Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][CH:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>CCO.O>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][CH:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)[Si](C)(C)OCCC1CO1
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCC(O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 29 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]thiazin-3-one (3.56 g, 19.8 mmol; commercial) and (RS)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (prepared according to J. Org. Chem. (2008), 73, 1093; 4.0 g, 19.8 mmol) in EtOH/H2O (9:1; 140 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a brown oil (2.20 g, 29% yield).
Reaction SMILES: CN(C)S(C1C2[N:12]([CH2:15][C:16](O)=[O:17])C=NC=2C=CC=1)(=O)=O.Cl[C:21]1[C:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:22]=1[N+:33]([O-:35])=[O:34]>>[N+:33]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[C:21]=1[NH:12][CH2:15][CH2:16][OH:17])([O-:35])=[O:34]
Reactant: CCCS(=O)(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: CN(C)S(=O)(=O)c1cccc2ncn(CC(=O)O)c12
Product: CCCS(=O)(=O)c1cccc([N+](=O)[O-])c1NCCO
Yield: 99 %

Procedure:
The compound was synthesized in 99% yield according to the procedure described for the synthesis of (7-dimethylsulfamoyl-benzoimidazol-1-yl)-acetic acid, part B, starting from 2-chloro-1-nitro-3-(propylsulfonyl)benzene. MS (ESI) m/z 289 [M+H]. 1H NMR (400 MHz, CDCl3) δ ppm 1.02 (t, J=7.4 Hz, 3H), 1.80-1.70 (m, 3H), 3.13-3.09 (m, 2H), 3.27-3.23 (m, 2H), 3.87-3.84 (m, 2H), 6.88 (t, J=8.0 Hz, 1H), 6.95 (broad s, 1H), 7.91 (dd, J=8.1, 1.5 Hz, 1H), 7.99 (dd, J=7.8, 1.8 Hz, 1H).
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][C:3](=[O:10])[O:2]1.[CH3:12][CH2:13][OH:14]>>[CH2:13]([O:14][C:3](=[O:10])[CH2:4][C:5]1([C:1]([OH:11])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:12]
Reactant: CCO
Reactant: O=C1CC2(CCCC2)C(=O)O1
Product: CCOC(=O)CC1(C(=O)O)CCCC1
Temperature: 70 °C
Reaction time: 22 h

Procedure:
A solution of 2-oxaspiro[4.4]nonane-1,3-dione (522 mg, 3.39 mmol) in anhydrous EtOH (15 ml) was allowed to stir at 70° C. for 22 hours under nitrogen. The reaction mixture was concentrated to give a crude 1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxylic acid (compound A, 672 mg). The product (86% purity) was used for next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 1.24 (t, J=7.2 Hz, 3H) 1.57-1.81 (m, 6H) 2.19-2.25 (m, 2H) 2.69 (s, 2H) 4.12 (q, J=7.2 Hz, 3H) 11.65 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([CH2:8][NH:9][C:10]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[S:34][C:10]([C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C(=O)NCC(=O)c2ccc(Cl)cc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CCOC(=O)c1ccc(-c2ncc(-c3ccc(Cl)cc3)s2)cc1
Yield: 89 %

Procedure:
In the same manner as in Example 111, ethyl 4-[N-(4-chlorobenzoylmethyl)carbamoyl]benzoate was reacted with Lawesson's reagent to obtain ethyl 4-[5-(4-chlorophenyl)-2-thiazolyl]benzoate. The product was recrystallized from xylene-isopropyl ether. Yield: 89%. Pale yellow prisms. Melting point: 167 to 168° C.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:30])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([F:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:21])[CH:17]=2)[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:11](=[O:30])[C:10]=1[C:8]#[N:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(NC1CCCCC1)c1c(O)c2cc(F)ccc2n(Cc2ccc(F)cc2)c1=O
Product: N#Cc1c(Cl)c2cc(F)ccc2n(Cc2ccc(F)cc2)c1=O
Yield: 50 %

Procedure:
A solution of Compound 43 (5.1 g, 12.36 mmol) in 20 ml neat phosphorus oxychloride was heated at 100° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 2.05 g (50%) of yellow solids. M.P. 236° C. 1H NMR (DMSO-d6): δ 5.54 (s, 2H), 7.14 (m, 2H), 7.33 (m, 2H), 7.59 (dd, J=4.0, 9.1 Hz, 1H), 7.72 (td, J=2.8, 7.9 Hz, 1H), 7.91 (dd, J=2.8, 8.9 Hz, 1H). EIMS m/z 331 (M+1).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:20][NH:21][C:22]([CH:24]1[NH:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([NH:33][C:34]2[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=2[CH3:42])=[O:32])[CH2:25]1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][N:26]([CH2:30][C:31]([NH:33][C:34]3[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=3[CH3:42])=[O:32])[CH2:25][CH:24]2[C:22]([NH:21][CH3:20])=[O:23])=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Reactant: CNC(=O)C1CN(CC(=O)Nc2c(C)cc(C)cc2C)CCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)C1CN(CC(=O)Nc2c(C)cc(C)cc2C)CCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
A mixture of 6.7 g of 1,1′-(4-iodobutylidene)bis[4-fluorobenzene], 5.2 g of 3-[(methylamino)carbonyl]-N-(2,4,6-trimethylphenyl)-1-piperazineacetamide, 2.3 g sodium carbonate and 38 ml DMF is stirred for 18 hours at 70° C. The reaction mixture is cooled and poured onto ice-water. The product is extracted with DCM. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is dried, yielding 4.23 g of 4-[4,4-bis(4-fluorophenyl)butyl]-3-[(methylamino)-carbonyl]-N-(2,4,6-trimethylphenyl)-1-piperazineacetamide (compound 1, mp. 82.3° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[C:9]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:18]([CH2:27]Cl)=[N:17][N:16]=2)=[CH:11][CH:10]=1>CN(C)C=O>[C:9]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:18]([CH2:27][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:17][N:16]=2)=[CH:11][CH:10]=1
Reactant: Fc1ccccc1-n1c(CCl)nnc1-c1ccc(-c2ccccc2)cc1
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1-n1c(CN2CCOCC2)nnc1-c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Morpholine (0.599 ml) was dissolved in N,N-dimethylformamide (6 ml), followed by addition of sodium hydride (60%, 275 mg) under ice cooling, and stirred at the same temperature for 30 minutes. Under ice cooling, 3-biphenyl-4-yl-5-chloromethyl-4-(2-fluorophenyl)-4H-1,2,4-triazole (599 mg) was added to the reaction solution, and stirred at ambient temperature for 17 hours. After the reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent: toluene/acetone=3/2 to 1/1), and recrystallized from a mixture solution of n-hexane and ethyl acetate, to afford the entitled compound as white crystal (211 mg, 74%). The physico-chemical values are as follows.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[C:6]([O:10][C:11](=[O:24])[NH:12][CH:13]([CH:21]1[CH2:23][O:22]1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11](=[O:24])[NH:12][CH:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:21]([OH:22])[CH2:23][NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C1CO1
Product: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
To 154.4 Kg isobutylamine, (1-Oxiranyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (53.3 Kg) was added, and then the solution was heated under reflux. Under reduced pressure, isobutylamine was removed from the reaction mixture, and then replaced by toluene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23](Br)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:44]1[O:45][CH:46]=[CH:47][N:48]=1)CCC.[F-].[K+]>O1CCOCC1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:44]4[O:45][CH:46]=[CH:47][N:48]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2ncco2)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
4-[5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.34 mmol, 0.2 g), 2-(tri-n-butylstannyl)oxazole (0.68 mmol, 0.24 g), tetrakis(triphenylphosphine)palladium (0.034 mmol, 0.04 g) in dioxane (5.0 mL) were degassed with nitrogen for 10 min and heated at 90° C. over night under nitrogen. Cooled, KF solution (2.0 M, 10 mL) was added, stirred at room temperature for 30 min. extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4) filtered and concentrated under reduced pressure. The product was purified by column chromatography using 25% ethyl acetate in hexanes to get 4-[6-butyl-5-(4-cyclohexyloxy-3-oxazol-2-yl-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=CC3NC4CCN(CCN(CC)CC)C(=O)C=4C=3C)[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:31].N1CCCCC1.[CH3:38][O:39][CH2:40][C:41](Cl)=[O:42]>O1CCCC1>[F:31][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:41](=[O:42])[CH2:40][O:39][CH3:38])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(N)c(F)cc43)c(C)c2C1=O
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -50 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A stirred solution of d 6-amino-5-fluoro-1,3-dihydro-indol-2-one (2.028 g, 12.2 mmol) obtained from Example 7 in 30 ml of tetrahydrofuran was added with piperidine (1.3 ml). The mixture was cooled to −50° C. in an ethanol-dry ice bath and added with methoxyacetyl chloride (1.35 g, 12.5 mmol) in 20 ml of tetrahydrofuran dropwise. Upon the completion of the addition, the resulting mixture was stirred at the room temperature overnight until the precipitate was formed. The solid was filtered, washed with water and recrystallized from methanol to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide (2.0 g, 69.2%) as a white solid.
Reaction SMILES: C(N1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])C1)C.C[C@H](OC1N=[C:42]2[C:38](N=[C:40](OC)[N:41]2[CH2:44]CCC2CCCNC2)=C(N)N=1)CCC.ICC>>[CH2:42]([N:41]1[CH2:44][CH2:8][CH2:7][CH:6]([CH2:5][CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])[CH2:40]1)[CH3:38]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Solvent: CCI
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCCN(CC)C3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and 2-iodoethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:17]([OH:25])(=[O:24])[C:18]([CH2:20][C:21](O)=[O:22])=[CH2:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:21](=[O:22])[CH2:20][CH:18]([C:17]([OH:25])=[O:24])[CH2:19]3)=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(CCc2ccc(F)cc2)cc1
Product: O=C(O)C1CC(=O)N(c2ccc(CCc3ccc(F)cc3)cc2)C1

Procedure:
In an analogous manner to that described in Example 36 c), the reaction of 4-[2-(4-fluoro-phenyl)-ethyl]-phenylamine with itaconic acid yields the (RS)-1-{4-[2-(4-fluoro-phenyl)-ethyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as a white solid; MS: m/e=326 (M−H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][NH:33]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29]([N:33]4[CH2:34][C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH2:32]4)=[O:30])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Reactant: c1ccc2c(c1)CNC2
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)N4Cc5ccccc5C4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,3-dihydro-1H-isoindole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)#[CH:38].C(NC(C)C)(C)C>C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:38]#[C:37][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: C#Cc1ccccn1
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3c(Cl)cc(C#Cc4ccccn4)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A solution of 4-[3-({4-[(5-chloro-7-iodo-1,3-benzodioxol-4-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]-1-methylpiperazin-2-one (0.17 g, 0.27 mmol), 2-ethynyl pyridine (0.056 g, 0.54 mmol) and diisopropylamine (0.075 ml, 0.54 mmol) in ethyl acetate (5 ml) was cooled to −20 C under a nitrogen atmosphere. To this was added copper (I) iodide (0.016 g, 0.081 mmol) and bis(triphenylphospine)palladium (II) chloride (0.038 g, 0.054 mmol). The reaction mixture was allowed to warm to ambient temperature and then stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 0-8% methanol in dichloromethane to give the product as a light brown solid (0.056 g, 35%). NMR Spectrum: (DMSOd6) 2.02 (m, 2H), 2.50 (t, 2H under DMSO), 2.72 (t, 2H), 2.84 (s, 3H), 3.01 (s, 2H), 3.28 (t, 2H under H2O), 3.94 (s, 3H), 4.20 (t, 2H), 6.23 (s, 2H), 7.21 (s, 1H), 7.32 (s, 1H), 7.45 (dd, 1H), 7.68 (d, 1H), 7.86 (m, 2H), 8.35 (s, 1H), 8.64 (d, 1H), 9.54 (s, 1H). Mass Spectrum: M+H+ 601 and M+H− 599.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[Br:18])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[O:10][C:4]1[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([S:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=2)[CH:3]=1
Reactant: N#Cc1ncc(Br)cc1Oc1ccc(F)cc1Br
Reactant: COc1cccc(S)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Sc2cnc(C#N)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.4 %

Procedure:
A 500 mL flask was charged with 5-bromo-3-(2-bromo-4-fluorophenoxy)picolinonitrile (10 g, 26.9 mmol), 3-methoxybenzenethiol (3.34 mL, 26.9 mmol), and DMF (250 mL). The reaction was cooled to 0° C. and NaH (0.710 g, 29.6 mmol) was added slowly. The reaction stirred for 30 minutes at 0° C. The reaction was poured into saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo to afford 3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)picolinonitrile (12.0 g, 104% yield) as an amber oil.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH:13]=O)=[CH:3]1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18]>N1C=CC=CC=1.N1CCCCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](/[CH:13]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:3]1
Reactant: Cn1cc(C=O)c(=O)c2ccccc21
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cn1cc(/C=C/C(=O)O)c(=O)c2ccccc21

Procedure:
A mixture of 1-methyl-3-formyl-4(1H)-quinolone (5.61 g) and malonic acid (4.5 g) in pyridine (45 ml) with 3 drops piperidine was heated on a steam-bath for two hours. The pyridine was removed in vacuo and the solid residue washed with water and dried. Recrystallisation from DMF/H2O gave the title compound. NMR confirmed the structure as pure trans-isomer, m.p. 248°-250° (with decomposition).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[CH3:5])[CH3:2].[H-].[Na+].[CH3:9][C:10]1[N:11]=[C:12](S(CC2C=CC=CC=2)=O)[O:13][CH:14]=1.O>CN(C)C=O>[CH2:1]([N:3]([C:12]1[O:13][CH:14]=[C:10]([CH3:9])[N:11]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: CCNC(C)=O
Reactant: Cc1coc(S(=O)Cc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(C)=O)c1nc(C)co1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
N-Ethyl-acetamide (1.18 g, 0.0135 m) in dry dimethylformamide (10 ml) was stirred at room temperature under nitrogen during the portionwise addition of 50% sodium hydride/oil dispersion (0.65 g, 0.0135 m). After the addition, the mixture was warmed to 50° C. and then 4-methyl-2-phenylmethylsulphinyloxazole (3.0 g, 0.0135 m) was added. The mixture was stirred at 50° C. for 5 hours and then hydrolysed with water. The solvent was evaporated in vacuo and the residue extracted with diethyl ether. Column chromatography on silica using ether gave a pale yellow oil which gave the title product as a colourless oil on distillation, b.p. 50°-51° C./0.05 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([NH2:13])[S:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[F:14].[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)[CH2:16][CH3:17]>>[F:14][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[N:12]=[C:11]([NH:13][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[S:10][CH:9]=2)=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(-c2csc(N)n2)ccc1F
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3ccc(F)c(C)c3)cs2)cc1

Procedure:
The title compound was prepared from 2-amino-4-(4′-fluoro-3′-methyl)phenylthiazole and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (31.5 m) with puriy >90%. MS (pos) m/z 391.2.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[N:14]=[C:13]4[NH:22][CH:23]=[CH:24][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[N:14]=[C:13]4[N:22]([CH2:32][C:33]5[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=5)[CH:23]=[CH:24][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C

Procedure:
A mixture of methyl 4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.943 g, 2.93 mmol) in N,N-Dimethylformamide (DMF) (6.0 mL) was treated with cesium carbonate (1.906 g, 5.85 mmol) and then 4-(bromomethyl)-1,2-difluorobenzene (0.561 mL, 4.39 mmol) and the mixture was heated to 80° C. for 75 minutes. The mixture was cooled to ambient temperature, diluted with ethyl acetate and then washed with water and brine. The water that was used for washing was back extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford a pale yellow residue: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25-7.17 (m, 2 H), 7.14-6.99 (m, 3 H), 6.96 (ddd, J=2.0, 4.1, 6.2 Hz, 1 H), 6.88 (d, J=8.4 Hz, 1 H), 6.44 (d, J=3.7 Hz, 1 H), 5.45 (s, 2 H), 4.30-4.20 (m, 2 H), 3.69 (s, 3 H), 2.84 (t, J=6.4 Hz, 2 H), 2.68 (s, 3 H), 2.14-1.96 (m, 2 H); LC/MS (m/z) ES+=449 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:2][C:1]1[C:3]2[C:4](=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[NH:5][N:13]=1
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
Following generally the procedure reported by Organic Synthesis 1955, Coll. Vol. 3, 660; 1940, 20, 73, 2-ethyl-5-nitroaniline (1.021 g, 6.14 mmol) was dissolved in glacial acetic acid (40 ml) and the mixture was cooled to 0° C. A solution of sodium nitrite (1 eq, 424 mg) in water (1 ml) was added all at once. Stirring was continued for 15 minutes at 25° C. After 3 hours, residual solids were filtered off and discarded, and the filtrate was allowed to stand for 3 days at room temperature. The solution was concentrate in vacuo, and the residue was diluted with 2 ml of water and stirred vigorously. The solid product was filtered and washed thoroughly with cold water, dried and purified by flash chromatography (4:1 hexanes/ethyl acetate) to give 3-methyl-6-nitro-1H-indazole (436 mg, 40.5%) as a solid.