Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1)=O.C(OC(=O)C)(=O)C.Cl[C:25](Cl)([F:30])[C:26]([O:28][CH3:29])=[O:27]>[Zn].[Cu]Cl.O1CCCC1>[F:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:1][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)C(F)(Cl)Cl
Reactant: O=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(F)=CC1(c2ccc(OC(F)(F)F)cc2)CC1
Yield: 31.5 %

Procedure:
The method of Example 1 was repeated using zinc powder (1 g), copper (I) chloride (0.16 g), molecular sieve 4A (1.1 g), tetrahydrofuran (18 ml), 1-formyl-1-(4-trifluoromethoxyphenyl)cyclopropane (1.08 g), acetic anhydride (0.6 ml) and methyl dichlorofluoroacetate (0.86 g) to yield the title compound (0.45 g, 34%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:27][CH:26]=1)[CH3:24]
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2cc(NC(=O)c3cccnc3)cnc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N45-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(4-ethylphenyl)-boronic acid (CAN 63139-21-9) as starting materials; LC-MS (UV peak area/ESI) 100%, 402.1409 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:17][C:18]([C:20]1[N:21]=[C:22]([CH2:25]Br)[S:23][CH:24]=1)=[O:19])C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:25][C:22]3[S:23][CH:24]=[C:20]([C:18]([OH:19])=[O:17])[N:21]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)c1csc(CBr)n1
Product: Cc1ccc(-c2ccc(OCc3nc(C(=O)O)cs3)cc2)cc1

Procedure:
2-(4′-Methyl-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure B from 4′-methyl-biphenyl-4-ol (purchased from Maybridge plc, Tintagel, Cornwall, UK or from Intermediate 5) and 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (Intermediate 3). Yield: 70 mg. Mass spectrum (ES) MH+=326.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:17])([C:10]1[N:14]([CH3:15])[C:13](=[O:16])[O:12][N:11]=1)[CH3:9])(C)(C)C.[ClH:19].O1CCOCC1>C(O)C>[ClH:19].[NH2:7][C:8]([C:10]1[N:14]([CH3:15])[C:13](=[O:16])[O:12][N:11]=1)([CH3:9])[CH3:17]
Reactant: Cn1c(C(C)(C)NC(=O)OC(C)(C)C)noc1=O
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cn1c(C(C)(C)N)noc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of [1-methyl-1-(4-methyl-5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (1.45 g, 5.64 mmol) in ethanol (15 mL) was added 4M-HCl in dioxane (5.64 mL, 22.5 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The solution was concentrated in vacuo to a volume of 5 mL. With stirring diethyl ether (15 mL) was added drop by drop over a period of 30 minutes and stirring was continued for another 30 minutes. The precipitate was isolated by filtration, washed with diethyl ether (3×1 mL) and dried in vacuo, to give the title compound (1.0 g, 95%) as white solid; GC-MS (EI) 157.0 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])=[C:6]([C:8]2[C:16]3[C:11](=[C:12]([O:30][CH3:31])[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[CH:15]=3)[N:10]([CH3:32])[CH:9]=2)[CH:7]=1.C(N(C(C)C)C(C)C)C.[CH2:51]([S:53](Cl)(=[O:55])=[O:54])[CH3:52].[OH-].[Na+]>ClCCl>[F:41][C:35]1[CH:36]=[C:37]([F:40])[CH:38]=[CH:39][C:34]=1[O:33][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:53]([CH2:51][CH3:52])(=[O:55])=[O:54])=[CH:7][C:6]=1[C:8]1[C:16]2[C:11](=[C:12]([O:30][CH3:31])[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH2:18]3)[CH:15]=2)[N:10]([CH3:32])[CH:9]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)cc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c3c(OC)nc(C4CCN(C(=O)OC(C)(C)C)CC4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of Example 183B (205 mg, 0.363 mmol) in 10 mL dichloromethane was added N-ethyl-N-isopropylpropan-2-amine (254 μL, 1.452 mmol) and ethanesulfonyl chloride (120 μL, 1.271 mmol). The mixture was stirred at ambient temperature overnight. The mixture was concentrated. The viscous oil residue was taken into dioxane (10 mL) and treated with sodium hydroxide (5446 μL, 5.45 mmol, 1N aqueous solution). The mixture was stirred at ambient temperature for 80 minutes and then quenched with saturated ammonium hydroxide solution, and partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel with a gradient of 0-60% ethyl acetate in heptanes to give the title compound (110 mg, 0.167 mmol, 46.1% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]3[C:21]([CH3:23])([CH3:22])[C:20](=[O:24])[NH:19][N:18]=3)=[N:9]2)=[N:6][CH:7]=1.[CH3:25]CN(C(C)C)C(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([F:15])([F:16])[F:14])=[CH:11][C:10]([C:17]3[C:21]([CH3:22])([CH3:23])[C:20](=[O:24])[N:19]([CH3:25])[N:18]=3)=[N:9]2)=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)NN=C1c1cc(C(F)(F)F)n(-c2ccc(Br)cn2)n1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN1N=C(c2cc(C(F)(F)F)n(-c3ccc(Br)cn3)n2)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Step-3: 1′-(5-Bromopyridin-2-yl)-4,4-dimethyl-5′-(trifluoromethyl)-1H, 1′H-[3,3′-bipyrazol]-5(4H)-one: To a stirred and (0° C.) cooled solution of step-2 intermediate (2.0 g, 4.76 mmol) and DIPEA (1.66 mL, 9.52 mmol) in DCM (20 mL) was added a solution of triphosgene (560 mg, 1.90 mmol) in DCM (5 mL) over a period of 10 min. The reaction mixture was warmed to room temperature and then stirred overnight. Reaction was cooled down to 0° C. and then quenched with ice water (5 mL). Water (25 mL) was added to the reaction followed by DCM (50 mL). The layers were separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and filtered. The filtrate was rotary evaporated to afford 1.50 g (78%) of the title compound as semisolid. 1HNMR (400 MHz, CDCl3) δ 8.85 (s, 1H, D2O exchangeable), 8.59 (d, J=2.0 Hz, 1H), 8.02 (dd, J=2.0 & 8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.31 (s, 1H), 1.60 (s, 6H); ESI-MS (m/z) 402, 404 [(MH)+, Br79,81].
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>ClCCl>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][S:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(C)CCN
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.8 g (30 mmol) of N,N-dimethylethylenediamine are placed in 100 ml of dichloromethane and 8.3 ml (60 mmol) of triethylamine. While cooling with ice a solution of 3.9 ml (30 mmol) of benzenesulphonic acid chloride in 100 ml of dichloromethane is added dropwise and the mixture is stirred overnight at ambient temperature. Water is added and the mixture is extracted with dichloromethane. The organic phase is dried and evaporated down.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].P([O-])([O-])(O)=O.[K+].[K+].S([O-])([O-])(=O)=O.[Mg+2].[Br:29]Br>C(Cl)Cl.O.C(Cl)(Cl)Cl>[Br:29][C:8]1[C:6]2=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=[C:5]2[S:10][CH:9]=1
Reactant: BrBr
Reactant: Clc1ccc2sccc2n1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Clc1ccc2scc(Br)c2n1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
1.00 g of 5-Chloro-thieno[3,2-b]pyridine (5.91 mmol), 497 mg of sodium bicarbonate (5.91 mmol), 1.54 g of potassium hydrogenphosphate (8.87 mmol) and 1.07 g of magnesium sulfate (8.87 mmol) are placed in a flask with 50 ml of chloroform. The reaction mixture is stirred under reflux for 30 min. 0.55 ml of Bromine (10.82 mmol) is added and stirred under reflux overnight. 0.55 ml of Additional bromine (10.82 mmol) is added and stirred under reflux for 1 day. The reaction mixture is cooled to room temperature and water and CH2Cl2 are added. Organic layer is separated. The water layer is adjusted to pH=14 with 5N NaOH and extracted with CH2Cl2. All organic layers are combined together and dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=5:1) to give 796 mg of the title compound (54%). 1H-NMR (CDCl3): 8.12 (d, 1H, J=7.9 Hz), 7.81 (s, 1H), 7.36 (d, 1H, J=7.9 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:13](O)=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>O.Cl>[S:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:13]1
Reactant: Nc1cnc2ccccc2c1S
Reactant: O=CO
Agent: Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: c1ccc2c(c1)ncc1ncsc12
Yield: 80 %

Procedure:
A mixture of 17.62 g (0.1 mole) of 3-amino-4-mercapto-quinoline, 150 ml of 100% formic acid and 1.5 g of sodium pyrosulfite is refluxed for 3 hours. The reaction mixture is cooled, diluted with a mixture of 800 ml of water and 40 ml of concentrated hydrochloric acid, made alkaline to pH 10 by adding a sodium hydroxide solution and extracted three times with 200 ml of benzene each. The benzene solution is evaporated. Thus 15.0 g of thiazolo[4,5-c]quinoline are obtained, m.p.: 114°-116° C., yield 80%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:6]3[CH:20]=[CH:21][NH:22][C:23](=[O:24])[C:5]=3[C:4]=2[CH:3]=1.Br[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33].OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+].N>O.[Cu]I.CS(C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[C:6]3[CH:20]=[CH:21][N:22]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][C:31]=4[C:32]([F:35])([F:34])[F:33])[C:23](=[O:24])[C:5]=3[C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1ccncc1Br
Reactant: COc1ccc(Cn2c3ccc(F)cc3c3c(=O)[nH]ccc32)cc1
Agent: [Cu]I
Agent: N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Cn2c3ccc(F)cc3c3c(=O)n(-c4cnccc4C(F)(F)F)ccc32)cc1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
8-Fluoro-5-(4-methoxybenzyl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (I-64b: 0.15 g, 0.00046 mol) was reacted with 3-bromo-4-(trifluoromethyl)pyridine (0.13 g, 0.00058 mol), 8-hydroxy quinoline (0.016 g, 0.00011 mol), K2CO3 (0.19 g, 0.0013 mol), CuI (0.026 g, 0.00013 mol) and DMSO (3 mL) to afford the crude product. The reaction mass was cooled to room temperature, added to ammonia solution in water and extracted with ethyl acetate. The organic layer was washed with brine solution and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 95 mg of the product (45.23% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].[F:12][CH2:13][CH2:14]I.O>CN(C=O)C>[F:12][CH2:13][CH2:14][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: FCCI
Reactant: COC(=O)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccn1CCF
Reaction time: 0.5 h

Procedure:
Methyl 1H-pyrrole-2-carboxylate (3.0 g, 23.3 mmol) was solved in DMF (40 ml). Sodium hydride (1.40 g, 34.9 mmol, 60% in oil) was added and the mixture was stirred for 30 minutes at room-temperature. 1-Fluoro-2-iodoethane (4.1 g, 23.2 mmol) was added and the mixture was stirred for 15 h at 50° C. Water was added and the mixture was extracted with diethylether. The mixture was washed with saturated aqueous ammonium chloride. The product was purified chromatographically, using a mixture of petroleum and ethylacetate as eluent. Yield 1.1 g (28%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:57]2[CH2:67][CH2:66][C:60]3([C:64](=[O:65])[O:63][CH2:62][CH2:61]3)[CH2:59][CH:58]=2)O1>>[O:42]=[S:38]1(=[O:41])[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][NH:32][C@:16]23[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]2[C@@H:18]2[C@@:13]([CH3:43])([CH2:14][CH2:15]3)[C@@:12]3([CH3:44])[C@@H:21]([C@:22]4([CH3:25])[C@@H:9]([CH2:10][CH2:11]3)[C:8]([CH3:45])([CH3:46])[C:7]([C:57]3[CH2:67][CH2:66][C:60]5([C:64](=[O:65])[O:63][CH2:62][CH2:61]5)[CH2:59][CH:58]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:36][CH2:37]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)OB(C2=CCC3(CCOC3=O)CC2)OC1(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC7(CCOC7=O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the procedure described in general procedure Step 5, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-oxaspiro[4.5]dec-7-en-1-one as reactants and 85° C. The product was obtained as a mixture of diasteroisomers and was used without further purification in the next step. MS: m/e 721 (M+H)+, 2.72 min (method 4).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[CH3:19][C:18]([NH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:20]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A suspension of 13.8 g of 3-nitroaniline and 20 mL of triethylamine in 200 mL methylene chloride was cooled to 0° C. under a nitrogen atmosphere atmosphere and treated with 10.2 g of acetyl chloride, added in a dropwise manner. The reaction mixture was allowed by warm to room temperature overnight. Removal of the volatiles in vacuo gave a crude yellow solid which was washed with 5% aqueous hydrochloric acid, water and was then dried. The yield of 3-nitroacetanilide was 17.4 g as a light yellow solid, m.p. 147°-149° C.; NMR (CDCl3 /DMSO-d6): δ 2.1 (3H, br s), 7.5 (1H, t, J=9 Hz), 8.0 (2H, br t), 8.6 (1H, br s) 10.1 (1H, br s); IR(KBr): 1675, 1550, 1525, 1350 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=O)[CH3:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1.Cl.O1CCOCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[C:19]2[C:18](=[CH:17][CH:16]=1)[NH:21][C:9]([CH3:10])=[C:8]2[C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)Cc1cccc(Br)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c(C)c(-c3cccc(Br)c3)c2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
The ketone from Step 1 (1.065 g, 5 mmol) and 4-methoxyphenylhydrazine hydrochloride (870 mg, 5 mmol) in toluene (20 is mL) were gently warmed up to 60° C. After 1 h, 4M HCl/dioxane (2 mL) was added and the mixture was heated at 60° C. for 1 h. It was then cooled, poured over ice water and ethyl acetate. The organic layer was separated, washed with dilute NaHCO3. Removal of the solvents left a residue which was purified by chromatography over SiO2 to afford the product (433 mg).
Reaction SMILES: [CH3:1][C:2]1[S:9][C:8]2[CH:7]=[CH:6][N:5]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[C:4]=2[C:3]=1[C:21](O)=[O:22].C[O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2([NH2:36])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N(CC)(CCC)CCC.[Li+].[OH-]>CN(C=O)C.O.C1COCC1.CO.CC(O)=O>[CH3:1][C:2]1[S:9][C:8]2[CH:7]=[CH:6][N:5]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=3)[C:4]=2[C:3]=1[C:21]([NH:36][C:33]1([C:30]2[CH:31]=[CH:32][C:27]([C:26]([OH:37])=[O:25])=[CH:28][CH:29]=2)[CH2:35][CH2:34]1)=[O:22]
Reactant: Cc1sc2ccn(Cc3ccc(C(F)(F)F)cc3)c2c1C(=O)O
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: CCCN(CC)CCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1sc2ccn(Cc3ccc(C(F)(F)F)cc3)c2c1C(=O)NC1(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
A mixture of 0.3 g of 2-methyl-4-(4-trifluoromethyl-benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid, 0.25 g of 4-(1-amino-cyclopropyl)-benzoic acid methyl ester, 0.5 g of HATU and 0.25 ml of Pr2NEt in 8 ml of DMF was stirred at room temperature for 16 h. The reaction was then diluted with 30 ml of water and extracted with 100 ml of EtOAc. The organic layer was washed with 50 ml of water and 50 ml of brine and dried over Na2SO4. The extract was filtered, and concentrated to give the crude methyl ester which was dissolved in 20 ml of 1:1 THF/MeOH and treated with 10 ml of 0.5 M aqueous LiOH solution. After stirring for 15 h at room temperature, 1 ml of AcOH was added and the reaction mixture was extracted with 75 ml of EtOAc. The organic layer was washed with 50 ml of brine, dried over Na2SO4. The extract was filtered and concentrated to give 0.25 g of the title compound as a light brown solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]2[NH:11][C:12](=[O:16])[CH:13]([CH3:15])[O:14][C:9]=2[CH:8]=1.[CH3:27]I.O>CN(C)C=O>[Cl:3][C:4]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:27])[C:12](=[O:16])[CH:13]([CH3:15])[O:14][C:9]=2[CH:8]=1
Reactant: CI
Reactant: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
First, 60% sodium hydride (0.2 g) was suspended in dimethylformamide (5 ml), and a solution of 7-(2-chloro -4-trifluoromethylphenoxy)-2-methyl-2H-1,4-benzoxazine-3 (4H)-one (0.4 g) prepared in Example 1 in dimethylformamide (5 ml) was dropwise added thereto while cooling with ice, and the mixture was stirred for 10 min. Then methyl iodide (0.7 g) was added thereto and the mixture was stirred for additional 10 min, and thereafter, water (20 ml) was added thereto to terminate the reaction. The reaction mixture was extracted with ethyl acetate (50 ml×2), washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=3/1) to prepare the title compound (0.4 g) as a colorless crystal (yield: 98%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Ni]>[C:1]1([C@H:7]2[CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: O[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
p-Phenylphenol (VI) (1 kg, 5.88 mols) dissolved in ethanol (2 l) was fed into a 5 l autoclave, and hydrogenation reaction was carried out at a reaction temperature of 150° to 160° C. under a hydrogen pressure of 30 to 40 kg/cm2 using a developed Raney nickel (100 g) as catalyst. When 17.6 mols of hydrogen were absorbed, the reaction was stopped. After cooling, the catalyst was filtered off, and the filtrate was concentrated to remove ethanol. The resulting residue was dissolved in toluene. The toluene solution was washed a few times with 2 N--NaOH aqueous solution and further with water, and toluene was then removed by concentration of the solution. The resulting raw crystals were recrystallized from ethanol to obtain trans-4-phenylcyclohexanol (VII) (200 g) having a melting point of 118.4°-119.2° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[CH:24]1([NH:27][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][N:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)NC2CC2)cn1
Yield: 81 %

Procedure:
As described for example 313b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (19 mg, 0.06 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (17 mg, 81%) which was obtained as a white solid. MS: m/e=352.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[C:3]=1[O:21][CH3:22].[CH2:23](Br)[CH2:24][CH2:25][CH3:26].[OH-].[K+]>CO>[CH2:23]([N:9]1[CH2:8][CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:5]=[C:4]([O:19][CH3:20])[C:3]([O:21][CH3:22])=[C:2]([Cl:1])[C:12]=2[CH2:11][CH2:10]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCBr
Reactant: COc1cc2c(c(Cl)c1OC)CCNCC2c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCc2c(cc(OC)c(OC)c2Cl)C(c2ccccc2)C1

Procedure:
A mixture of 4.5 g of 6-chloro-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 0.02 ml of n-butyl bromide and 0.02 mol of potassium hydroxide is dissolved in 120 ml of dry methanol and refluxed for 48 hours. The reaction mixture is evaporated to dryness, taken up in ethyl acetate and filtered to remove inorganic salts. The filtrate is washed with water, dried and evaporated to give 3-n-butyl-6-chloro-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Product: N#CCc1cccc(N)c1
Reaction time: 2 h

Procedure:
A solution of 3-nitrophenyl acetonitrile (500 mg, 3.1 mmol) in 5% ACOH (10 ml) was heated to 80° C. Iron powder (1.5 g, 27 mmol) was then added and the resulting mixture stirred for 2 h. The reaction mixture was filtered through celite and the filter cake washed with MeCN (4×50 ml). The combined MeCN layers were evaporated in vacuo and the residue was re-dissolved in EtOAc (30 ml) followed by 2M HCl (30 ml). The aqueous layer was separated, basified to pH 10 with 6M NaOH, and extracted with EtOAc (3×80 ml). The combined organic layers were dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound.