Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@:7]2([CH3:29])[C:11](=[O:12])[N:10]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O-])=[O:15])[C:9](=[O:21])[N:8]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][C@H:31]([C:40]1[CH:45]=[CH:44][C:43]2[O:46][CH2:47][O:48][C:42]=2[CH:41]=1)[CH2:32][C:33]([O:35]C(C)(C)C)=[O:34]>>[C:1]1([C@@:7]2([CH3:29])[C:11](=[O:12])[N:10]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([NH:30][C@H:31]([C:40]3[CH:45]=[CH:44][C:43]4[O:46][CH2:47][O:48][C:42]=4[CH:41]=3)[CH2:32][C:33]([OH:35])=[O:34])=[O:15])[C:9](=[O:21])[N:8]2[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C[C@@H](C(=O)[O-])N1C(=O)N(Cc2ccccc2)[C@@](C)(c2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1ccc2c(c1)OCO2
Product: CC(C)C[C@@H](C(=O)N[C@@H](CC(=O)O)c1ccc2c(c1)OCO2)N1C(=O)N(Cc2ccccc2)[C@@](C)(c2ccccc2)C1=O

Procedure:
The compound was prepared analogously to Example 1 by reaction of 169.5 with tert-butyl (S)-3-amino-3-(3,4-methylenedioxyphenyl)propionate (prepared analogously to S. G. Davis et al., Tetrahedron Asymmetry 1991, 2, 183), cleavage of the tert-butyl ester with trifluoroacetic acid as described in Example 1, and subsequent purification of the crude product by means of preparative HPLC (RP18: eluent: acetonitrile/water=50/120). ES(+)-MS: 586.4 (M+H)+
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[C:18]([F:21])[CH:17]=[C:16]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[I-].[K+]>C1(N)CC1>[CH:25]1([NH:24][C:22]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][NH:24][CH:25]5[CH2:27][CH2:26]5)=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[C:18]([F:21])[CH:17]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Agent: NC1CC1
Agent: [I-]
Agent: [K+]
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC3CC3)o2)cc1

Procedure:
4′-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 34) (50 mg) and potassium iodide (22 mg) were stirred in cyclopropylamine (2 ml) for 48 hours. The reaction was absorbed onto silica and purified by chromatography on a biotage column (silica, 9 g), eluting with DCM/methanol (99:1). The product fractions were reduced to dryness under vacuum to give N-cyclopropyl-4′-{5-[(cyclopropylamino)methyl]-1,3,4-oxadiazol-2-yl}-5-fluoro-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.C([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(OC(C)(C)C)=O.N1C=CN=C1C=O>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:36][C:35]4[NH:31][CH:32]=[CH:33][N:34]=4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=Cc1ncc[nH]1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN(Cc4ncc[nH]4)CC3)cc2n1

Procedure:
Via 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine, prepared from 1-BOC-piperazine followed by treatment with HCL and subsequent reaction with imidazole-2-carboxaldehyde using standard reductive amination conditions. The amine, 2-chloro-6-[4-(1H-imidazol-2-ylmethyl)-piperazin-1-ylmethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was subsequently isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1>C(O)C.[Pt]=O>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: O=[Pt]
Solvent: CCO
Product: Nc1cc(F)ccc1O
Reaction time: 8 h
Yield: 106.2 %

Procedure:
To a solution of 4-fluoro-2-nitrophenol (48.3 g, 0.30 mole) in 300 ml ethanol was added 0.24 g platinum oxide under nitrogen atmosphere. The mixture was hydrogenated with a Parr shaker for 8 hours at 45 psi. The catalyst was filtered off and the filtrate was concentrated to leave 40.5 g of the title compound as a brown powder. The NMR spectrum showed absorption at 4.79 (br.s, 2H), 6.11 (m, 1H), 6.36 (dd, 1H, J=11, 3 Hz), 6.53 (dd, 1H, J=5, 9 Hz) and 8.89 (s, 1H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12)CCC.[C:23]([NH:27][C:28]([C:30]1[C:38]2[C:33](=[N:34][CH:35]=[C:36](Br)[N:37]=2)[N:32]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:31]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.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.[Cu]I>[C:23]([NH:27][C:28]([C:30]1[C:38]2[C:33](=[N:34][CH:35]=[C:36]([C:6]3[N:7]=[CH:8][N:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=34)[N:37]=2)[N:32]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:31]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncn2ccccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ncn4ccccc34)nc12
Temperature: 90 °C
Yield: 45.5 %

Procedure:
To a solution of 1-tributylstannyl-imidazo[1,5-a]pyridine (250 mg, 0.61 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (150 mg, 0.35 mmol) in DMF (2 mL) were added Pd(PPh3)4 (20 mg, 0.018 mmol) and copper(I) iodide (13 mg, 0.07 mmol). The reaction mixture was heated at 90° C. for 2 h then cooled to room temperature overnight. The reaction was quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) then dried over MgSO4 and concentrated. The residue was chromatographed once with 0% to 3% MeOH/CH2Cl2 (0.5% NH4OH) and then with 30% to 60% EtOAc/hexanes to afford 74 mg (45%) of 2-imidazo[1,5-a]pyridin-1-yl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a bright yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 9.35 (s, 1H), 8.53 (d, J=9.4 Hz, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 8.12 (d, J=7.2 Hz, 1H), 8.05 (s, 1H), 6.99 (dd, J=9.4, 6.6 Hz, 1H), 6.77-6.87 (m, 1H), 5.74 (s, 2H), 3.54-3.68 (m, 2H), 1.67 (s, 9H), 0.90-1.06 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:35]=1[CH2:36][CH2:37][NH2:38].C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:18])[NH:38][CH2:37][CH2:36][C:35]3[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:34]=3[Cl:33])=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4Cl)cc3)c(Cl)cc21
Temperature: 5 °C
Reaction time: 20 h

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid was dissolved in 700 mL of dichloromethane containing 8 drops of DMF and cooled to 5° C. Oxalyl chloride (31 mL, 355 mmol) was added as a solution in 10 mL of dichloromethane dropwise over 20 minutes keeping the reaction temperature between 8 and 11° C. After stirring at ambient temperature for 20 hours, the solution was cooled to 0° C. and 2,4-dichlorophenethyl amine (55 mL, 365 mmol) was added as a solution in 20 mL of dichloromethane dropwise over 20 minutes keeping the reaction temperature below 10° C. To the resulting thick, cream-colored slurry was added diisopropyl ethyl amine (70 mL, 402 mmol) dropwise over 20 minutes keeping the reaction temperature below 10° C. After 3 hours at ambient temperature, the reaction mixture was diluted with 2 L of dichloromethane and washed sequentially with three 500 mL portions of 1 N HCl, two 500 mL portions of water and two 500 mL portions of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 178 g of crude ethyl 6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate. The crude material was slurried in hot ethyl acetate, cooled to ambient temperature and the solids were collected, washing with 20% ethyl acetate in hexanes. The white solids were dried under high vacuum to give ethyl 6-chloro-7-(4-(2,4-dichlorophenethyl-carbamoyl)phenoxy)chroman-4-carboxylate (145 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.4 Hz, 2H), 7.40 (s, 1H), 7.36 (s, 1H), 7.20 (s, 2H), 6.96 (d, J=8.6 Hz, 2H), 6.53 (s, 1H), 6.12 (t, J=5.3 Hz, 1H), 4.21-4.29 (m, 4H), 3.67-3.75 (m, 3H), 3.05 (t, J=6.7 Hz, 2H), 2.30-2.35 (m, 1H), 2.05-2.14 (m, 1H), 1.31 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].[C:34]([O:38][CH3:39])(=[O:37])[CH:35]=[CH2:36]>>[CH3:39][O:38][C:34](=[O:37])[CH2:35][CH2:36][N:13]1[C:12](=[O:22])[C:11]2([CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=3)[CH2:24][CH2:23]2)[N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14]1
Reactant: C=CC(=O)OC
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Product: COC(=O)CCN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=558.2 (M+H+), was prepared in accordance with the general method of example 59 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and methyl acrylate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][CH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=1)([O-])=O.Cl.[OH-].[NH4+]>O.C(OCC)(=O)C>[C:15]1([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][C:6]3[CH:5]=[C:4]([NH2:1])[CH:23]=[CH:22][CH:21]=3)[N:14]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(OCc2cccc(-c3ccccc3)n2)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccc(OCc2cccc(-c3ccccc3)n2)c1
Temperature: 90 °C
Yield: 86.9 %

Procedure:
A suspension of 6.2 g (0.02 mol) of 6-[(3-nitrophenoxy)methyl]-2-phenylpyridine in a solution of 50.0 g (0.18 mol) of ferrous sulfate heptahydrate and 0.3 ml of concentrated hydrochloric acid in 100 ml of water is heated on a steambath to 90° C. Concentrated ammonium hydroxide is added in 3 increments of 10 ml over a period of 10 minutes. Heating is discontinued and the reaction mixture is allowed to cool over a period of 45 minutes while vigorously stirring. The reaction mixture is diluted with 300 ml of water/300 ml of ethyl acetate and filtered through Celite. The filter cake is extracted once with 300 ml of ethyl acetate, and the combined ethyl acetate solution is concentrated in vacuo to obtain an oil (4.8 g). The oil is chromatographed with ethyl acetate/hexane as eluent. Fractions 8-11 are combined and concentrated to obtain 2.0 g (37%) of an oil, MS (CI) 277 (M+ H). The product is used without further purification in subsequent reactions.
Reaction SMILES: C[O:2][C:3]1[CH:38]=[CH:37][C:6]2[C:7]3[C:8]([CH:19]([C:22]4[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)=[CH:24][CH:23]=4)[O:20][CH2:21][C:5]=2[CH:4]=1)=[C:9]1[C:14](=[CH:15][CH:16]=3)[CH:13]=[C:12]([O:17]C)[CH:11]=[CH:10]1.C(S)C.[Na].O.[ClH:44]>CN(C=O)C.C(OCC)(=O)C>[ClH:44].[N:29]1([CH2:28][CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]([CH:19]3[C:8]4=[C:9]5[C:14](=[CH:15][CH:16]=[C:7]4[C:6]4[CH:37]=[CH:38][C:3]([OH:2])=[CH:4][C:5]=4[CH2:21][O:20]3)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]5)=[CH:36][CH:35]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COc1ccc2c(c1)COC(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(OC)ccc12
Agent: Cl
Agent: [Na]
Solvent: CCS
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc2c(c1)COC(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2cc(O)ccc12

Procedure:
Dissolve 1-{2-[4-(2,8-dimethoxy-11,13-dihydro-12-oxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-11-yl)-phenoxy]-ethyl}-piperidine (195 mg, 0.383 mmol) in DMF. Add sodium ethanethiol (306 mg, 3.65 mmol) and reflux. Reflux the reaction for 48 hours. Add more sodium ethanethiol (230 mg) and reflux for an additional 10 hours. Pour reaction onto ice and partion between water and ethyl acetate. Bring aqueous layer to a pH of about 1-2 using 6M HCl. Extract the aqueous layer three times with ethyl acetate. Combine extracts and wash with brine. Concentrate in vacuo and purify on a SCX column to yield 62 mg of free base title compound. Extract the aqueous layer again to retrieve more product. Combine the products and purify by precipitation from ether. Filter the solid and redissolve with methanol and 1M HCl. Concentrate in vacuo to yield 140 mg of the title compound. 1H NMR (d6-DMSO) δ 10.87 (s, 1H), 10.02 (s, 1H), 9.71 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.15 (m, 1H), 6.83 (d, J=1.8 Hz, 2H), 6.7 (m, 4H), 6.58 (m, 3H), 4.50 (ab, Jab=12.5 Hz, 1H), 4.32 (ab, Jab=11.3 Hz, 1H), 4.24 (s, 2H), 3.32 (m, 4H), 2.90 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=S(=O)(OCC1CCCCO1)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cn(C(CC2CCCCO2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
4.20 g (11.2 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 4.17 g (16.8 mmol) of tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulphonate (racemate) and 11.8 ml (11.8 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 125 ml of THF were reacted according to General Method 7B. Purification by column chromatography (100 g silica cartridge, flow rate: 50 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 2.6 g (49% of theory)
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH2:27]>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH:27][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=1
Reactant: NCCc1ccccc1F
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Product: CCCCCCCCOc1ccc(CNCCc2ccccc2F)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-(octyloxy)benzaldehyde and 2-(2-fluorophenyl)ethylamine gave the title compound as an oil. HPLC (Condition A), Rt: 4.37 min (HPLC purity: 76.0%).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[C:7](Cl)=[C:8]([Cl:12])[CH:9]=[CH:10][CH:11]=1>C(O)=O>[Cl:12][C:8]1[CH:9]=[C:10]([Cl:1])[CH:11]=[C:6]([Cl:5])[CH:7]=1
Reactant: [Cl-]
Reactant: Clc1cccc(Cl)c1Cl
Agent: [Al+3]
Solvent: O=CO
Product: Clc1cc(Cl)cc(Cl)c1

Procedure:
To carry out the process according to the invention, the formic acid and the aluminum trichloride are added to the trichlorobenzene which has initially been introduced, and the mixture in the reactor is warmed to the desired temperature in the absence of moisture. The reaction mixture is worked up by filtering it off from the catalyst, washing the residue neutral with water, and distilling the filtrate in the customary manner to isolate the pure 1,3,5-trichlorobenzene. The non- isomerized trichlorobenzenes, which are obtained, for example, as a distillation residue, can be recycled to the isomerization. By this measure, the yield of 1,3,5-trichlorobenzene can be further increased.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]1OS(C)(=O)=O)=[O:4].N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=1)=[O:4]
Reactant: COC(=O)C1CCCC2(CCCC2)C1OS(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=CC2(CCCC2)CCC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 37.3 %

Procedure:
To a solution of the crude 6-methanesulfonyloxy-spiro[4.5]decane-7-carboxylic acid methyl ester (22 g) obtained in Step 4 in tetrahydrofuran (135 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (13.8 mL), followed by stirring the reaction mixture at 60° C. for 1.5 hours. After ice-cooling and adding 1N aqueous hydrochloric acid solution (102 mL), the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=3:97 to 25:75) to give spiro[4.5]dec-6-ene-7-carboxylic acid methyl ester (5.485 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([Br:17])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:7])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CC(=O)c1ccccc1OC
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)C(Br)C(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(2-methoxy-phenyl)-3-oxo-propionic acid ethyl ester (5.3 g, 23.9 mmol; prepared as reported in J. Org. Chem. 2001, 66, 6323-6332) in carbon tetrachloride (50 ml) was added of N-bromosuccinimide (5.1 g, 28.7 mmol) portion-wise The reaction mixture was stirred at room temperature under an Ar atmosphere for 4 hours. Water was added, the resulting mixture was extracted with CHCl3, and the organics were dried over Na2SO4 and evaporated under reduced pressure to yield the title compound as a yellow oil. 1H NMR (200 MHz, CDCl3) δ 1.25 (t, 3H, COOCH2CH3, J=7), 3.92 (s, 3H, OCH3), 4.25 (q, 2H, COOCH2CH3, J=6.4), 5.82 (s, 1H, CHBr), 6.97-7.11 (m, 2H, Ar), 7.51-7.60 (m, 1H, Ar), 7.90-7.95 (m, 1H, Ar).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]1(=O)[O:13][C:11](=[O:12])[CH:10]=[CH:9]1>C(O)(=O)C>[O:12]=[C:11]1[CH:10]=[CH:9][C:8](=[O:13])[N:1]1[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C1C=CC(=O)O1
Reactant: NCCCC(=O)O
Solvent: CC(=O)O
Product: O=C(O)CCCN1C(=O)C=CC1=O
Temperature: 130 °C
Yield: 48.2 %

Procedure:
20.0 g (193.9 mmol) of 4-aminobutyric acid is mixed with 19 g of maleic acid anhydride, 290 ml of acetic acid, and it is heated for 4 hours in an oil bath at 130° C. It is azeotropically concentrated by evaporation with repeated addition of toluene, the residue is dissolved in dichloromethane and purified by chromatography on fine silica gel. 17.1 g (93.4 mmol, 48%) of the title compound is isolated as a crystalline solid.
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[N:10][OH:11])[CH:2]=[CH2:3].[CH3:12][N:13]=[C:14]=[O:15]>CC(C)=O.C(N(CC)CC)C>[CH2:1]([N:4]1[C:8](=[O:9])[CH2:7][S:6][C:5]1=[N:10][O:11][C:14](=[O:15])[NH:13][CH3:12])[CH:2]=[CH2:3]
Reactant: CN=C=O
Reactant: C=CCN1C(=O)CSC1=NO
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CCN1C(=O)CSC1=NOC(=O)NC
Reaction time: 8 h

Procedure:
To a solution of (1.7 g) 3-allyl-2-oximino-4-thiazolidinone in 20 ml of acetone was added 1.0 ml methylisocyanate and 1 drop of triethylamine. The mixture was placed in a pressure bottle and left standing overnight at ambient temperature. The solution was concentrated to a solid residue. Recrystallized from ethyl acetate. Weight 1.7 g. m.p. 108°-110°C.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([S:42]([CH3:41])(=[O:44])=[O:43])[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)Nc2c(C)cc3cn(S(C)(=O)=O)nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a suspension of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropylamide (0.800 g, 1.71 mmol) in dichloromethane (5.0 mL) was added triethylamine (0.476 mL, 3.42 mmol), followed by methanesulphonyl chloride (0.265 mL, 3.42 mmol). The dark colored homogeneous reaction mixture was stirred for 1 h at 20° C. The reaction mixture was then concentrated in vacuo and the residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 4:1) yielding a brown solid that was recrystallized from ethyl acetate to afford the title compound as colourless crystals with a melting range of 135-175° C. (with decomposition).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH:14]=[CH:13][C:12]=1[I:22])[CH3:9].[C]=[O:24].C[CH2:26][O:27][CH2:28]C>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:8]([O:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH:14]=[CH:13][C:12]=1[C:26]([O:27][CH3:28])=[O:24])[CH3:9].[CH2:8]([O:10][C:11]1[CH:16]=[C:15]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[CH:14]=[CH:13][C:12]=1[I:22])[CH3:9]
Reactant: CCOCC
Reactant: [C]=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCOc1cc(C(C)(C)CO)ccc1I
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOc1cc(C(C)(C)CO)ccc1C(=O)OC
Yield: 48 %

Procedure:
Triethylamine (3.5 mL, 25.1 mmol) was added to a solution 2-ethoxy-4-(2-hydroxy-1,1-dimethylethyl)iodobenzene (4.0 g, 12.5 mmol) in methanol (20 mL) under an atmosphere of nitrogen. The reaction was purged twice with carbon monoxide, and palladium (II) acetate (0.2 g, 0.9 mmol) was added. The reaction was stirred at 80° C. for 18 h under a positive pressure of carbon monoxide. The reaction was diluted with ether, washed with 10% hydrochloric acid, aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by flash chromatography over silica gel using 20-75% ethyl acetate in hexanes gave methyl 2-ethoxy-4-(2-hydroxy-1,1-dimethylethyl)benzoate (1.5 g, 48%) as a yellow oil and 0.91 g of unreacted 2-ethoxy-4-(2-hydroxy-1,1-dimethylethyl)iodobenzene.