Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:29])([F:28])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:27]([CH:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:28])[F:29])=[CH:24][CH:23]=3)[CH3:26])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Product: CC(c1ccc(OCC(F)(F)F)cc1)N1Cc2c(ccnc2Cl)C1=O
Yield: 62 %

Procedure:
The title compound is prepared in 62% yield (131 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(4-(2,2,2-trifluoroethoxy)phenyl)ethanamine hydrochloride (124 mg, 0.57 mmol, Amine-10, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([Br:20])[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:22](=[O:26])[CH:23]([CH3:25])[CH3:24].O>O1CCCC1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([Br:20])[CH:14]=1)[C:23]([CH3:25])([CH3:24])[CH:22]2[OH:26])=[O:21])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cc(C)cc(Br)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(C)cc(Br)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.5 %

Procedure:
To a mixture of 4-{[1-(3-bromo-5-methyl-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.5 g, 7.3 mmol) and ytterbium(III) triflate hydrate (0.45 g, 0.73 mmol) in dry tetrahydrofuran (15 mL) at 25° C. was added isobutyraldehyde (0.53 g, 7.3 mmol) and water (0.13 mL, 7.3 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-5-methyl-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.1 g, 100%) as a light yellow oil: LC/MS m/e calcd for C21H24BrNO3 M+: 418.3, observed: 400.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[C:33]([CH3:34])=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:27][CH3:26])=[C:33]([CH3:34])[CH:32]=5)[CH:3]=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)cc1C
Temperature: 80 °C
Yield: 40.3 %

Procedure:
To N-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.15 g, 0.41 mmol), 2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.15 g, 0.61 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.024 g, 0.02 mmol) in 1,2-dimethoxyethane (2.46 mL), aqueous saturated Na2CO3 (410 uL) was added. The reaction mixture was stirred and heated at 80° C. for 18 hours under N2 atmosphere. The reaction mixture was diluted with 1,2-dimethoxyethane, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (0.075 g, 40%). ESI-MS m/z calc. 453.44. found 454.5 (M+1)+. Retention time 2.24 minutes.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[ClH:11].CN.[C:14]([BH3-])#[N:15].[Na+].Cl>>[ClH:11].[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:15][CH3:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Product: CNCc1ccc(C#N)cc1
Yield: 52 %

Procedure:
Prepared analogously to Example 61a) from 4-cyanobenzaldehyde, methylamine-hydrochloride and sodium cyanoborohydride. The resulting base was converted into the corresponding hydrochloride by treating the methanolic solution with ethereal hydrogen chloride. Yield: 52% of theory. Colourless crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17](Cl)(=[O:19])=[O:18])[C:5](=[O:21])[CH2:4]1)[CH3:2].[NH2:22][C:23]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:22][C:23]2[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:19])=[O:18])[C:5](=[O:21])[CH2:4]1)[CH3:2]
Reactant: CCN1CCN(Cc2cc(F)ccc2S(=O)(=O)Cl)C(=O)C1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN1CCN(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C(=O)C1
Reaction time: 17 h
Yield: 60.3 %

Procedure:
A solution of 2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 174, 0.368 g) and methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.219 g) in pyridine (3 mL) and DCM (3 mL) was left to stand at room temperature for 17 hours. The mixture was evaporated in vacuo and the residue was dissolved in water and DCM and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 50-100% to give a gum which was triturated with ether and filtered to give methyl (1aRS,7bSR)-5-[2-(4-ethyl-2-oxopiperazin-1-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (0.312 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([S:5](Cl)=[O:6])([CH3:4])[CH3:3].Cl.[NH2:9][C:10]([CH3:14])([CH3:13])[C:11]#[N:12].C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([C:10]([NH:9][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([CH3:14])[CH3:13])#[N:12]
Reactant: CC(C)(C)S(=O)Cl
Reactant: CC(C)(N)C#N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C#N)NS(=O)C(C)(C)C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
2-methylpropane-2-sulfinic chloride (1.28 g, 9.12 mmol) was added to a stirring solution of 2-amino-2-methylpropanenitrile hydrochloride (1.0 g, 8.3 mmol) in DCM (21 ml) and N-ethyl-N-isopropylpropan-2-amine (3.04 ml, 17.4 mmol) at rt. DMAP (10 mg, 0.083 mmol) was added and the reaction was allowed to stir 1 h. The mixture was then diluted with dichloromethane and washed with sat NH4Cl aq, and sat NaCl aq. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product N-(2-cyanopropan-2-yl)-2-methylpropane-2-sulfinamide (1.45 g, 7.71 mmol, 93% yield) consistent by LCMS and NMR. LC-MS retention time: 2.15 min; m/z (MH+): 189. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.76 (s, 3H), 1.69 (s, 3H), 1.24 (s, 9H).
Reaction SMILES: [CH:1]1([C:4](=[O:29])[C:5](=[CH:25]OCC)[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:7])[CH2:3][CH2:2]1.Cl.[NH2:31]O.C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]1([C:4]2[O:29][N:31]=[CH:25][C:5]=2[C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3][CH2:2]1
Reactant: NO
Reactant: CCOC=C(C(=O)c1ccc(C(F)(F)F)cc1Sc1ccccc1)C(=O)C1CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(c1ccc(C(F)(F)F)cc1Sc1ccccc1)c1cnoc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A mixture of 3-cyclopropyl-2-ethoxymethylene-1-(2-phenylsulphenyl-4-trifluoromethylphenyl)propan-1,3-dione (7 g), hydroxylamine hydrochloride (1.24 g) and sodium acetate (1.5 g) in ethanol was stirred at 25° C. for 2 hours. The mixture was then poured into water and extracted with ethyl acetate. The solution was dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated and the residue purified by column chromatography on silica, using a mixture of ethyl acetate and hexane as eluent. The resulting solution was evaporated and the residue crystallized from cyclohexane to give 3.06 g of 5-cyclopropyl-4-(2-phenylsulphenyl-4-trifluoromethylbenzoyl)isoxazole (compound 1), m.p. 115° C.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3](=[O:6])[CH:4]=[CH2:5].[C:18]1([NH:24][C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][N:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][N:2]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3](=[O:6])/[CH:4]=[CH:5]/[C:28]1[CH:27]=[N:26][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:30][CH:29]=1
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Reactant: Brc1ccc(Nc2ccccc2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(Nc2ccccc2)nc1
Temperature: 25 °C
Yield: 69 %

Procedure:
N-Methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (from Example 76 (a)) was taken up in propionitrile (50 mL). To this solution was added with stirring 2-phenylamino-5-bromopyridine (1.3 g, 5.2 mmole), DIEA (1.8 mL, 10 mmole), Pd(OAc)2 (112 mg, 0.5 mmole) and P(o-tol)3 (304 mg, 1.0 mmole). The reaction was purged with argon then stirred at reflux for 16 h. After cooling to room temperature the reaction was concentrated to dryness under vacuum. Flash chromatography on silica gel (5% methanol/CHCl3) followed by a second flash column on silica gel (50-70% EtOAc/CHCl3) left a residue that was triturated with EtOAc/petroleum ether. Filtration and drying under vacuum gave the title compound (1.42 g, 69%) as an off-white powder: MS (ES) m/e 396.20 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([Cl:25])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:24]=[C:23]([Cl:25])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(-c3ccno3)nc3sc(Cl)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=O.[CH2:17]([NH2:19])[CH3:18]>C(Cl)Cl>[CH3:16][O:15][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH3:14])[C:6]([NH:19][CH2:17][CH2:18][C:3]1[CH:12]=[CH:11][CH:10]=[C:5]([CH3:6])[CH:4]=1)=[O:8]
Reactant: CCN
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1
Solvent: ClCCl
Product: COc1cc(C(=O)NCCc2cccc(C)c2)cc(OC)c1OC

Procedure:
A solution of methyl 3,4,5-trimethoxybenzoate (31.3 g, 0.138 mol) and 2-)3-methylphenyl)ethylamine (18.6 g. 0.138 mol) was heated at 180° for 6 h. The dark reaction mixture was taken up in methylene chloride and washed with dilute HCl. The solvent was evaporated and the residue was chromatographed on 150 g of neutral alumina. Elution with methyl chloride/hexane (3:1) removed some by-products and elution with methylene chloride gave nearly pure amide F1 which was recrystallized from i-PrOH to give pure F1 (5.2 g, 11%), mp 105°-108°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9](OCC)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH2:9][OH:10]
Reactant: CCOC(=O)c1cccc(-c2ccco2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1cccc(-c2ccco2)c1
Yield: 83 %

Procedure:
Ethyl 3-(2-furyl)benzoate [J. Chem. Soc., (B), 1971, 2305 was dissolved in 5 ml of anhydrous ethyl ether. With stirring under ice cooling, 23 mg of lithium aluminium hydride was added The mixture was stirred for 40 minutes. After the reaction, water and ethyl ether were added to extract the reaction mixture The extract was worked up in a customary manner to give 170 mg (yield 83%) of 3-(2-furyl)benzyl alcohol
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>O1CCOCC1.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>[Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (5.0 g, 16.75 mmol) in dioxane (200 ml) was added water (20 ml), Pd(PPh3)4 (924 mg, 0.80 mmol), K3PO4 (7.0 g, 32.98 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (6.3 g, 33.17 mmol) with stirring overnight at 100° C. under nitrogen. The resulting mixture was concentrated under vacuum and dissolved in water (250 ml), extracted with ethyl acetate (3×200 ml) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the residue, which was re-crystallized from 50% ether in hexane to afford 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline as a yellow solid (4.2 g, crude). Next, to a solution of 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline (3.7 g, crude) in ethanol (300 ml) and hydrogen chloride (3.0 ml) was added Zn powder (4.55 g, 70.0 mmol) in several bacthes with stirring for 20 min at room temperature. The resulting solution was stirred for 7 h at 85° C. The solids were filtered out and the filtrate was concentrated under vacuum to give a residue, which was dissolved in water (100 ml). The mixture was adjusted to pH 7 with saturated aqueous sodium carbonate, extracted with ethyl acetate (3×300 ml) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by a silica gel column eluted with 10% to 50% ethyl acetate in petroleum ether to produce 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine as brown oil (2.9 g,). Finally, the solution of 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine (150 mg, 0.52 mmol) in pentafluoropropanoic acid (1 ml) was stirred overnight at 80° C. The result mixture was diluted with water (50 ml) and adjusted to pH 7 with saturated aqueous sodium carbonate. The resulting solution was extracted with ethyl acetate (3×50 ml), combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column eluted with 0.5% to 6.5% ethyl acetate in petroleum ether to produce 5-chloro-2-(pentafluoroethyl)-6-[4-(trifluoromethyl)phenyl]-1H-1,3-benzodiazole as a white solid (112.6 mg, 52%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)#[CH:28]>>[CH3:25][N:24]([CH3:26])[CH2:23][C@H:11]([NH:10][S:7]([C:5]1[S:6][C:2]([C:28]#[C:27][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:3][CH:4]=1)(=[O:9])=[O:8])[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: C#Cc1ccccc1
Reactant: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Br)s1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(C#Cc2ccccc2)s1
Yield: 87 %

Procedure:
According to the method described in example S76a, (R)-benzyl 3-(5-bromothiophene-2-sulfonamido)-4-(dimethylamino)butanoate was reacted with ethynylbenzene to give the title compound as a brown oil (55 mg, 87%). MS ESI 483.3 [M+H]+, calcd for [C25H26N2O4S2+H]+ 483.13.
Reaction SMILES: C[O-].[Na+].C[C:5](C)(C([O-])=O)[C:6]([O-])=[O:7].[C:13]1(=[C:19](C#N)[C:20]([NH2:22])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>CO>[O:7]=[C:6]1[NH:22][C:20](=[O:21])[CH2:19][C:13]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:5]1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Reactant: N#CC(C(N)=O)=C1CCCCC1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC2(CCCCC2)CC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
204 ml of a 5.4 M solution of sodium methylate in methanol, 550 ml methanol and 145.5 g of dimethylmalonate are placed in a 2 litre flask equipped with a mechanical stirrer, thermometer and condenser, under nitrogen flow. After 30 minutes, 148 g of cyclohexylidenecyanoacetamide are added over a period of 30 minutes. The mixture is left under agitation for 1.5 hours at 30° C., after which 626 g of 15% NaOH are added, then heated under reflux for 1.5 hours. 400 ml of methanol are distilled and the mixture is acidified with 36% HCl to pH 3 then heated under reflux for 3 hours. By cooling to 25° C. a precipitate is formed which is filtered off, washed with water until the washing waters are neutral and dried under vacuum at 45° C. 69 g of 2,4-dioxo-3-azaspiro[5,5]undecane are obtained.
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:14]=[C:15]([OH:21])[CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.Br[CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:28]=1.O>CN(C=O)C>[C:3]12([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[O:21][CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:28]=3)[CH2:4][CH:5]3[CH2:11][CH:9]([CH2:8][CH:7]([CH2:6]3)[CH2:12]1)[CH2:10]2
Reactant: COc1ccc(O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1csc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1csc(COc2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c1

Procedure:
210 mg (7 mmol) of sodium hydride (80% in oil) and 10 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. A solution of 1.8 g (7 mmol) of 3-(1-adamantyl)-4-methoxyphenol in 20 ml of DMF was added dropwise and the mixture was stirred until the evolution of gas had ceased. A solution of 1.7 g (7.2 mmol) of methyl 2-bromomethyl-4-thiophenecarboxylate in 15 ml of DMF was then added and the mixture was stirred at room temperature for two hours. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The solid obtained was triturated from hexane, filtered off and dried. 2.6 g (90%) of the expected methyl ester, having a melting point of 97°-8° C., were recovered.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:10]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:40]=[N+:41]=[N-:42].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:42][N:41]=[N:40][N:17]=3)[CH2:15][C@@:9]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:10]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#C[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Example 137; 4 g, 7.4 mmol), sodium azide (1.4 g, 22 mmol) and ammonium chloride (1.2 g, 22 mmol) were stirred at 120° C. in N,N-dimethylformamide (15 ml) for 20 hours. On cooling to room temperature the mixture was poured into water (250 ml) and extracted (×2) with ethyl acetate. The combined organic extracts were washed (×3) with water then dried (MgSO4), filtered and concentrated. Residue was chromatographed on silica gel eluting with 1, 2 and 4% methanol/dichloromethane to give the title compound (2.7 g, 63%).
Reaction SMILES: C([N:8]([CH2:32][CH2:33][O:34]C(C)(C)C)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:16]=2[CH:31]=1)=[O:10])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].CO>Br>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:17]1[C:16]2[CH:31]=[C:12]([NH:11][C:9]([NH:8][CH2:32][CH2:33][OH:34])=[O:10])[CH:13]=[CH:14][C:15]=2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=1
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)N(CCOC(C)(C)C)Cc3ccccc3)ccc21
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)CN=C(c2ccccc2F)c2cc(NC(=O)NCCO)ccc21

Procedure:
1.5 g (0.003 M) of 1-benzyl-1-(2-tert.butoxyethyl)-3-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea are dissolved in 15 ml of 48% aqueous hydrogen bromide solution, the mixture is heated on a steam-bath for 10 minutes, made alkaline with sodium bicarbonate, treated with a small amount of methanol and extracted three times with methylene chloride. The extracts are combined, dried over sodium sulphate, filtered and concentrated. The residue is purified in a pressure column (0.2-0.4 atmosphere of nitrogen) on 300 g of silica gel (particle size 0.04-0.06 mm) using acetone as the eluting agent and crystallised from acetone/ether. There is obtained 1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea which, according to the IR spectrum, is identical with a sample of this substance prepared in another manner (see Example 7).