Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([S:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.[Na+].[C:21](O)(=O)C.CN(C)C=O>ClC1C=CC=CC=1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:12]2[CH:11]=[C:10]([CH3:19])[CH:15]=[CH:14][C:13]=2[S:16]([CH3:21])(=[O:18])=[O:17])=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(=O)O
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(C)(=O)=O)c(-c2c[nH]c3ccccc23)c1
Temperature: 150 °C

Procedure:
A stirred mixture of 5.0 g (0.043 mole) of indole, 1.5 g (0.05 mole) of p-formaldehyde, 7.65 g (0.043 mole) of sodium p-toluenesulfinate, 3.87 ml of glacial acetic acid and 36.6 ml of N,N-dimethylformamide was heated at approximately 150° C. for approximately four hours. The slightly cooled reaction mixture was then slowly poured with stirring into approximately 110 ml of water and 75.0 ml of chlorobenzene was added. The layers were separated after approximately twenty minutes and the water layer extracted a second time with 75.0 ml of fresh chlorobenzene and separated. The organic extracts were combined, washed with cold water and separated. A solid separated and was collected by filtration from the combined chlorobenzene layers and dried to obtain 2.18 g of [(3-indolyl)(4-methylphenylsulfonyl)]methane (Formula X: R=4--CH3 ; R1 =R2 =R3 =R4 =H; n=0) as a white solid which melted at 152°-153° C. developing a dark purple color.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:33][C:2]([F:1])([F:34])[C:3]1[CH:32]=[CH:31][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)COc1cc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc([C@@H]2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)cc1OCC(=O)O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A mixture of 3-(3-ethoxycarbonylmethoxy-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester (118 mg, 0.25 mmol), potassium carbonate (68 mg, 0.49 mmol), methanol (10 mL) and water (2 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 110 mg (97%) of (S)-3-(3-carboxymethoxy-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a white solid.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:13](=O)([O-:15])[O-:14].[Cs+].[Cs+].C(=O)=O.COC1C=CC(CCl)=CC=1>CN(C)C=O>[CH2:2]([O:3][C:13](=[O:14])[OH:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:1]([O:11][CH3:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: COC(=O)[C@@H](O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: COc1ccc(CCl)cc1
Agent: O=C=O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(O)c1ccccc1
Product: O=C(O)OCc1ccccc1
Temperature: 25 °C
Yield: 190.7 %

Procedure:
Methyl (S)-(+)-mandelate (332 mg, 2 mmol) is dissolved in anhydrous N,N-dimethylforamide (8 mL), and powdered cesium carbonate (1.95 g, 6 mmol, 3 eq) is added. The suspension is then stirred at room temperature while passing carbon dioxide gas for 1 hour before 4-methoxybenzyl chloride (0.81 mL, 6 mmol, 3 eq) is added to the solution. Carbon dioxide gas is continuously bubbled through the solution for another 2˜3 hours until the starting material is consumed. The reaction is quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The resulting organic layer is washed consecutively with water (3×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo provides an oil, which is purified by column chromatography (9:1 Hexanes-EtOAc) to yield 607 mg of the desired methyl mandelate benzyl carbonate (92%): IR (thin film) 3036, 2957, 2838, 1748, 1614, 1517, 1456, 1383, 1246, 1175, 1028, 928, 824 cm−1; 1H NMR (360 MHz, CDCl3) d 3.73 (s, 3H), 3.79 (s, 3H), 5.16 (s, 2 H), 5.88 (s, 1H), 6.88-7.48 (m, 9 H); 13C NMR (90 MHz, CDCl3) d 52.57, 55.11, 70.04, 113.81, 127.47, 128.67, 129.30, 130.26, 133.10, 154.27, 159.83, 168.90. EM Anal. Calcd. C18H18O6: C, 65.45; H, 5.49. Found: C, 65.51; H, 5.55.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:23])[N:4]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1.S(OCC)(O[CH2:28]C)(=O)=O>>[Cl:1][C:2]1[C:3](=[O:23])[N:4]([C:19]([CH3:20])([CH3:22])[CH3:21])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([O:18][CH3:28])=[O:17])=[CH:14][CH:15]=1
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(C)(C)n1ncc(NCc2ccc(C(=O)O)cc2)c(Cl)c1=O
Product: COC(=O)c1ccc(CNc2cnn(C(C)(C)C)c(=O)c2Cl)cc1

Procedure:
The compounds as identified in Table 12 were prepared in the synthetic manner and after-treatment similar to those in Example 5 except that the carboxylic acids with Y1, Y2, Y3, R1, R2 and R3 as identified in Table 12 were used instead of the starting 4-chloro-5-(4-carboxybenzylamino)-2-t-butyl-3(2H)pyridazinone used in Example 5. For the preparation of Compound No. 52, diethyl sulfate was used as an esterifying agent. In the NMR data, only the characteristic absorptions are given in Table 12.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH:10]([C:11]2[O:12][C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH2:9][CH2:8][C:7]1=[O:28].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:37]([O:36][C:34]([CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][N:6]1[CH:10]([C:11]2[O:12][C:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)[CH2:9][CH2:8][C:7]1=[O:28])=[O:35])[CH3:38]
Reactant: O=C1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1Cc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc(CN2C(=O)CCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 101.7 %

Procedure:
A solution of 1-(3-hydroxybenzyl)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.13 g), ethyl bromoacetate (0.21 g), potassium carbonate (99 mg) and potassium iodide (catalytic amount) in acetonitrile (10 ml) was refluxed for 9 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-(3-ethoxycarbonylmethoxybenzyl)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (0.16 g). MS (m/z): 497 (M+ +1) NMR (CDCl3, δ): 1.28 (3H, t, J=7.1 Hz), 2.20-2.96 (4H, m), 4.23 (2H, q, J=7.1 Hz), 4.38 (1H, d, J=14.7 Hz), 4.43 (2H, s), 4.70 (1H, d, J=14.7 Hz), 4.76 (1H, m), 6.70-6.87 (3H, m), 7.15 (1H, t, J=7.8 Hz), 7.33-7.56 (6H, m), 7.57-7.61 (4H, m)
Reaction SMILES: [OH:1][C:2](C1C=C2C(=CC=1)C=C(C(OC)=O)C=C2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[OH:44][C:45]([C:73]1[CH:74]=[C:75]2[C:80](=[CH:81][CH:82]=1)[CH:79]=[C:78](C(O)=O)[CH:77]=[CH:76]2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.C(=O)([O-])[O-].[NH4+].[NH4+].C1(P([N:106]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C.O.C(N(CC)CC)C>[OH:1][C:2]([C:78]1[CH:79]=[C:80]2[C:75](=[CH:76][CH:77]=1)[CH:74]=[C:73]([C:45]([NH2:106])=[O:44])[CH:82]=[CH:81]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(O)(c1ccc2cc(C(N)=O)ccc2c1)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.0 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid and this compound was dissolved in DMF (10 mL). Ammonium carbonate (558 mg), diphenylphosphorylazide (0.91 mL) and triethylamine (0.98 mL) were added and the resulting mixture was stirred at room temperature for 12 h. The mixture was diluted with water, extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluent; hexane:THF=1:2) to give the titled compound (1.96 g) as a colorless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.[I:27]I>C1COCC1>[I:27][C:3]1[C:2]([NH:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11])=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncccc1I
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
N-(pyridin-2-yl)pivalamide (14.25 g, 80 mmole) and TMEDA (29.80 ml, 200 mmole) were dissolved in THF (400 ml) under nitrogen and n-BuLi (125 ml, 200 mmole; 1.6 M solution in n-hexane) was added dropwise at −75° C. The mixture was stirred for 15 minutes at −75° C. and then for 2 hours at −10° C. After renewed cooling to −75° C. a solution of iodine (50.76 g, 200 mmole) in THF (200 ml) was added dropwise and the reaction mixture was stirred for 2 hours. The mixture was heated to 0° C. and quenched with saturated aqueous sodium thiosulfate solution. The aqueous phase was extracted with DCM (2×150 ml) and the combined organic phases were dried over MgSO4. After filtering off the drying agent and removing the solvent on a rotary evaporator, the residue was purified by column chromatography (ether: cyclohexane=3:1) and N-(3-iodopyridin-2-yl)pivalamide (14.80 g, 61%) was thereby obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][NH:14][CH2:15][C:16]([NH2:18])=[O:17].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[ClH:20].[NH2:18][C:16](=[O:17])[CH2:15][N:14]([CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:19])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: CN(C)CCCOc1ccccc1CNCC(N)=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CN(C)CCCOc1ccccc1CN(CC(N)=O)C(=O)c1ccc(Cl)cc1
Product: Cl
Reaction time: 16 h

Procedure:
Ten grams of 2-[[[2-[3-(Dimethylamino)propoxy]phenyl]methyl]amino]acetamide (see Example 2B) and 7.1 g of p-chlorobenzoyl chloride are reacted in 110 ml of chloroform as described in Example 1. The finely-divided, solid product separates at the end of the addition; crude yield, after standing for about 16 hours at room temperature, 10.2 g; melting point 195°-197° C. dec, sintering at 175° C. Work-up of the mother liquor does not yield any additional product. Following crystallization (of 9.7 g) from 50 ml of warm methanol -100 ml of ether, the material weighs 6.3 g; melting point 198°-200° C., dec, sintering at 175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([N:8]2[C:16]([Cl:17])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)[CH:7]=1.[S-:19][C:20]#[N:21].[NH4+].BrBr.O>C(O)(=O)C>[NH2:21][C:20]1[S:19][C:3]2[CH:4]=[C:5]([F:18])[C:6]([N:8]3[C:16]([Cl:17])=[C:15]4[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]4)=[N:9]3)=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2cc(-n3nc4c(c3Cl)CCCC4)c(F)cc2s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
2-(5-Amino-2-fluorophenyl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (22.97 g) was dissolved in 95% aqueous acetic acid (79.53 g), and ammonium thiocyanate (15.92 g) was added thereto at room temperature (ca. 20° C.). To the resultant mixture, a solution of bromine (15.89 g) in acetic acid (23.77 g) was dropwise added in 105 minutes. After being allowed to stand overnight, the mixture was heated to 100° C., and hot water (173 ml) was added thereto, followed by filtration. The filtrate was cooled and neutralized with sodium carbonate. The precipitated crystals were collected by filtration and dried to give 2-(2-amino-6-fluorobenzothiazol-5-yl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (8.77 g). m.p., 212.4° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15](=[O:29])[CH2:16][C:17]1[C:18](=[O:28])[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([OH:27])[CH:21]=2>>[CH3:13][O:14][C:15](=[O:29])[CH2:16][C:17]1[C:18](=[O:28])[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([O:27][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:12])[CH:21]=2
Reactant: COC(=O)Cc1cc2ccc(O)cc2[nH]c1=O
Reactant: CC(C)(C)OC(=O)NCCCBr
Product: COC(=O)Cc1cc2ccc(OCCCNC(=O)OC(C)(C)C)cc2[nH]c1=O

Procedure:
The title compound is prepared according to the procedure of Example 75 except that (3-bromopropyl)-carbamic acid tert-butyl ester is used in place of (2-bromoethyl)-carbamic acid tert-butyl ester and that (7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester is used in place of (7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[C:13]3[C:12]([C:24]#[N:25])=[CH:11]2)(=O)=O)C=CC=CC=1.CCO.[OH-].[Na+]>ClCCl.CO>[S:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]1[CH:18]=[C:13]2[C:12]([C:24]#[N:25])=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: N#Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3cccs3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: N#Cc1c[nH]c2ncc(-c3cccs3)cc12
Temperature: 105 °C
Yield: 67.3 %

Procedure:
A mixture of 11 (18.3 mg, 50.1 μmol), EtOH (2.0 mL) and 10% aqueous NaOH (1.0 mL) was refluxed (oil bath temp. 105° C.) for 40 min. The mixture was poured onto water (3 mL), extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated. The product was isolated by PTLC using dichloromethane:methanol (19:1) as eluent to give 12 as a white solid (7.6 mg, 68%); 1H NMR (400 MHz, CDCl3) δ 10.30-10.10 (bs, NH), 10.74 (d, J=1.9 Hz, 1H), 8.31 (d, J=1.9 Hz, 1H), 7.90 (s, 1H), 7.39 (m, 2H), 7.16 (dd, J=5.0, 3.6 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][OH:21])[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][C:11]=1F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].O>C1COCC1>[CH2:1]([N:8]1[C:9](=[O:18])[C:10]2[CH:15]=[CH:14][N+:13]([O-:16])=[CH:12][C:11]=2[O:21][CH2:20][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc[n+]([O-])cc1F)N(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2cc[n+]([O-])cc2OCCN1Cc1ccccc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
To a solution of the compound (0.60 g) obtained in step 3 in THF (15 mL) was added sodium hydride (60% in oil, 0.34 g), and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was poured into water, and the resultant product was extracted three times with ethyl acetate. The organic layer was washed with brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 80% ethyl acetate/hexane→5% ammonia/ethyl acetate) to give 4-benzyl-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one 8-oxide (0.27 g, 48%) as a white powder.
Reaction SMILES: [CH:1]1([N:4]([CH3:19])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:51])[C:23]([C:26]1[CH:31]=[CH:30][C:29](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:28][CH:27]=1)([CH3:25])[CH3:24].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:20][O:21][C:22](=[O:51])[C:23]([C:26]1[CH:27]=[CH:28][C:29]([C:18]#[C:17][C:9]2[CH:8]=[CH:7][C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:19])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:30][CH:31]=1)([CH3:25])[CH3:24]
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2N(C)C1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene (Intermediate 168, 0.16 g, 0.63 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.18 g, 0.58 mmol), triethyl amine (3 mL), copper(I)iodide (0.048 g, 0.25 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.027 mmol) followed by flash column chromatography over silica gel (230–400 mesh) and preparative normal phase HPLC using 6% ethyl acetate in hexane as the mobile phase, the title compound was obtained (0.14 g, 56%).
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:3]([OH:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:1][CH:2]([CH:3]([OH:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of 20 mg of the resultant compound of Example 11 and 0.05 ml of triethylamine in 1 ml of dichloromethane was cooled to 0° C. and treated with 0.01 ml of acetic anhydride. After 30 min, the solution was partitioned between water and dichloromethane, and the organic phase was dried over Na2SO4 and concentrated to give 23 mg (100%) of the desired compound (Rf 0.5, 10% methanol in chloroform). Mass spectrum: (M+H)+ =413.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([F:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14]([O:17]C(=O)C)(=O)[CH3:15].[N:21]([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[C:14]([N:1]1[C:2]2[CH:11]=[CH:10][C:9]([F:12])=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=2[CH:13]=[N:21]1)(=[O:17])[CH3:15]
Reactant: O=N[O-]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1c(F)ccc(N)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1c(F)ccc2c1cnn2C(C)=O
Temperature: 75 °C
Reaction time: 16 h
Yield: 5 %

Procedure:
Methyl 3-amino-6-fluoro-2-methylbenzoate (7.50 g, 0.041 mol) was dissolved in 150 mL of acetic acid. To this was added acetic anhydride (14.6 g, 0.143 mol) and the mixture was warmed to 75° C. Sodium nitrite (11.3 g, 0.164 mol) was added in portions to the reaction mixture (evolution of an gas observed). The mixture was stirred at 75° C. for 16 hours, then allowed to cool to ambient temperature, and then poured into cold 10% aqueous potassium carbonate solution. This material was extracted twice with EtOAc, the extracts dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (1:1 EtOAc/Hexanes) afforded 0.48 g of methyl 1-acetyl-5-fluoro-1H-indazole-4-carboxylate. The crude material was then added to 5 mL of 4M HCl/dioxane and 15 mL of methanol in a pressure tube and heated to 60° C. for 2 hours. The mixture was concentrated under reduced pressure and the resulting solids were taken up in 10% aqueous potassium carbonate/EtOAc. The organic layer was isolated, dried over sodium sulfate and concentrated under reduced pressure to give 0.483 g (5%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=2)[C:6]1=[O:18].[N:23]1([CH2:29][CH2:30][NH2:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl-:1].[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([NH:31][CH2:30][CH2:29][NH+:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:17])[CH:11]=2)[C:6]1=[O:18]
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1ccccc1Cl)C2=O
Reactant: NCCN1CCCCC1
Product: O=C(NCC[NH+]1CCCCC1)c1ccc2c(c1)C(=O)N(Cc1ccccc1Cl)C2=O
Product: [Cl-]

Procedure:
2-(2-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 2-piperidin-1-yl-ethylamine (113 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 131 mg (90%) was obtained by following the procedure described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[CH:4][CH:3]=1.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:10]=1[C:11](Cl)=[O:12]>C1(C)C=CC=CC=1>[CH3:9][C:10]([C:4]1[CH:3]=[C:2]([NH:1][C:11](=[O:12])[C:10]2[C:9]([O:8][CH3:7])=[CH:17][CH:16]=[CH:15][C:14]=2[O:18][CH3:19])[S:6][N:5]=1)([CH3:14])[CH3:11]
Reactant: Nc1ccns1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C(=O)Nc1cc(C(C)(C)C)ns1
Yield: 30 %

Procedure:
A solution of the 5-amino-isothiazole and 1.1 g of 2,6-dimethoxybenzoyl chloride in 50 ml of toluene was heated at reflux for two hours, during which time a precipitate formed. The precipitate was collected by filtration and dried to give 340 mg of N-[3-(1,1-dimethylethyl)-5-isothiazolyl]-2,6-dimethoxybenzamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=[C:4]([O:17][CH3:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.COC1C=C(C2C=CC=CC=2)N=C(N2C=CC(C(F)(F)F)=N2)N=1>>[CH3:18][O:17][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[N:5]=1
Reactant: COc1cc(Cl)nc(-n2ccc(C(F)(F)F)n2)n1
Reactant: COc1ccc(B(O)O)cc1
Agent: COc1cc(-c2ccccc2)nc(-n2ccc(C(F)(F)F)n2)n1
Product: COc1ccc(-c2cc(OC)nc(-n3ccc(C(F)(F)F)n3)n2)cc1
Yield: 55 %

Procedure:
4-Methoxy-6-(4-methoxy-phenyl)-2-(3-trifluoromethyl-pyrazol-1-yl)-pyrimidine 307d was synthesized from compound 305 (1 g, 3.59 mmol) and (4-methoxy-phenyl)-boronic acid 306d (819 mg, 5.39 mmol), according to the procedure as described for compound 307b, as a beige solid in 55% yield. MS (ESI, EI+): m/z=351 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[NH:5][NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].FC(F)(F)[C:28]([OH:30])=[O:29]>>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[NH:5][NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:28]([O:30][C:8]([CH3:13])([CH3:9])[CH3:7])=[O:29])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)CC[C@H](NNC(=O)c1ccc(N)cc1[N+](=O)[O-])C(=O)OC
Reactant: O=C(O)C(F)(F)F
Product: COC(=O)CC[C@H](NNC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC

Procedure:
The synthesis was achieved in analogy to example 3. From 17 g of dimethyl-N-(4-(tert.-butoxycarbonylamino)-2-nitrobenzamido)-L-glutamate 19.5 g of N-(4-amino-2-nitrobenzamido)-L-glutamic acid-dimethylester×trifluoroacetic acid salt were obtained which were used directly in example 4(c).