Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:5]=1[C:6](OC)=[O:7])[CH3:2].[NH2:17][OH:18]>CO>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:5]=1[C:6]([NH:17][OH:18])=[O:7])[CH3:2]
Reactant: NO
Reactant: CCOc1ccc([N+](=O)[O-])cc1C(=O)OC
Solvent: CO
Product: CCOc1ccc([N+](=O)[O-])cc1C(=O)NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-ethoxy-5-nitrobenzoate (6.099 g, 26.99 mmol) and 50% wt/v aqueous hydroxylamine (40 ml) were taken up in MeOH (100 ml) and stirred at RT overnight. The resulting precipitated yellow solid was collected by filtration, washed with IPA and dried in vacuo. The filtrate was evaporated in vacuo and the residue was triturated with IPA (25 ml). The solid that didn't dissolve was filtered off, washed with a minimum quantity of IPA and dried in vacuo. The two crops of solid were suspended in H2O (300 ml) and the pH was lowered to 2 by careful addition of concentrated HCl. The solid was filtered off, washed with MTBE and dried in vacuo to give 3.9 g of crude 2-ethoxy-5-nitro-N-hydroxybenzamide. The IPA mother liquors from above were combined with the crude 2-ethoxy-5-nitro-N-hydroxybenzamide and evaporated in vacuo. The residue was triturated with CH2Cl2 (25 ml) and the solid was filtered off and dried in vacuo to give 2-ethoxy-5-nitro-N-hydroxybenzamide (2.39 g, 39%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=O)[CH2:13][CH2:14][CH3:15])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:17][C:18]([NH2:21])([CH3:20])[CH3:19]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:17][C:18]([N:21]=[C:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:2]([CH3:1])[CH2:3][CH2:4][CH2:5]2)[CH2:13][CH2:14][CH3:15])([CH3:20])[CH3:19]
Reactant: CCCC(=O)c1ccc2c(c1)CCCN2C
Reactant: CC(C)(C)N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCC(=NC(C)(C)C)c1ccc2c(c1)CCCN2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)butan-1-one (2.94 g, 13.5 mmol) in CH2Cl2 (14 mL) was added 2-methylpropan-2-amine (5.7 mL, 54.2 mmol, 4.0 eq). The mixture was cooled to 0° C. before TiCl4 (1.0M in CH2Cl2, 8.8 mL, 8.8 mmol, 0.65 eq) was added via syringe pump over 30 min. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NaHCO3 (15 mL) then extracted by CH2Cl2 (5×25 mL). The combined organic layers were dried over Na2SO4 then concentrated to give a crude product which was carried over to next step without further purification. LC-MS 273.1 [M+H]+, RT 0.65 min. (1 min Method).
Reaction SMILES: Cl.CO[C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[N:25]([CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[C:26]=[S:27]>ClCCl>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:7][CH:5]2[NH:6][C:26](=[S:27])[N:25]([CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[C:4]2=[O:17])=[CH:9]1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: S=C=NCCN1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(Cc2c[nH]c3ccccc23)NC(=S)N1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.5 %

Procedure:
To a solution of L-tryptophan methyl ester hydrochloride (0.250 mg, 0.001 mol.) in dichloromethane (10 mL) was added triethyl amine (3.0 eq.) followed by 4-(2-isothiocyanato-ethyl)-morpholine (0.190 gm, 0.0011 mol.). The reaction mixture was stirred at room temperature for 24 hr, and then concentrated. The residue obtained was purified by column chromatography on silica gel using 60% ethyl acetate-hexane to give 893-17 (292 mg, 83%): mp 167-169° C., 1H NMR (500 MHz, CDCl3): 2.45-2.51 (m, 6H), 3.02-3.07 (dd, J=9.5 and 15.0 Hz, 1H), 3.46-3.50 (dd, J=4.0 and 15.0 Hz, 1H), 3.65 (m, 4H) 3.89 (d, J=7.0 Hz, 2H), 4.35-4.38 (m, 1H), 6.38 (s, 1H), 7.12 (d, J=2.5 Hz, 1H), 7.16-7.19 (m, 1H), 7.23-7.25 (dd, J=1.5 and 8.0 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:8]=1)([O-])=O.[H][H]>[Pd].CO>[S:9]([N:7]1[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]1)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)n2cc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(N)cn2)cc1
Yield: 71.5 %

Procedure:
4-nitro-1-tosyl-1H-pyrazole (example 9-1c) (3 g, 11.2 mmol) and 10% palladium on carbon (800 mg) in MeOH (150 mL) were stirred under 2 atmospheres of hydrogen on the Parr hydrogenator for 3 hours. The mixture was filtered through celite, concentrated and purified by silica gel chromotography (80% ethyl acetate in hexanes) to afford 1-tosyl-1H-pyrazol-4-amine (1.9 g, 71%) as a pink solid. 1H NMR (CDCl3, 400 MHz) δ 2.40 (s, 3H), 3.01 (bs, 2H), 7.29 (d, 2H, J=8 Hz), 7.41 (d, 1H, J=1.2 Hz), 7.53 (d, 1H, J=1.2 Hz), 7.81 (d, 2H, J=8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[CH:45][C:46]([CH3:49])=[N:47][CH:48]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:41]([CH3:42])=[CH:40][C:39]([C:43]6[CH:48]=[N:47][C:46]([CH3:49])=[CH:45][CH:44]=6)=[CH:38][C:37]=5[CH3:50])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1ccc(-c2cc(C)c(Br)c(C)c2)cn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccc(C)nc6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 5-(4-bromo-3,5-dimethyl-phenyl)-2-methyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.12 min; Mass spectrum (ESI+): m/z=538 [M+H]+.
Reaction SMILES: C(O[C:4](=[O:15])[NH:5][S:6]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)(=[O:8])=[O:7])C.[NH2:16][C:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][C:22]([NH:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:23]([F:28])[CH:24]=2)[N:19]([CH:36]([CH3:38])[CH3:37])[CH:18]=1>C1(C)C=CC=CC=1>[Cl:14][C:11]1[S:10][C:9]([S:6]([NH:5][C:4]([NH:16][C:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][C:22]([NH:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:23]([F:28])[CH:24]=3)[N:19]([CH:36]([CH3:38])[CH3:37])[CH:18]=2)=[O:15])(=[O:7])=[O:8])=[CH:13][CH:12]=1
Reactant: CC(C)n1cc(N)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Solvent: Cc1ccccc1
Product: CC(C)n1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Temperature: 110 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
287 mg of ethyl[(5-chloro-2-thienyl)sulfonyl]carbamate was dissolved in 5.0 ml of toluene, and 250 mg of 3-amino-7-(cyclohexylamino)-6-fluoro-1-isopropylquinolin-4(1H)-one was added, followed by overnight stirring at 110° C. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. Then, ethyl acetate was added and the insoluble materials were collected by filtration, thereby obtaining 280 mg of 5-chloro-N-({[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinolin-3-yl]amino}carbonyl)thiophene-2-sulfonamide.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32](O)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2>>[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:1][CH2:2][C@H:3]4[CH2:7][CH2:6][CH2:5][N:4]4[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Yield: 62.9 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.48 g, 7.37 mmol) was reacted with 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (1.0 g, 2.95 mmol), (prepared as described for the starting material in Example 7), and the product purified by column chromatography, eluting with methanol/methylene chloride (1/9) containing 0.1% triethylamine to give tert-butyl (2R)-2-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]pyrrolidine 1-carboxylate (970 mg, 62%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[CH3:33][C:34]([C:38]1[CH:39]=[CH:40][C:41](=[C:43]([CH3:45])[CH3:44])[CH:42]=1)([CH3:37])[CH2:35][CH3:36]>C1COCC1.CCOCC.O>[CH3:37][C:34]([C:38]1[CH:39]=[CH:40][CH:41]([C:43]([C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)([CH3:44])[CH3:45])[CH:42]=1)([CH3:33])[CH2:35][CH3:36]
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Reactant: CCC(C)(C)C1=CC(=C(C)C)C=C1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(C)(C)C1=CC(C(C)(C)c2cc(C(C)(C)C)cc3c2Cc2ccc(C(C)(C)C)cc2-3)C=C1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
To a solution of 2.14 g (7.7 mmol) of 3,6-di-tert-butylfluorene in 40 ml of THF, 5.0 ml (8.1 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. To the resulting red solution, a solution of 1.81 g (10.3 mmol) of 3-(1,1-dimethylpropyl)-6,6-dimethylfulvene in 30 ml of THF was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 3 days. After the reaction solution was diluted with 100 ml of ether, 5 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was isolated and purified by column chromatography (silica gel, developing solvent: hexane) to obtain 2.06 g (4.53 mmol) of a white solid (yield: 59%). The analyzed values are given below.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][P:26](=[O:29])([OH:28])[OH:27])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1.[OH-].[Na+:31]>>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][P:26](=[O:27])([O-:28])[O-:29])(=[O:23])=[O:24])=[CH:20][CH:21]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1.[Na+:31].[Na+:31].[Na+:31]
Reactant: COc1ccc(-c2c(Cl)ncn2-c2ccc(S(=O)(=O)NP(=O)(O)O)cc2)cc1F
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2c(Cl)ncn2-c2ccc(S(=O)(=O)NP(=O)([O-])[O-])cc2)cc1F

Procedure:
Following a similar procedure to that described in example 2, but using N-[4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]phenylsulfonyl]-phosphoramidic acid (obtained in example 6) instead of diethyl N-[4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]phenylsulfonyl]phosphoramidate and 3 equivalents of NaOH instead of 1, and recrystallizing then the crude product obtained from PriOH, the title compound of the example was obtained as a white solid.
Reaction SMILES: CO[C:3]1[CH2:7][CH2:6][CH2:5][N+:4]=1[CH3:8].[CH3:9][O:10][S:11]([O-:14])(=[O:13])=[O:12].[CH3:15][NH:16][CH3:17]>C1C=CC=CC=1>[CH3:15][N:16]([CH3:17])[C:3]1[CH2:7][CH2:6][CH2:5][N+:4]=1[CH3:8].[CH3:9][O:10][S:11]([O-:14])(=[O:13])=[O:12]
Reactant: CNC
Reactant: COC1=[N+](C)CCC1
Agent: COS(=O)(=O)[O-]
Solvent: c1ccccc1
Product: CN(C)C1=[N+](C)CCC1

Procedure:
Add dropwise, with stirring, 22.5 g of 2-methoxy-1-methyl-1-pyrrolinium-methylsulfate to a solution of 6.76 g of dimethylamine in 45 ml of benzene and then boil the obtained admixture under reflux for 1 hour. Separate off the resulting heavy phase; extract it twice by shaking it out with diethyl ether and then free the extract from solvent residue in a vacuum to obtain 19.4 g (81.4% of theory) of title compound as reddish brown oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:37]>CO.[Pd].[C]>[NH2:1][C@@H:2]([C:10]([NH:12][C@H:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:37]
Reactant: CC(C)(C)OC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC[C@H](NC(=O)[C@H](N)Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
22.0 g of Z-Phe-Ser(tBu)-OtBu are dissolved in methanol and catalytically (Pd/carbon) hydrogenated at pH 4.5 with the addition of methanolic hydrochloric acid by means of an autotitrator. After the hydrogenation is complete, the catalyst is filtered off with suction through kieselguhr, and the filtrate is concentrated. The residue is triturated with diethyl ether. The substance solidifies and can be filtered off with suction.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:35]1([NH:45]N)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:36]4[C:35](=[C:44]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]5=[CH:38][CH:37]=4)[NH:45][C:22]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc([N+](=O)[O-])c4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1-naphthylhydrazine hydrochloride: ESMS m/e: 575.1 (M+H)+.
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:8]=[CH:9][C:10]([CH3:29])=[C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH3:28])[C:20](=[O:27])[N:21]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]3=[CH:15][CH:14]=2)[CH:12]=1)([CH3:6])[CH3:5])=[N+]=[N-]>CCO.[Pd]>[NH2:1][C:4]([C:7]1[CH:8]=[CH:9][C:10]([CH3:29])=[C:11]([C:13]2[N:18]=[C:17]3[N:19]([CH3:28])[C:20](=[O:27])[N:21]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:16]3=[CH:15][CH:14]=2)[CH:12]=1)([CH3:6])[CH3:5]
Reactant: Cc1ccc(C(C)(C)N=[N+]=[N-])cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C(C)(C)N)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reaction time: 15 h

Procedure:
To a solution of 42-1 (1.4 g, 3.6 mmol) in EtOH (9 mL) was added 10% Pd/C (500 mg) and the flask was purged with hydrogen and fitted with a balloon filled with hydrogen gas. After 15 hours, the solution was filtered, concentrated and purified by reverse phase chromatography (1-100% Acetonitrile, 0.1% TFA in H2O) and the desired fractions were concentrated to give product. MS (M+H)+: observed=367.2, calculated=367.5.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([S:37]([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH2:33][CH2:32]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:43]2[CH:44]=[CH:45][C:40]([S:37]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)(=[O:38])=[O:39])=[CH:41][CH:42]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: CN1CCN(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN(S(=O)(=O)c2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc2)CC1
Temperature: 85 °C
Yield: 87.7 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 250 mg) and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfonyl)piperazine (177 mg) in acetonitrile (8 mL) was treated with aqueous sodium carbonate solution (2M, 0.483 mL) and then nitrogen was bubbled through the mixture. 1,1 bis(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added and the mixture was heated at 85° C. under nitrogen for 18 h. The mixture was purified by chromatography on silica eluting with ethyl acetate/isohexane (70:10 to 100:0), then methanol/ethyl acetate (5:95) and then methanol/ethyl acetate/triethylamine (5:95:1) to afford the sub-titled compound (267 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=O.[Cl:25][C:26](Cl)(Cl)[C:27]([F:30])([F:29])[F:28].C(OC(=O)C)(=O)C>[Zn].CN(C)C=O>[Cl:24][C:14]1[CH:15]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:22])[Cl:23])[CH:17]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11]/[CH:12]=[C:26](\[Cl:25])/[C:27]([F:30])([F:29])[F:28]
Reactant: O=CCOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: FC(F)(F)/C(Cl)=C/COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 14 %

Procedure:
To a mixture of 1.21 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetaldehyde, 0.57 g of zinc dust and 10 ml of N,N-dimethylformamide was added 0.82 g of 1,1,1-trichlorotrifluoroethane. After stirring at room temperature for 1.5 hours, 0.44 g of acetic anhydride was added. The reaction mixture was stirred at room temperature for 3 hours and then filtered. The filtrate was poured into 20 ml of diluted hydrochloric acid and extracted twice with 50 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.21 g of (Z)-3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(5-(3-chloro-4,4,4-trifluoro-2-butenyloxy)pentyloxy)benzene [the integrated CF3 signal ratio of Z/E=94/6 as determined by 19F-NMR (CDCl3 /CFCl3)] (yield, 14%), nD26.5 1.5123.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:20][C:19]=2[Cl:30])[N:16]=[CH:15][C:14]=1[C:31]#[N:32]>C(Cl)(Cl)Cl>[C:1]([NH:12][C:13]1[N:17]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([S:25][C:26]([F:27])([F:28])[F:29])=[CH:20][C:19]=2[Cl:30])[N:16]=[CH:15][C:14]=1[C:31]#[N:32])(=[O:4])[CH2:2][CH3:3]
Reactant: N#Cc1cnn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c1N
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1c(C#N)cnn1-c1c(Cl)cc(SC(F)(F)F)cc1Cl
Reaction time: 20 h
Yield: 83.1 %

Procedure:
First 10 ml (0.11 mole) of propionyl chloride and then 1.8 ml (0.02 mole) of pyridine in 15 ml of chloroform are added to a suspension of 3.5 g (0.01 mole) of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylthio-pheny)-pyrazole in 50 ml of chloroform at 0° C., with stirring. A clear solution is obtained, and, when the addition has ended, stirring is continued at room temperature for 20 hours. The solution thus obtained is evaporated to dryness. For working up, the residue is taken up in 50 ml of ethanol, aqueous ammonia is added until the reaction is alkaline, the mixture is heated under reflux for 10 minutes, the volatile constituents are removed in vacuo, the residue is taken up in 100 ml of chloroform, the mixture is washed with water, then with 2N aqueous hydrochloric acid and again with water and dried over sodium sulphate and the solvent is removed in vacuo. 3.4 g (83% of theory) of 5-propionylamino-4-cyano-1-(2,6-dichloro-4-trifluoromethylthio-phenyl)-pyrazole of melting point 153° C. to 156° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=1)[CH2:6][CH2:5]2.[CH3:23][O:24][CH2:25][C:26](Cl)=[O:27]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH:22][C:26](=[O:27])[CH2:25][O:24][CH3:23])[CH:19]=[CH:18][C:16]=3[N:17]=1)[CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1ccc2c(c1)COC(NC1CCc3cc(F)ccc31)=N2
Yield: 40.3 %

Procedure:
Prepared from rac-N2-(5-fluoro-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 11) (100 mg, 0.336 mmol) and methoxyacetyl chloride (34 ul, 0.370 mmol) according to the procedure described for Example 17. Obtained the title compound as a white solid (50 mg, 40%), MS (ISP) m/e=370.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].Cl>C1(C)C(C)=CC=CC=1>[Cl:9][CH2:10][CH2:11][CH2:12][C:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:14]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1ccc(O)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1ccc(OC(=O)CCCCl)cc1
Temperature: 130 °C
Yield: 95.1 %

Procedure:
A mixture of 4-methylphenol (54 g) and 4-chlorobutyryl chloride (77.5 g) was dissolved in xylene (250 ml). The mixture was heated gently until, at about 130° C., a vigorous reaction occurred. After the reaction had subsided, the mixture was heated at reflux for approximately 40 minutes, until the evolution of hydrogen chloride had ceased. The xylene was then removed in vacuo, and the residue was distilled to give 4-methylphenyl 4-chlorobutyrate (101 g), b.p. 116°-118° C./0.2 mm Hg.
Reaction SMILES: [CH3:1][NH2:2].[O:3]1[CH2:29][CH:4]1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)=[CH:12][C:13]([CH3:18])([CH3:17])[O:14]2)=[CH:9][CH:8]=1>C(O)C>[C:19]1([C:11]2[C:10]3[C:15](=[CH:16][C:7]([O:6][CH2:5][CH:4]([OH:3])[CH2:29][NH:2][CH3:1])=[CH:8][CH:9]=3)[O:14][C:13]([CH3:18])([CH3:17])[CH:12]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CN
Reactant: CC1(C)C=C(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Solvent: CCO
Product: CNCC(O)COc1ccc2c(c1)OC(C)(C)C=C2c1cccc2ccccc12
Reaction time: 48 h
Yield: 63 %

Procedure:
Methylamine (9.5 ml) was added to 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-(1-naphthyl)-2H chromene (4.5 g., 0.013 moles) in ethanol (9.5 ml) and the solution left to stand at room temperature for 48 hours. Removal of solvent gave the title compound as an orange oil (3.2 g., 63%). N.M.R. (τCDCl3) 8.54(s, 3H, CH3 --), 8.48(s, 3H, CH3 --), 7.06(s, 3H, N--CH3), 6.72(d, 2H, --CHCH2 --), 6.05(d, 2H, --CH2CH--), 4.31(s. 1H, vinylic CH), 3.40-3.80 (m, 3H, aromatic H's), 2.10-2.75 (m, 7H, aromatic H's).