Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[C:13]([F:43])=[CH:14][C:15]([F:42])=[C:16]([C:18]2[C:19](=[O:41])[N:20]([CH2:39][CH3:40])[C:21]3[C:26]([CH:27]=2)=[CH:25][N:24]=[C:23]([N:28]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH3:29])[CH:22]=3)[CH:17]=1.[N-]=C=O>C1COCC1.CCOC(C)=O>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:28]([CH3:29])[C:23]2[CH:22]=[C:21]3[C:26]([CH:27]=[C:18]([C:16]4[C:15]([F:42])=[CH:14][C:13]([F:43])=[C:12]([NH:11][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)=[O:10])[CH:17]=4)[C:19](=[O:41])[N:20]3[CH2:39][CH3:40])=[CH:25][N:24]=2)=[CH:36][CH:35]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Reactant: O=C=Nc1cccc(F)c1
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(F)c3)c(F)cc2F)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
3-Fluorophenyl isocyanate (81 mg, 0.444 mmol) was added to a solution of Example A7 (200 mg, 0.444 mmol) in THF (5 mL) and the mixture was stirred at RT overnight. The reaction was treated with additional isocyanate (10 mg) and stirred at RT for a further 4 h. The mixture was diluted with EtOAc, washed successively with water, satd. NaHCO3, and brine, dried (Na2SO4), concentrated in vacuo, purified by reverse phase chromatography (MeCN/water with 0.1% TFA) and partially concentrated to give an aqueous solution. The solution was diluted with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried (Na2SO4) and evaporated at reduced pressure to give 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(3-fluorophenyl)urea (207 mg, 79% yield, ˜75% pure) as a light yellow solid, which was used without further purification. MS (ES-API) m/z: 588.2 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]([NH2:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCCCC1>C(OCC)C>[CH:10]([NH:23][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCCBr
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CCOC(=O)CCCNC(c1ccccc1)c1ccccc1

Procedure:
19.5 g of ethyl 4-bromobutyrate, 55 g of benzhydrylamine and 30 ml of cyclohexane are stirred at room temperature for 12 days. The resultant crystal paste is diluted with diethyl ether, filtered at the pump and the filtrate concentrated by evaporation. The residue (after evaporation) is distilled in vacuo. The first run which distils over at 100° to 110° (0.02 mm Hg) is excess benzhydrylamine. The main distillate obtained is 21.1 g (71% of theory) of ethyl 4-benzylhydrylaminobutyrate [B.P. 150° to 155° (0.02 mm Hg)].
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][O:27][CH3:28]>>[CH3:20][O:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][O:27][CH3:28])[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Reactant: COCCNCCOC
Product: COCCN(CCOC)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1H-indazol-5-yl)-amide (Intermediate 16) and bis(2-methoxyethyl)amine (Aldrich), the title compound was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:13]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].[NH:34]1C=N[N:36]=[N:35]1>>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:13]2[C:5]3[O:4][C:3]([C:1]4[NH:36][N:35]=[N:34][N:2]=4)=[CH:8][C:7](=[O:9])[C:6]=3[CH:10]=[CH:11][CH:12]=2)=[CH:21][CH:20]=1
Reactant: N#Cc1cc(=O)c2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1
Reactant: c1nnn[nH]1
Product: O=c1cc(-c2nnn[nH]2)oc2c(COc3ccc(OCc4ccc5ccccc5n4)cc3)cccc12

Procedure:
When the nitrile of Example 12, Step 7 is replaced with the cyano product from Example 33, Step 4 above, 5- 8-(4-(quinolin-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1- benzopyran-2-yl)tetrazole is obtained; m.p. >250° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:12].[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:25]=[CH:24][C:19]([CH2:20][N:21]=[C:22]=[O:23])=[CH:18][CH:17]=1>>[F:1][C:2]1[C:3]([NH:12][C:22]([NH:21][CH2:20][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:26])=[CH:25][CH:24]=2)=[O:23])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Reactant: Nc1c(F)ccc2cnccc12
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)Nc1c(F)ccc2cnccc12

Procedure:
Prepared from 6-fluoroisoquinolin-5-amine (Description 89) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to Description 61. m/z (ES+) 394 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH2:20])[N:19]=[C:15]4[CH:14]=[CH:13][N:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>C(#N)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH:20][C:31]([CH:28]5[CH2:30][CH2:29]5)=[O:32])[N:19]=[C:15]4[CH:14]=[CH:13][N:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Nc1nc2ccnc(-c3ccc4c(c3)OCCO4)n2n1
Reactant: O=C(Cl)C1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2ccnc(-c3ccc4c(c3)OCCO4)n2n1)C1CC1
Temperature: 25 °C

Procedure:
To a solution of 5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-ylamine (0.04 g, 0.148 mmol) in dry acetonitrile (2 mL) was added triethylamine (0.052 mL, 0.371 mmol) followed by cyclopropanecarbonyl chloride (0.034 mL, 0.371 mmol). The reaction mixture was then allowed to warm to ambient temperature, and the solvent removed under reduced pressure. The crude product was purified by preparatory HPLC. 1H NMR (300 MHz, DMSO): 1.84-1.88 (m, 4H), 2.00-2.08 (m, 1H), 4.31-4.36 (m, 4H), 7.06 (d, 1H), 7.64 (d, 1H), 8.21 (dd, 1H), 8.35 (d, 1H), 8.39 (d, 1H), 11.37 (s, 1H). LCMS Method: 2: RT: 3.51 min, MI: 338 [M+1].
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[CH3:13][NH:14][CH3:15]>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[O:3][C:2]([N:14]([CH3:15])[CH3:13])=[N:6][C:5]=2[CH:7]=1
Reactant: CNC
Reactant: COc1ccc2oc(Cl)nc2c1
Solvent: O
Product: COc1ccc2oc(N(C)C)nc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-5-methoxy-benzooxazole (1.52 g, 8.31 mmol) and a 40% solution of dimethylamine in water (15 mL) was refluxed for two hours before it was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a black oil (1.14 g): MS: (+) m/z 397.19 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:34])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(N)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
Into a solution of 4.00 g (16.0 mmol) of tert-butyl 4-(3-aminophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate and 5.60 mL (32.0 mmol) of diisopropylethylamine in 100 mL dichloromethane was slowly added 1.90 mL (19.0 mmol) of isobutyryl chloride. The reaction mixture was stirred at room temperature for 2 hours, washed with water, dried (MgSO4), and concentrated in vacuo. The residue was purified by column chromatography (silica, 50:46:3:1, hexanes:dichloromethane:methanol:isopropyl amine) to afford 2.90 g (52.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.34 (d, 1H, J=7.8 Hz), 7.27 (t, 1H, J=7.8 Hz), 7.11 (d, 1H, J=7.8 Hz), 6.04 (s, 1H), 4.05 (s, 2H), 3.62 (apparent t, 2H, J=4.9 Hz), 2.51 (m, 3H), 1.49 (s, 9H), 1.25 (d, 6H, J=7.4 Hz); ESMS m/e: 345.5 (M+H)+. Anal. Calc. for C20H28N2O3+0.175CHCl3: C, 66.33; H, 7.77; N, 7.67. Found: C, 66.20; H, 7.41; N, 7.88.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:34][CH2:35][CH3:36])=[C:8]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[C:13](=[C:24]3[N:28]([CH3:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[S:25]3)[S:12]2)[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.C1COCC1>[CH2:16]([N:15]1[C:14](=[O:23])[C:13](=[C:24]2[N:28]([CH3:29])[C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[S:25]2)[S:12][C:11]1=[N:10][C:8]1[CH:9]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:34][CH2:35][CH3:36])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1ccc(C(C)O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
The product of Example 38 was reduced with sodium borohydride in 1:1 MeOH/THF and chromatographed (TEA-washed silica gel, 0–10% MeOH/DCM) to afford the title compound. 1H-NMR (CDCl3): δ 7.47–7.54 (3H, m), 7.28–7.37 (4H, m), 7.17 (1H, m), 6.99–7.06 (3H, m), 6.57 (1H, d), 5.19 (2H, s), 4.80 (1H, q), 3.76 (3H, s), 3.01 (2H, q), 1.48 (3H, d), 1.04 (3H, s); MS(ESI): 517 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12]O.C(Cl)Cl.[Br:17]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[Br:17][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: OCCc1c[nH]c2ccc(F)cc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1ccc2[nH]cc(CCBr)c2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-(5-Fluoro-1H-indol-3-yl)-ethanol (20.0 g, 112 mmol) was dissolved in abs. CH2Cl2 (250 ml), and tetrabromomethane (56.0 g, 170 mmol) was added at RT. Triphenylphosphine (44.0 g, 165 mmol) was then added in portions at RT, while cooling with water. The solution was stirred at RT for 2.5 h and then concentrated i. vac. The residue was absorbed on to silica gel and divided into two equal portions. The crude product was purified by flash chromatography over 2 columns each with 500 g of silica gel and cyclohexane/ethyl acetate (9:1→4:1). Yield: 25.4 g (93%), red solid
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[C:20]([O:22][CH3:23])=[O:21]>CCOC(C)=O>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:24][C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1cccs1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1cccs1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(2-thienyl)-propionate (Bachem), the title compound was prepared as a solid (mp=145-147° C.). The reaction was monitored by tlc (Rf=0.9 in 100% EtOAc) and the product was purified by preparative tlc using EtOAc as the eluent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[C@H:10]([CH2:26][O:27][C:28]2[N:29]=[N:30][C:31]([CH2:47][CH2:48][CH2:49][CH3:50])=[C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[CH:36][CH:35]=3)[CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([CH2:26][O:27][C:28]2[N:29]=[N:30][C:31]([CH2:47][CH2:48][CH2:49][CH3:50])=[C:32]([C:34]3[CH:35]=[CH:36][C:37]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[CH:38][CH:39]=3)[CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2OC(=O)c2ccc([N+](=O)[O-])cc2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a stirred solution of (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-(4-nitro-benzoyloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.914 mmol, 0.63 g) in a mixture of methanol (8 mL) and water (2 mL) was added sodium hydroxide (0.3 g) and continued stirring for 3 h at room temperature. The volatiles were removed under reduced pressure and the residue was dissolved in water (20 mL). This was extracted with ethyl acetate (3×15 mL), combined organic layer was dried, filtered and concentrated. The residue was purified by flash silica gel column chromatography by eluting with 20% ethyl acetate in hexanes to provide (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.395 g) as an white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33]C(C1N(C)C(C(S(C2C=CC=CC=2)(=O)=O)N)=CC(=O)C=1OCC1C=CC=CC=1)=O>>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:30]
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)c1
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2cccc(C)c2)n1C
Yield: 60.64 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-04) (250.0 mg, 60.64%) was synthesized as a white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-3-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-04) (400.0 mg, 0.905 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyoxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-01).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[CH3:24])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>N1C=CC=CC=1>[CH3:22][C:21]1[CH:20]=[C:19]([O:23][S:33]([CH3:32])(=[O:35])=[O:34])[CH:18]=[C:17]([CH3:24])[C:16]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:2]([F:1])[CH:7]=2)[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OS(C)(=O)=O)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.9 %

Procedure:
To an ice-cooled solution of ethyl 3-{2-fluoro-4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (310 mg, 0.736 mmol) in pyridine (8 mL) was added dropwise methanesulfonyl chloride (168 mg, 1.47 mmol). The mixture was stirred at room temperature for 2 days. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) to give the title compound (320 mg, yield 87%) as a colorless oil.
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:16]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:11][CH:10]=1)[Si](C(C)(C)C)(C)C.[OH-].[Na+]>CCO>[OH:1][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:16]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1C(c2ccc(OC)cc2)c2ccccc2C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1C(c2ccc(O)cc2)c2ccccc2C1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of ethyl(1RS,2SR,3SR)-1-(4-t-butyldimethylsiloxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylate (723 mg, 1.4 mmol) in EtOH (20 ml) was added 1M NaOH (1.6 ml, 1.6 mmol), and the resulting mixture was stirred at room temperature for 30 min. The mixture was then partitioned between 3M HCl and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with H2O and saturated aqueous NaCi and dried. The solvent was removed in vacuo to afford the title compound (554 mg, 100%).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[OH:9])(=[O:3])[CH3:2].[Na].C(O)C.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17]>>[CH2:16]([O:15][C:14]([CH2:2][C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[OH:9])=[O:3])=[O:18])[CH3:17]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1sccc1O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(=O)c1sccc1O
Reaction time: 15 h

Procedure:
4.8 g (0.0337 mol) of 2-acetyl-3-hydroxythiophene in 150 ml of diethyl carbonate are heated to 90°-100° C. 5 g of small sodium pieces are then added. Stirring is continued for 15 hours at 90°-100° C. To decompose remainders of sodium, a little ethanol is added. For working up, the mixture is extracted twice using 75 ml of water, the aqueous phase is then acidified with 10 ml of concentrated HCl, extracted 3 times with 50 ml portions of ether, dried, distilled in vacuo, and the fraction between 70° and 100° C. (0.6 mbar, educt) and between 113° and 118° C. (0.4 mbar product) is collected.
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[CH3:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:26][CH2:27][CH2:28][NH2:29]>>[F:25][C:24]1[C:19]([CH3:18])=[C:20]([CH2:26][CH2:27][CH2:28][NH:29][C@H:4]2[CH2:5][CH2:6][C@H:1]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[O:14][C:10]=4[CH:9]=3)[CH2:2][CH2:3]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(F)cccc1CCCN
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Product: Cc1c(F)cccc1CCCN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1

Procedure:
Coupling of ketone 5 and 3-(2-methyl-3-fluorophenyl)-1-propylamine, using the method given in Example 1, gave 6-{trans-4-[3-(3-fluoro-2-methylphenyl)propylamino]cyclohexyl}-3H-benzoxazol-2-one (1.4 g, 56%): 1H NMR (500 MHz, DMSO-d6): δ 7.16-7.10 (m, 2H), 7.01-6.93 (m, 4H), 2.65 (dd, J=8, 8 Hz, 2H), 2.60 (dd, J=7, 7 Hz, 2H), 2.49-2.39 (m, 2H), 2.18 (d, J=2 Hz, 3H), 1.98-1.93 (m, 2H), 1.81-1.75 (m, 2H), 1.68-1.61 (m, 2H), 1.45 (dddd, J=13, 13, 13, 3 Hz, 2H), 1.13 (dddd, J=13, 13, 13, 3 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:12]=[C:11](Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[S-:16][C:17]#[N:18].[K+]>C(O)(=O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[N:12]=[C:11]([S:16][C:17]#[N:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: FC(F)(F)c1nc(Cl)c2ccccc2n1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(=O)O
Product: N#CSc1nc(C(F)(F)F)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
46.5 g of 2-trifluoromethyl-4-chloro-quinazoline is added, while stirring, to a mixture of 97 g of potassiumthiocyanate and 200 ml of acetic acid. The reaction mixture is stirred for 2 hours at room temperature, the resultant light-yellow precipitate is drawn off, consecutively washed with a small amount of acetic acid and water and subsequently dried in air. The 2-trifluoromethyl-4-thiocyano-quinazoline thus obtained has a melting point of 134°-136°C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>O1CCCC1>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH:1][C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8]
Reactant: CC(C)(CN)CO
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCC(C)(C)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 32.2 g (0.31 mol) of 3-amino-2,2-dimethyl-propan-1-ol in 60 ml tetrahydrofuran was added dropwise to a solution of 25 g of diketene (0.30 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 150 ml of ethyl acetate. This gave 40.6 g (0.21 mol, 73% yield) of a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=1.[NH2:18][C:19]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:26]([Cl:35])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>>[NH2:18][C:19]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:14]([C:13]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][O:11][C:12]=3[CH3:17])=[O:16])[CH2:31][CH2:30]2)[C:26]([Cl:35])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(Cl)c(N2CCNCC2)cc1N
Reactant: COc1ccccc1-c1noc(C)c1C(=O)O
Product: COC(=O)c1cc(Cl)c(N2CCN(C(=O)c3c(-c4ccccc4OC)noc3C)CC2)cc1N

Procedure:
3-(2-Methoxyphenyl)-5-methylisoxazole-4-carboxylic acid and methyl 2-amino-5-chloro-4-(piperazin-1-yl)benzoate (TFA salt) were coupled under the conditions described in Preparation M to give methyl 2-amino-5-chloro-4-(4-(3-(2-methoxyphenyl)-5-methylisoxazole-4-carbonyl)piperazin-1-yl)benzoate. 1H-NMR (CDCl3, 400 MHz): δ 7.82 (1H, s), 7.60-7.47 (2H, m), 7.13-6.97 (2H, m), 6.01 (1H, s), 3.85 (3H, s), 3.84 (2H, s), 3.80 (3H, s), 3.25 (2H, s), 2.99 (2H, s), 2.58 (3H, s), 2.42 (2H, s).