crude product was extracted with DCM and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (102 mg, 56%). Mixture of rotamers: (600 MHz, DMSO-d6) δ 0.67-0.76, 0.79-0.91, 0.92-1.04, 1.06-1.48, 2.30-2.76, 3.23-3.42, 3.43-3.53, 4.05-4.17, 4.37-4.47, 5.17-5.26, 7.14-7.27, 7.36-7.56. Total no of protons: 22. HRMS (M+H)+: calculated 313.1728. found 313.1714.
Reaction SMILES: [CH2:1]([N:17]=[C:18]=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25]>O1CCCC1>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][C:18]([NH:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:19]
Reactant: CN(C)CCCN
Reactant: CCCCCCCCCCCCCCCCN=C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNC(=O)NCCCN(C)C

Procedure:
1.34 ml (5 meq) of hexadecyl isocyanate and 0.7 ml (5 meq) of 3-dimethylaminopropylamine are combined in 5 ml of tetrahydrofuran and reacted over a weekend at room temperature. The reaction mixture is filtered, washed with tetrahydrofuran, dried in vacuo and recrystallized from acetone to yield 1.2 gm of title compound with a m.p. of 78°-79° C.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.Br[C:20]1[S:21][CH:22]=[C:23]([Br:25])[CH:24]=1>>[Br:25][C:23]1[CH:24]=[C:20]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:18])[N:3]=2)[S:21][CH:22]=1
Reactant: Brc1csc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(Br)cs2)n1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)pyridine (example A.31) (4.0 g, 9.36 mmol) and commercially available 2,4-dibromothiophene (2.518 g, 10.41 mmol) according to the general procedure IVc protocol b. Obtained as a white solid (2.12 g, 54%). MS (ISP) 398.0 [(M+H)+] and 400.0 [(M+2+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:18])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.[C:19](Cl)(=[O:21])[CH3:20].C(N(CC)CC)C>ClCCl>[C:19]([O:16][C:14]1[CH:13]=[C:12]([CH3:17])[N:11]=[C:10]([S:9][CH2:8][C:7]2[C:6]([CH3:18])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[N:15]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Cc1cc(O)nc(SCc2c(C)cncc2Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cc(C)nc(SCc2c(C)cncc2Cl)n1
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
In a 250 mL round bottom flask, 2-{[(3-chloro-5-methylpyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (565 mg, 2.0 mmol) was dissolved in dichloromethane (25 mL). Acetyl chloride (0.21 mL, 3.0 mmol) was added, followed by triethylamine (0.42 mL, 3.0 mmol). After 30 minutes, the reaction mixture was evaporated. The crude product was purified by column chromatography (0˜35% ethyl acetate/hexane) to provide 2-{[(3-chloro-5-methylpyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-yl acetate as a white solid (500 mg, 77% yield); 1H NMR (500 MHz, CDCl3): δ 2.35 (s, 3H), 2.45 (s, 3H), 2.52 (s, 3H), 4.57 (s, 2H), 6.73 (s, 1H), 8.29 (s, 1H), 8.44 (s, 1H); M+ 324.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH:13]([CH3:15])[CH3:14])[N:6]=[CH:5]2.[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2)=[O:19]>>[CH3:16][O:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([CH2:11][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]3[C:8]=1[N:7]([CH:13]([CH3:15])[CH3:14])[N:6]=[CH:5]3)[N:24]=[CH:23]2)=[O:19]
Reactant: CC(C)n1ncc2cc(Br)cc(CO)c21
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Product: COC(=O)c1ccc2c(cnn2Cc2cc(Br)cc3cnn(C(C)C)c23)c1
Yield: 30 %

Procedure:
Compound 30 was prepared following general method 3A, using compound 22 as a starting material and 1H-indazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 30%.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(O)C.Cl.C(Cl)Cl.O=[Pt]=O>[C:34]([N:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[C:17]1[CH:16]=[C:11]([CH:10]=[C:9]([CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH3:8])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:36])[CH3:35]
Reactant: C=C(c1ccccc1)c1cc(C(=O)OC)cc(-c2ccccn2)c1
Reactant: CC(=O)Cl
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(C(C)C2CCCCC2)cc(C2CCCCN2C(C)=O)c1
Reaction time: 0.5 h

Procedure:
To an argon purged solution of methyl 3-(1-phenylvinyl)-5-(pyridin-2-yl)benzoate (73 mg, 0.23 mmol) in ethanol (5 mL) and HCl (conc. 1 mL) was added PtO2 (7 mg, 0.023 mmol). The mixture was hydrogenated under a hydrogen atmosphere (35 psi) for 6 h. The reaction mixture was purged with argon, filtered through a 0.2 μm filter, and concentrated. The resulting crude material was taken up with CH2Cl2 (5 mL) after which iPr2NEt (0.1 mL, 0.58 mmol) and acetyl chloride (18 μL, 0.25 mmol) were successively added. The mixture was stirred for 30 min, then diluted with CH2Cl2 (30 mL) and washed successively with 0.5 M HCl (1×10 mL), 9% sodium carbonate (1×10 mL), brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue containing the title compound was used without further purification. MS m/z=372 [M+1]+; Calc'd for C23H33NO3: 371.
Reaction SMILES: CC([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9]C=2)[C:5]=1[OH:14])=O.C12C(=[O:24])C(CCC1)CCC2.N1CCCC1>C1(C)C=CC=CC=1>[O:14]1[C:5]2[C:6](=[CH:11][CH:12]=[CH:13][CH:4]=2)[CH2:7][CH2:8][CH:9]1[OH:24]
Reactant: CC(=O)c1ccc2ccccc2c1O
Reactant: O=C1C2CCCC1CCC2
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: OC1CCc2ccccc2O1
Reaction time: 10 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-hydroxy-2-acetonaphthone, 8.29 g (0.06 mole) of bicyclo[3,3,1]nonan-9-one and 8 g (0.113 mole) of pyrrolidine in 300 cc of toluene, and the solution was boiled for 10 hours and water was separated. After termination of the reaction, toluene was removed under reduced pressure, and the remaining chromanone compound was crystallized with acetone. Then, the chromanone compound was dissolved in 200 cc of methanol and sodium boron hydride was gradually added to the solution to form a chromanol compound. Then, 7.47 g of this chromanol compound was heated at 150° C. to 160° C. together with 4.5 g of anhydrous copper sulfate in a carbon dioxide current for 10 minutes, and the obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 6.9 g of a chromene compound represented by the following formula: ##STR161##
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:26]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([NH:31][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[O:21])=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:28]=[CH:27][C:26]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1cc(N)ccc1-c1ccccc1
Reactant: CCCCCC(=O)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCCCC(Nc1ccc(-c2ccccc2)c(OC)c1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared by the general method exemplified in Example 1 using 3-(4-hexanoyl-benzoylamino)-propionic acid methyl ester (Preparation 5) and 2-methoxy-biphenyl-4-ylamine as starting materials. MS (ES): 475.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([N:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([OH:16])=O)=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:17].C(N1C=CN=C1)(N1C=CN=C1)=O.[Na].[CH:42]([S:47]([NH2:50])(=[O:49])=[O:48])=[CH:43][CH2:44][CH2:45][CH3:46].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:21]=[C:20]([N:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:23])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14](=[O:16])[NH:50][S:47](/[CH:42]=[CH:43]/[CH2:44][CH2:45][CH3:46])(=[O:49])=[O:48])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:17]
Reactant: CCCC=CS(N)(=O)=O
Reactant: CCOC(=O)N(C)c1ccc(Cn2c(C)nc3ccc(C(=O)O)nc32)c(Cl)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCC/C=C/S(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)OCC)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
3-(2-Chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (150 mg) was dissolved in dry N,N-dimethylformamide (1.5 ml), and carbonyldiimidazole (91 mg) was added, which was followed by stirring at room temperature for 1.5 hr. To the reaction mixture was added 1-penten-1-ylsulfonamide sodium salt (96 mg) and the mixture was stirred at room temperature for 7 hr. 1N Hydrochloric acid was added dropwise under ice-cooling to adjust to pH 4. Water (1.5 ml) was added and the mixture was applied to ultrasonic washer for 15 min and then stirred for 15 min. The precipitate was collected by filtration, washed with water, suspended in ethanol (0.5 ml), heated in a boiling bath and stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with ethanol, and recrystallized from N,N-dimethylformamide and water to give 3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (165 mg) as colorless crystals.