Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:26])([F:25])[CH:8]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[O:9][Si](CC)(CC)CC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[F:26][C:7]([F:6])([F:25])[CH:8]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[OH:9]
Reactant: CC[Si](CC)(CC)OC(c1ccnc(C#N)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C(O)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
To 40 ml of tetrahydrofuran was added 12 g of 4-[2,2,2-trifluoro-1-(triethylsilyloxy)ethyl]pyridine-2-carbonitrile, and 15 ml of tetrabutylammonium fluoride (1M tetrahydrofuran solution) was added at 0° C. After the mixture was stirred at room temperature for 5 hours, water was added to the reaction solution, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 5.6 g of 4-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carbonitrile.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([OH:18])=[C:12]([C:14](OC)=[O:15])[N:13]=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:14]([C:12]2[N:13]=[C:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:9][C:10](=[O:19])[C:11]=2[OH:18])=[O:15])=[CH:29][CH:28]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Product: O=C(NCc1ccc(F)cc1)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Yield: 17.9 %

Procedure:
The synthesis performed as in Example 21 using methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.070 g, 208 μmol) and 4-fluorobenzylamine (0.5 ml; 4.38 mmol) to provide the title compound as an off-white solid (0.016 g; 18%). LCMS: m/z=430 (MH+).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][N:3]=1.Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[CH:14]1([CH2:13][N:4]2[C:5]3[C:10](=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=3)[C:2]([I:1])=[N:3]2)[CH2:16][CH2:15]1
Reactant: Cc1ccc2[nH]nc(I)c2c1
Reactant: BrCC1CC1
Product: Cc1ccc2c(c1)c(I)nn2CC1CC1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield from 3-iodo-5-methyl-indazole and (bromomethyl)cyclopropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.38-0.41 (2H, m), 0.54-0.59 (2H, m), 1.31-1.34 (1H, s), 2.48 (3H, s), 4.24 (2H, d, J=7.2 Hz), 7.23-7.29 (3H, m).
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=2)[C:5](=[O:13])[C:4]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:15])=[CH:3]1.[CH2:25]([OH:28])[C:26]#[CH:27]>C(NCC)C.C(O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:27]#[C:26][CH2:25][OH:28])=[CH:9][CH:10]=2)[C:5](=[O:13])[C:4]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:15])=[CH:3]1
Reactant: Nn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCNCC
Product: Nn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Amino-N-(4-chlorobenzyl)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.25 g) from Preparation No. 57, copper (I) iodide (32 mg), and bis(triphenylphosphine)palladium (II) chloride (19 mg) are suspended in diethylamine (8 mL). Propargyl alcohol (39 μL) is added and the mixture is allowed to stir at room temperature for 16 h. The mixture is diluted with ethanol and then concentrated in vacuo. The crude solid is triturated with dichloromethane and recrystallized in acetic acid to affording 76 mg of the title compound as a beige solid.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:5]2[CH:12]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:14][C:4]=2[C:3]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[CH:28]([C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1B(O)O)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:22]1([C:3]2[C:4]3[S:14][C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][C:5]=3[N:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]=2[C:31]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:30]=2[CH:28]=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(B(O)O)c(C=O)c1
Reactant: COC(=O)Cn1c(Br)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)Cn1c(-c2ccc(OC)cc2C=O)c(C2CCCCC2)c2sc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Yield: 57 %

Procedure:
tert-Butyl 5-bromo-6-cyclohexyl-4-(2-methoxy-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate (1 eq., prepared as described in Example 1, Step 3) and 2-formyl-4-methoxyphenylboronic acid (1.5 eq.) were dissolved in dioxane (0.1 M) and treated with 2 M Na2CO3 solution (2 eq.). The solution was degassed by bubbling argon through it and Pd(PPh3)2Cl2 (0.1 eq.) was added. The reaction mixture was heated to reflux for 20 min. After cooling down to RT, the mixture was diluted with EtOAc and washed with 1 N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo and the residue purified by chromatography (PE:EtOAc, 9:1) to afford the pure title compound (57%) as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 9.64 (s, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 7.41-7.38 (m, 2H), 4.92 (d, J 18.0, 1H), 4.73 (d, J 18.0, 1H), 3.90 (s, 3H), 3.50 (s, 3H), 2.14-2.09 (m, 1H), 1.73-1.19 (m, 10H), 1.54 (s, 9H). MS (ES+) m/z: 534 [M+Na]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[SH:31])([CH3:24])[CH3:23].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)c1ccccc1S
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)c1ccccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.05 mmol of 2-isopropylbenzenethiol, and 1.05 mmol of piperidine in 20 mL of dichloromethane. The product was triturated with ether to afford a solid (m.p. 216°-217° C.). 1H NMR (DMSO-d6) δ 1.17 (d, J=6.8 Hz, 6 H), 3.20 (m, 1 H), 3.77 (bs, 2 H), 5.64 (d, 1 H), 6.45 (t, 1 H), 6.92 (t, 1 H), 7.12 (d, 1 H), 7.32 -7.48 (m, 10 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.ClC1C=CC=C(C(OO)=[O:20])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-:20])=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Oc1cccc2cccnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1cccc2cccc(O)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
To a solution of 8-hydroxyquinoline (1.45 g, 10 mmol) in dichloromethane (50 ml) was added 3-chloroperbenzoic acid (MCPBA) (1.24 g, 13 mmol). The mixture was stirred at room temperature for 10 min, poured into 1.0N sodium bicarbonate (100 ml), and then extracted with dichloromethane (3×50 ml). The extract was washed with water, dried over magnesium sulfate, and evaporated to give a brown solid which was crystallized from dichloromethane and diethyl ether affording 8-Hydroxyquinoline 1-oxide (5a) (1.34 g, 83%) as yellow needle crystals. mp: 132°-133° C.; 1H-NMR (CDCl3): δ7.04-8.28 (m, 6H, Ar--H), 15.02 (br s, 1H, OH).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:8]([CH3:26])[C:9](=[O:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][C:13]([CH3:23])=[C:12]([CH3:24])[CH:11]=2)(=O)=O.[NH3:27].CO>C1COCC1>[NH2:27][CH2:6][C:7]1[N:8]([CH3:26])[C:9](=[O:25])[C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][C:13]([CH3:23])=[C:12]([CH3:24])[CH:11]=2
Reactant: N
Reactant: Cc1cc2c(-c3ccccc3)c(COS(C)(=O)=O)n(C)c(=O)c2cc1C
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c(-c3ccccc3)c(CN)n(C)c(=O)c2cc1C
Temperature: 140 °C

Procedure:
A mixture of the compound (0.68 g) obtained in Step 1, THF (20 ml) and 15% ammonia/methanol (20 ml) was heated for 20 hours at 140° C. in a sealed tube. The solvent was distilled off. To the residue was added ethyl acetate, and the mixture was washed with an aqueous solution of potassium carbonate and water, successively, then dried (MgSO4). The solvent was distilled off to leave the title compound as colorless crystals (0.37 g),
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([NH:17]C(=O)OCC3C=CC=CC=3)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].C([O-])=O.[NH4+]>[Pd].CO>[NH2:17][C:12]1[CH:13]=[C:14]2[C:9]([C:8]3[CH:7]=[C:6]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]=3[NH:15]2)=[CH:10][CH:11]=1
Reactant: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(NC(=O)OCc5ccccc5)ccc4c3c2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(N)ccc4c3c2)c1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
A mixture of benzyl 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazol-2-ylcarbamate (95 mg, 0.204 mmol, Example 136), palladium on carbon (10%) (39.5 mg, 0.037 mmol) and ammonium formate (77 mg, 1.224 mmol) in MeOH (5 mL) was flushed with nitrogen and heated at reflux for 1 hr. The reaction mixture was cooled to room temperature and filtered. The solvent was removed from the filtrate to leave 7-amino-3-(3-methoxyphenyl)-9H-carbazole-1-carboxamide (68 mg, 0.189 mmol, 93% yield) as a solid. MS (ESI) m/z 332.1 (M+H). 1H NMR (MeOD) δ ppm 8.31 (1H, d, J=1.53 Hz), 8.02 (1H, d, J=1.53 Hz), 7.89 (1H, d, J=8.24 Hz), 7.26 -7.47 (3H, m), 6.83-7.01 (2H, m), 6.71 (1H, dd, J=8.24, 1.83 Hz), 3.91 (3H, s).
Reaction SMILES: C([Li])CCC.Br[C:7]1[O:11][C:10]([CH2:12][CH2:13][CH3:14])=[N:9][C:8]=1[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[CH2:31][CH2:30][C:29]([N+:37]([O-:39])=[O:38])=[CH:28]2>C1COCC1>[CH3:36][O:35][C:34]1[CH:33]=[C:32]2[C:27](=[CH:26][C:25]=1[O:24][CH3:23])[CH:28]([C:7]1[O:11][C:10]([CH2:12][CH2:13][CH3:14])=[N:9][C:8]=1[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH:29]([N+:37]([O-:39])=[O:38])[CH2:30][CH2:31]2
Reactant: CCCc1nc(COC2CCCCO2)c(Br)o1
Reactant: COc1cc2c(cc1OC)CCC([N+](=O)[O-])=C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1nc(COC2CCCCO2)c(C2c3cc(OC)c(OC)cc3CCC2[N+](=O)[O-])o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
n-Butyllithium (2.5M in hexane, 10 mmol) was added to a solution of the compound from step 29c (2.70 g, 8.88 mmol) in 40 mL of THF cooled to -78° C. The resulting yellow solution was stirred for 30 min at -78° C., and a solution of 1,2-dihydro-6,7-dimethoxy-3-nitronaphthalene (2.227 g, 9.48 mmol), from Example 1b, precooled to -78° C., was added via cannula. The reaction was stirred for 2 hours at -78° C., then the reaction was quenched by the addition of 10 mL of satd. NH4Cl. After warming to room temperature, the organic layer was separated, and the aqueous layer was extracted with 2×50 mL of methylene chloride. The organics were combined, dried over MgSO4 and concentrated. The crude product was dissolved in 45 mL of methanol and treated with 8 mL of triethylamine. This solution was stirred for 15 hours at room temperature. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel, eluting with 30-60% ethyl acetate in hexane, to afford after removal of the solvent and drying, 3.64 g (89% yield) of the title product as an oil. MS: 461 (M+H)+. NMR showed a mixture of diastereomers.
Reaction SMILES: [CH2:1]([OH:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:14]([O:16][CH2:17]Cl)[CH3:15].C(OCC)(=O)C>CN(C)C=O>[CH2:14]([O:16][CH2:17][O:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)[CH3:15]
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCOCc1ccc2c(c1)OCO2
Reaction time: 0.5 h

Procedure:
4.56 g of piperonyl alcohol and 1.20 g of 60% sodium hydride were suspended in 30 ml of N,N-dimethylformamide. After stirring for 30 minutes under ice-cooling, 2.28 ml of chloromethyl ethyl ether was added thereto, and the mixture was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution. The mixture was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:20), to give 4.98 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3].Cl[C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][C:16]=2[C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:12]=[CH:11][N:10]=1.C(OCC)C>C(Cl)Cl.Cl>[CH3:22][CH:20]([C:18]1[S:19][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:14]=2)=[C:16]([C:23]2[CH:24]=[C:25]([NH:29][S:30]([C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:17]=1)[CH3:21]
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2)c(-c2ccnc(Cl)n2)s1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1
Temperature: 56 °C
Yield: 21.1 %

Procedure:
[2-(Methylsulfonyl)ethyl]amine (267 mg, 2.169 mmol) and N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide (100 mg, 0.217 mmol) were combined and heated to 56° C. overnight. The reaction mixture was cooled to rt and diluted with DCM and 10% aqueous HCl. The layers were separated and the water layer was extracted twice more with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated to yield an oil. The oil was chromatographed on silica gel eluting with 100% DCM to 4:6 [DCM:(9:1 EtOAc:MeOH)]. The clean fractions were combined and concentrated to yield an oil. Diethyl ether was added to the oil and concentrated to obtain the title compound as a light brown solid (25.1 mg, 20% yield). 1H NMR (400 MHz, DMSO-d6 heated to 60° C.) δ ppm 10.53-10.65 (m, 1H) 8.06-8.16 (m, 1H) 7.88 (s, 1H) 7.30-7.42 (m, 1H) 7.16-7.30 (m, 4H) 7.05 (d, J=3.6 Hz, 1H) 6.53-6.65 (m, 1H) 6.14-6.27 (m, 1H) 3.59-3.74 (m, 2H) 3.24-3.43 (m, 3H) 2.97 (br. s., 3H) 1.36 (dd, J=6.6, 2.7 Hz, 6H). MS (ESI): 548.0[M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].C([Li])CCC.[C:15]1(=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.Cl>O1CCCC1>[CH2:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)([CH3:3])[CH3:2])=[CH:16]1
Reactant: O=C1CCc2ccccc21
Reactant: CC(C)c1ccccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C1=CCc2ccccc21)c1ccccn1

Procedure:
A solution of 10.8 g (0.09 mol) of 2-isopropylpyridine in 47 ml of tetrahydrofuran was cooled to −20° C. and 62.5 ml of n-butyllithium (1.6M in hexane, 0.11 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature and was stirred for a further one hour. A solution of 15.84 g (0.12 mol) of 1-indanone in 12 ml of tetrahydrofuran was then added at such a rate that the temperature remained at 25° C. The mixture was stirred for a further 12 hours and hydrolyzed with 200 ml of dilute hydrochloric acid. The organic phase was separated off, the aqueous phase was extracted once with diethyl ether, the aqueous phase was subsequently neutralized with aqueous ammonia solution and was extracted three times with 100 ml each time of chloroform. The organic phases were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. This gave 16.6 g (77%) of 2-[1H-inden-3-yl)-1-methylethyl]pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([F:20])([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.Cl.[OH:24][NH2:25].C([O-])(=O)C.[Na+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([F:20])([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[N:25][OH:24])=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=O)cc2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=NO)cc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-fluoro-3-(4-formyl-phenyl)-azetidine-1-carboxylic acid tert-butyl ester (4.5 g, 16.11 mmol, 1 eq) in mixture of methanol (50 mL) and water (40 mL) was added hydroxyl amine hydrochloride (1.66 g, 24.17 mmol, 1.5 eq) followed by addition of sodium acetate (2.37 g, 29.0 mmol, 1.8 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 24 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford to yellow colored residue, which was diluted by water (120 mL) and extracted with ethyl acetate (3×80 mL). Combined organic phase was washed with brine solution (70 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get yellow semi solid (2.3 g, Crude). Crude was purified by Combiflash using 40 g Redisep column. Desired compound was eluted in 19% ethyl acetate in hexane to afford title compound as yellow semi solid (1.0 g, 21.1%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.20-4.27 (m, 2H), 4.36-4.44 (m, 2H), 7.47 (d, J=8.28 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 8.13 (s, 1H). LC-MS (m/z): 293.1 (M−H).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]=[C:11]1[N:15](C(OC(C)(C)C)=O)[CH:14]([CH2:23][O:24]C(OC(C)(C)C)=O)[CH2:13][S:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O>[OH:24][CH2:23][CH:14]1[CH2:13][S:12][C:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[N:15]1
Reactant: CC(C)(C)OC(=O)N=C1SCC(COC(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1=NC(CO)CS1
Temperature: 20 °C
Reaction time: 4 h
Yield: 34.4 %

Procedure:
10 cm3 of aqueous 1N sodium hydroxide are added to a solution of 2 g of tert-butyl 2-[(tert-butoxycarbonyl)imino]-(4RS)-4-[(tert-butoxycarbonyl)oxy]methyl-1,3-thiazolidine-3-carboxylate in 20 cm3 of methanol and the mixture is then stirred at a temperature in the region of 20° C. for 4 hours. The reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained is taken up in 30 cm3 of water, filtered and washed with ethyl acetate and then with water. 0.37 g of tert-butyl N-[(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolyl]-carbamate is obtained in the form of a white solid [mass spectrum: DCI m/z=233 MH30 m/z=177 (M—C4H7)+].
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8](Cl)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][O:20][C:21]2[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>O.ClCCl>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH2:16][CH2:17]2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1ccc(OCCC2CCNCC2)cc1
Reactant: CCCCc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCc1ccc(N2CCC(CCOc3ccc(C(=O)OCC)cc3)CC2)nn1
Temperature: 140 °C
Reaction time: 4 h
Yield: 20.8 %

Procedure:
A mixture of 2.4 parts of 3-butyl-6-chloropyridazine, 4.2 parts of ethyl 4-[2-(4-piperidinyl)ethoxy]benzoate and 2.1 parts of sodium carbonate was stirred for 4 hours at 140° C. After cooling, the reaction mixture was taken up in water and dichloromethane. The separated organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off, washed with 2,2'-oxybispropane and dried at 50° C., yielding 1.2 parts (20.8%) of ethyl 4-[2-[1-(6-butyl-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoate; mp. 91.4° C. (comp. 84).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:11])[CH2:10][CH2:9]2)=[C:4]([F:12])[CH:3]=1.C(Cl)Cl.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:11][Si:20]([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21])[CH2:9][CH2:10]2)=[C:4]([F:12])[CH:3]=1
Reactant: OC1(c2ccc(Br)cc2F)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1(c2ccc(Br)cc2F)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(4-bromo-2-fluorophenyl)cyclopropanol (9.01 g, 39.0 mmol, 1 eq) in DCM (100 mL) imidazole (5.33 g, 78 mmol, 2 eq) was added at 0° C. followed by TBDMSCl (7.08 g, 46.8 mmol, 1.2 eq) and the reaction mixture was stirred for 3 h. The reaction mixture was washed with water (100 mL), brine (100 mL), dried over Na2SO4 and the solvent was evaporated to get (1-(4-bromo-2-fluorophenyl)cyclopropoxy)(tert-butyl)dimethylsilane which was purified by CC using PE as eluent to yield pure (1-(4-bromo-2-fluorophenyl)cyclopropoxy)(tert-butyl)dimethylsilane (9.01 g, 67%; TLC system: PE, Rf: 0.8) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[F:18][C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24](O)=[O:25]>>[CH:8]1([NH:7][C:5]([C:4]2[CH:11]=[CH:12][C:13]([C:14]([F:15])([F:16])[F:17])=[C:2]([NH:1][C:24](=[O:25])[C:23]3[CH:27]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=3[N+:28]([O-:30])=[O:29])[CH:3]=2)=[O:6])[CH2:9][CH2:10]1
Reactant: Nc1cc(C(=O)NC2CC2)ccc1C(F)(F)F
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Product: O=C(NC1CC1)c1ccc(C(F)(F)F)c(NC(=O)c2cc(F)ccc2[N+](=O)[O-])c1

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 1 which is concerned with the preparation of starting materials, 3-amino-N-cyclopropyl-4-(trifluoromethyl)benzamide was reacted with 5-fluoro-2-nitrobenzoic acid to give N-[5-[(cyclopropylamino)carbonyl]-2-(trifluoromethyl)phenyl]-5-fluoro-2-nitrobenzamide; Mass Spectrum: M−H+ 410.