Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[CH:8]=1.[N+:14]([O-])([OH:16])=[O:15]>>[Cl:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cc(Cl)n(C)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1nn(C)c(Cl)c1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
Concentrated H2SO4 (35 g) was added to 10 ml of 90% HNO3 and at 75°-85° C., 13 g (0.1 mol) of 5-chloro-1,3-dimethylpyrazole was added dropwise with stirring to maintain the temperature at 85° C. After completion of the addition, the mixture was heated at 75 -85° C. for 1.5 hr. The nitration mixture was cooled and poured into ice. The suspension was filtered and the solid was washed with water and dried to give 14.5 g of the title compound. m.p. 70° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]([C:11]2[N:19]3[C:14]([CH:15]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18]3)=[C:13]([C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(N)(=[O:39])C>C1COCC1.O.[Pd](Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]([C:11]2[N:19]3[C:14]([CH:15]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:18]3)=[C:13]([C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[C:12]=2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32])=[O:10])[CH:6]=[CH:7][CH:8]=1)(=[O:39])[NH2:2]
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1cccc(C#N)c1
Reactant: CC(N)=O
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1cccc(C(N)=O)c1
Temperature: 23 °C
Yield: 87.9 %

Procedure:
A solution of methyl 3-{3-[(3-cyanophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (125 mg, 0.257 mmol), palladium(II) chloride (9.1 mg, 0.051 mmol), and acetamide (152 mg, 2.57 mmol) in THF (1.5 mL) and water (0.5 mL) is heated at 50° C. for 3 h then cooled to 23° C. and partitioned between water and Et2O. The organics are washed with water, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 75% EtOAc in hexanes) gives methyl 3-{3-[(3-carbamoylphenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (114 mg, 88%).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:33])[CH:6]([O:11][CH:12]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:41][CH2:42][F:43]>C(#N)C>[C:1]([CH2:3][NH:4][C:5](=[O:33])[CH:6]([O:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:41][CH2:42][F:43])[CH2:25][CH2:26]2)=[O:20])=[CH:15][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: FCCBr
Reactant: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCNCC2)cc1)C(=O)NCC#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCN(CCF)CC2)cc1)C(=O)NCC#N
Temperature: 85 °C

Procedure:
To a solution of N-(cyanomethyl)-4-methyl-2-{phenyl[4-(piperazin-1-ylcarbonyl)phenyl]methoxy}pentanamide from example 17, step 7 (79 mg, 0.18 mmol) in acetonitrile (1 mL), was added Na2CO3 (37 mg, 0.36 mmol) and 2-bromofluoroethane (39 μL, 0.525 mmol). The reaction was heated in a sealed tube at 85° C. for 16 hours and was then cooled down to room temperature. The mixture was then concentrated and the crude residue chromatographed on silica gel using 1% NH4OH and 9% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]#[N:15])=[CH:5][CH:4]=1.N.[H][H]>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc2cccc(CC#N)c2c1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc2cccc(CCN)c2c1

Procedure:
A solution of (7-methoxynaphth-1-yl)acetonitrile in ethanol saturated with ammonia is placed in an autoclave. Raney nickel and hydrogen at 300 atmospheres are added.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:33])[NH:27]2>C1(C)C(C)=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[F:32][C:29]1[CH:30]=[CH:31][C:22]([N:21]=[CH:11][C@@:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:19][CH3:20])[CH3:18])=[C:23]2[C:28]=1[NH:27][C:26](=[O:33])[CH:25]=[CH:24]2
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Reactant: Nc1ccc(F)c2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1C
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1ccc(F)c2[nH]c(=O)ccc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 300 mg (1.01 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 180 mg (1.01 mmol) of 5-amino-8-fluoroquinolone and 0.48 ml of titanium tetraisopropoxide in 9 ml of xylene are reacted to give 8-fluoro-5-{[(2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentylidene]amino}quinolin-2(1H)-one. 80 mg of imine purified by column chromatography (silica gel, hexane; CH2Cl2/i-PrOH 0-5%) are cyclized, in the same way as in Example 1, at −40° C. using 1.7 ml (1.5 mmol) of 1 M boron tribromide solution to give the desired product and the ether-cleaved Example 8.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:15][CH:14]2[CH2:16][CH:11]1[CH2:12][NH:13]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.C(=O)(O)[O-]>CS(C)=O>[CH2:3]([N:10]1[CH2:15][C@H:14]2[CH2:16][C@@H:11]1[CH2:12][N:13]2[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CN2CC3CC2CN3)cc1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2C[C@H]3C[C@@H]2CN3Cc2ccccc2)cc1
Yield: 51.2 %

Procedure:
A stirring solution of title compound 206 (0.5 g, 1.914 mmol) and ethyl 4-fluorobenzoate (0.421 ml, 2.87 mmol) in DMSO (19.14 mL) was stirred at 140° C. overnight. The mixture was cooled down and poured over a diluted aqueous solution of bicarbonate and extracted with ethyl acetate (twice). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography: 0% to 60% ethyl acetate in hexanes over 20 min on 20 g SiO2 to afford title compound 207 (0.33 g, 51%) as beige oil. LRMS: (calc) 336.18. (found) 337.4 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])[CH3:11].C[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:11]/[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(=O)c1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(/C=C/c1ccc(Br)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To an ethanol (500 mL) solution of 25.3 g (137 mmol) of 4-bromobenzaldehyde, 15.6 mL (139 mmol) of 2-acetylpyridine and 25.3 g of sodium methoxide (28% methanol solution, 131 mmol) were added under argon atmosphere, and the mixture was stirred at room temperature for 8 h. A formed solid was collected by filtration and washed with methanol to obtain 13.1 g (yield: 33%) of (E)-3-(4-bromophenyl)-1(2-pyridyl)-2-propen-1-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH:13]([CH:15]=[CH2:16])=O>O1CCOCC1>[CH3:12][O:11][C:7]1[C:3]([C:4]([OH:6])=[O:5])=[C:2]2[C:10]([CH:13]=[CH:15][CH:16]=[N:1]2)=[CH:9][CH:8]=1
Reactant: C=CC=O
Reactant: COc1cccc(N)c1C(=O)O
Solvent: C1COCCO1
Product: COc1ccc2cccnc2c1C(=O)O
Temperature: 200 °C
Yield: 20.9 %

Procedure:
In 1 g separate batches a mixture of 2-amino-6-methoxybenzoic acid (11 g, 66 mmol) and acrolein (4.8 mL, 72 mmol) in 1,4-dioxane (66 mL) was heated in a microwave reactor for 20 min at 200° C. After combining the reactions, the mixture was concentrated and purified via silica gel chromatography (0-10% MeOH in DCM) to give the title compound (2.8 g, 20%). MS (ESI) mass calcd. for C11H19NO3, 203.1; m/z found 204.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Cl[C:25]1[S:26][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:28][N:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[S:26][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:28][N:29]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: NS(=O)(=O)c1cnc(Cl)s1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ncc(S(N)(=O)=O)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (336 mg, 1.0 mmol) and 2-chloro-thiazole-5-sulfonamide (199 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (209 mg, 42%). MS (ISN) 496.0 [(M−H)−]; mp 123° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C.ClC(Cl)C>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1

Procedure:
Using similar reaction conditions as described in step-iii of example-133, tert-butyl 4-oxopiperidine-1-carboxylate (3 gm, 15.0 mmol) and 4-bromoaniline (2.59 gm, 15.0 mmol) were reacted using Na(OAc)3BH (105 mg, 0.494 mmol) and 3 drops of acetic acid in dichloroethane (80 mL) to afford 6.7 gm (crude) of the titled compound. MS: m/z=256.8 (M-Boc+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][O:8][CH2:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[I:17]I>C1COCC1>[I:17][C:4]1[CH:3]=[CH:2][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][O:8][CH2:9]2
Reactant: Brc1ccc2c(c1)COCC2
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Ic1cccc2c1CCOC2
Reaction time: 0.02 h

Procedure:
A solution of 7-bromoisochroman (6.6 g; 30.98 mmol) in THF (100 ml) was cooled to -78° C. and treated with 2.1 eq of tert-butyllithium (40 ml of a 1.7M solution). After stirring the solution for one minute, iodine (8.64 g; 34.08 mmol) was added as a THF solution (50 ml). The reaction mixture was stirred for 30 minutes at -78° C. and one hour at room temperature. It was quenched with saturated aqueous ammonium chloride, and the organic phase was washed with aqueous sodium thiosulfate and brine, dried, and freed of solvent. The crude product was recrystallized from hexane to provide the pure 5-iodoisochroman as a white crystalline solid, mp= 54°-56° C. (4.1 g; 51%). 1H NMR (CDCl3): δ2.79 (t, 2H); 3.94 (t, 2H); 4.70 (s, 2H); 6.85 (d, 1H); 7.32 (s, 1H); 7.46 (d, 1H). IR (nujol): 2931, 2852, 1550, 1252, 1190, 1105, 1005, 987 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([NH:8][CH2:9][C:10](=[O:12])[CH3:11])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+].[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([N:8]([CH2:9][C:10](=[O:12])[CH3:11])[C:29](=[O:30])[CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:6])[CH3:7]
Reactant: CC(=O)CNC(C)(C)c1cccc(Cl)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CN(C(=O)Cc1ccccc1)C(C)(C)c1cccc(Cl)c1
Temperature: 0 °C
Yield: 62.5 %

Procedure:
22.6 g (0.1 mol) of 1-(3-chloro-α,α-dimethylbenzylamino)-2-propanone prepared by the method of Reference Example 5, was dissolved in 200 ml of acetone, and 14.0 g (0.11 mol) of potassium carbonate was added thereto. The mixture was cooled with ice water, and then 15.5 g (0.1 mol) of phenylacetyl chloride was gradually dropwise added thereto under stirring. After completion of the dropwise addition, the reaction mixture was returned to room temperature and stirred for 3 hours. Then, the solvent was distilled off under reduced pressure, and then water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from n-hexane to obtain 21.5 g (yield: 62.5%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[C:28]([Cl:30])[CH:29]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])[CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(Cl)cc(Cl)c4)cc3)c2cc1OC
Yield: 86.6 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) was dissolved in toluene (5 ml) with heat, 3,5-dichlorophenyl isocyanate (76 mg) was added, and the admixture was refluxed with heat for 8 minutes. The separated crystals were filtered and then washed with toluene to obtain 75 mg of the title compound (yield: 87%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][CH:9]=1.[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH3:25][O:24][C:18]1[CH:23]=[CH:22][C:21]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([O:6][CH3:5])=[O:17])=[CH:9][CH:10]=2)=[O:15])=[CH:20][CH:19]=1
Reactant: COc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)c2ccc(OC)cc2)cc1

Procedure:
2.1 g (16 mmol) of aluminum chloride and 2.4 g (12 mmol) of 4-chlorocarbonyl benzoic acid monomethyl ester were stirred in 15 ml of dichloromethane under stirring under cooling with ice. 1.0 g (9.3 mmol) of anisole was added to the resultant mixture. Two hours after, the temperature was elevated to room temperature, and the mixture was stirred overnight. After the treatment with dichloromethane as the extractant in an ordinary manner, the solvent was distilled off. The residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[CH:12]1([C:15](O)=O)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[NH:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[N:11]=2)[CH2:14][CH2:13]1
Reactant: O=C(O)C1CC1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Product: O=[N+]([O-])c1ccc2[nH]c(C3CC3)nc2c1
Yield: 98 %

Procedure:
By analogy with a described method (WO 96/04270), a solution of 5 g (32.65 mmol) of 4-nitro-1,2-phenylenediamine in 77 ml (0.979 mol) of cyclopropanecarboxylic acid is stirred at reflux for 14 hours. The reaction mixture is then concentrated under reduced pressure and taken up in 150 ml of ethyl acetate and 100 ml of sodium hydrogen carbonate. The organic phase is washed with 100 ml of water and then with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. 6.5 g of a brown oil are obtained, and are used without further purification in the following step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[C:14](=[O:16])=[O:15]>C(OCC)C.CCCCCC>[Br:8][C:4]1[N:3]=[C:2]([C:14]([OH:16])=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)c1cccc(Br)n1
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
A suspension of 2,6-dibromopyridine (19 g) in diethylether (200 ml) was added to a mixture of n-butyl lithium (130 ml of a 1.6M solution in hexane) and diethylether (200 ml) cooled to -50° C. The resulting solution was stirred at -50° C. for 10 minutes before pouring onto a slurry of diethyl ether(100 ml) and dry-ice. The mixture was allowed to warm to room temperature and filtered. The resulting solid was dissolved in 2N sodium hydroxide (350 ml) and extracted with diethyl ether (2×300 ml). The aqueous layer was separated and acidified with 2N hydrochloric acid. The resulting precipitate was filtered and washed with water to give 6-bromo-2-pyridine carboxylic acid (7.25 g): NMR (d6DMSO) δ7.69(d,1H), 7.95(d,1H), 8.05(dd,1H); m/e 202(M+H)+.
Reaction SMILES: C([CH:8]([CH:10]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:20]=3[O:27][CH3:28])[C:12]=2[O:11]1)[NH2:9])C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>>[CH3:28][O:27][C:20]1[C:21]([O:25][CH3:26])=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[C:12]2[O:11][CH:10]([CH2:8][NH:9][C:39](=[O:40])[O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:14][C:13]=2[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(-c2cccc3c2OC(C(N)Cc2ccccc2)C3)c1OC
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)c1OC
Yield: 91.2 %

Procedure:
Treatment of (±)-benzyl[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.7 g, 8.39 mmol) with diisopropylethylamine (1.63 g, 12.59 mmol) and benzyl chloroformate (1.72 g, 10.07 mmol) generally according to the procedure described for Intermediate 12 provided 3.21 g (91%) of (±)-benzyl {[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][CH:14]=[O:15])[C:3]([NH:5][C:6]1[S:7][C:8]([CH3:11])=[N:9][N:10]=1)=[O:4].Cl>O>[CH3:11][C:8]1[S:7][C:6]([N:5]2[CH:14]([OH:15])[CH2:13][CH2:12][N:2]([CH3:1])[C:3]2=[O:4])=[N:10][N:9]=1
Reactant: Cc1nnc(NC(=O)N(C)CCC=O)s1
Agent: Cl
Solvent: O
Product: Cc1nnc(N2C(=O)N(C)CCC2O)s1

Procedure:
The dimethyl acetal of 3-[1-methyl-3-(5 -methyl-1,3,4-thiadiazol-2 -yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2 -f)-3-methyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([CH:17]([CH:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH2:11]3)=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>>[CH3:23][CH:22]([CH3:24])[CH:17]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:34]([NH:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([F:25])([F:36])[F:37])=[O:35])=[CH:7][CH:6]=3)[CH:9]=2)[CH2:13]1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: COC(=O)C(C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1
Product: COC(=O)C(C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4C(F)(F)F)cc3)cc2C1
Yield: 34 %

Procedure:
The compound of example 678 was prepared analogous to the compound of example 7 by reaction of compound of example 673 with 2-trifluoromethyl phenyl isocyanate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([CH2:9][S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][OH:19])([OH:8])[CH:4]([C:20]2([CH3:28])[O:27][CH:21]2[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:3]1[O:29][CH3:30].[Cl:31][CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34].O>ClCCl>[Cl:31][CH2:32][C:33]([NH:35][C:36](=[O:37])[NH:1][CH:2]1[CH2:7][CH2:6][C:5]([CH2:9][S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][OH:19])([OH:8])[CH:4]([C:20]2([CH3:28])[O:27][CH:21]2[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:3]1[O:29][CH3:30])=[O:34]
Reactant: O=C=NC(=O)CCl
Reactant: COC1C(N)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Solvent: ClCCl
Solvent: O
Product: COC1C(NC(=O)NC(=O)CCl)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
In dichloromethane (20 ml) was dissolved 4-amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (629 mg). To the solution was added dropwise, under ice-cooling, chloroacetyl isocyanate (0.22 ml). The mixture was stirred for 10 minutes, to which was then added water to suspend the reaction. The reaction product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride and, then, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography (carrier 30 g, developing solvent: ethyl acetate - hexane=3:2) to afford 4-(N'-chloroacetylureido)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (514 mg: yield 64%) as a colorless powdery product.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.Br[CH:13]([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[C:3]([O:11][CH:13]([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: COC(=O)c1scc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1scc(Br)c1OC(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (1.42 g), tert-butyl 2-bromopropanoate (1.2 mL), potassium carbonate (2.45 g) and DMF (30 mL) was stirred at 50° C. for 2 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give the title compound (2.16 g, 99%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:35]/[OH:36])/[CH2:9][C@H:10]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccnc(Cl)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1ccnc(Cl)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 132, step 6, from 4′-[(R)-3-(2-chloro-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as an off-white foam, MS (ESI−): m/z=469.1 ([M−H]−).