Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15](OS(C)(=O)=O)[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11].[NH3:22]>O.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15]([NH2:22])[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: N
Reactant: Cc1cccc(C)c1N(CC(C)OS(C)(=O)=O)S(C)(=O)=O
Solvent: O
Solvent: CO
Product: Cc1cccc(C)c1N(CC(C)N)S(C)(=O)=O

Procedure:
A mixture of 1.0 g (3 mmoles) of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-methanesulfonyloxy-propane, 10 ml of methanol and 5 ml of concentrated aqueous ammonia is heated at 110° C. for 6 hours in a steel bomb. The mixture is cooled, diluted with 30 ml of water, and methanol is evaporated under reduced pressure. The residue is extracted thrice with 20 ml of chloroform, each. The chloroform solutions are combined, washed thrice with 20 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is triturated with 3 ml of diisopropyl ether. 0.55 g of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-amino-propane are obtained; m.p.: 106°-109° C.
Reaction SMILES: [C:1]([O:5][P:6]([CH2:17][CH:18]([CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH2:8][NH:9]CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[NH2:9][CH2:8][P:6]([CH2:17][CH:18]([CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)CCC(CP(=O)(CNCc1ccccc1)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCC(CP(=O)(CN)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 96 h
Yield: 98.6 %

Procedure:
To a solution of di-tert-butyl 2-[((tert-butoxy){[benzylamino]methyl}phosphoryl)methyl]pentane-1,5-dioate (8.20 g, 16.5 mmol) in ethanol (100 mL) was added palladium on carbon (0.50 g), and the suspension was shaken under hydrogen (50 psi) for 4 days. The catalyst was removed by filtration through a pad of Celite. The filtrate was concentrated to give 6.629 g of colorless oil (99% yield): 1H NMR (CD3OD) δ1.40-1.60 (m, 27H), 1.80-2.00 (m, 3H) 2.2-2.4 (m, 3H), 2.7-3.0 (m, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]=[C:5]=[O:6].[N:7](=[C:9]1[CH:13]([CH3:14])[O:12][CH2:11][S:10]1)[OH:8]>CCOCC.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][NH:4][C:5]([O:8][N:7]=[C:9]1[CH:13]([CH3:14])[O:12][CH2:11][S:10]1)=[O:6]
Reactant: CC1OCSC1=NO
Reactant: COCN=C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COCNC(=O)ON=C1SCOC1C

Procedure:
A quantity of 5 ml of methoxymethyl isocyanate was caused to react with 5 grams of 4-oximino-5-methyl-1,3-oxathiolane dissolved in 100 ml of anhydrous ether containing 10 drops of triethylamine over a period of 48 hours at room temperature. Conventional workup and recrystallization from isopropyl ether/ethyl acetate afforded 5.5 grams of product, mp 78°-79°; structure confirmed by spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[Cl:18][C:19]1[O:23][C:22]([CH:24]=O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[O:23][C:22]([CH2:24][NH:16][C:14]([CH3:17])([CH3:15])[CH2:13][O:12][C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])=[CH:21][CH:20]=1
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Reactant: O=Cc1ccc(Cl)o1
Product: CC(C)(COc1ccc2ccccc2c1Cl)NCc1ccc(Cl)o1
Yield: 32 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and 5-chlorofuran-2 carbaldehyde in 32% yield as a yellow oil.
Reaction SMILES: Br[CH:2]([C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(#N)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([CH:2]([C:4]3[NH:13][C:12](=[O:14])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH3:3])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: COc1ccc(S(=O)(=O)N2CCNCC2)cc1
Reactant: CC(Br)c1nc2ccccc2c(=O)[nH]1
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccccc4c(=O)[nH]3)CC2)cc1
Yield: 449.2 %

Procedure:
In a flask containing of 2-(1-bromo-ethyl)-3H-quinazolin-4-one (500.0 mg, 0.20 mmol) in acetonitrile (20 ml) was added KI (496.0 mg, 0.30 mmol), and 1-(4-methoxy-benzenesulfonyl)-piperazine (509.6 mg, 0.20 mmol). The reaction was heated for 18 hours. The solution was concentrated under reduced pressure. The residue was partitioned between water (20 ml) and dichloromethane (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solvent was removed under vacuum. The resulting residue was purified by silica gel chromatography with 50% dichloromethane in hexane. The product was collected and dried under reduced pressure to give 2-{1-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3H-quinazolin-4-one (Yield 385.0 mg, 45.18%). 1H NMR (400 MHz, DMSO-6): δ 1.25 (d, 3H, J=6.82 Hz), 2.67-2.56 (m, 4H), 2.88 (s, br, 4H), 3.85 (s, 3H), 3.53 (q, 1H, J=13.89, 6.82 Hz), 7.15 (d, 2H, J=8.84), 7.34 (t, 1H, J=7.33 Hz), 7.51 (d, 1H, J=8.34 Hz), 7.68-7.61 (m, 3H), 8.00 (d, 1H, J=7.83 Hz). MS m/z calc. 428.15, found (ESI); 429.4 (M+1)+. Retention time 2.68 minutes.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH2:3][CH2:2]1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:10]3[N:11]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[S:8][CH:9]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1csc(N2CCOCC2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(N2CCOCC2)n1
Yield: 5.48 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-morpholinothiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-morpholino-1,3-thiazole-4-carboxylic acid (0.454 g, 2.117 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.5 g, 1.764 mmol. The product was purified by Flash-chromatography. Yield 5.48%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 3.38-3.43 (m, 4H), 3.67-3.72 (m, 4H), 4.27-4.45 (m, 3H), 6.95 (d, 1H), 7.40 (s, 1H), 7.83 (d, 1H), 7.92 (dd, 1H), 7.97 (d, 1H), 7.98 (dd, 1H), 8.06 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>N1C=CC=CC=1>[NH:17]([C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:4][CH:3]=1)[NH2:18]
Reactant: N#Cc1cccc(-c2ccc(Cl)nn2)c1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1cccc(-c2ccc(NN)nn2)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A solution of 3-(6-chloro-pyridazin-3-yl)-benzonitrile (75.6 g, 350 mmol) in 900 mL of dried pyridine was cooled in an ice bath and 119.2 mL of hydrazine hydrate was added. The cooling was continued so as to keep the temperature below 30° C. at which time yellow needle separated. The mixture was then heated to 65° C. and stirred overnight. Then the mixture was concentrated and the residue was washed with water and Methanol to return the title compound (60 g, 81%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 8.38˜8.39 (m, 1H), 8.32˜8.35 (m, 1H), 8.24 (s, 1H), 7.97˜8.00 (d, 1H), 7.82˜7.85 (m, 1H), 7.64˜7.69 (m, 1H), 7.09˜7.12 (d, 1H), 4.39 (s, 2H); MS (m/z) 212.1 [M++1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([NH:25][NH2:26])=[O:24])[O:20][N:19]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2N=C3C=CC([F:42])=CN3C=2CC2N=C(C(OCC)=O)ON=2)=CC=1.O.NN>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([F:42])=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([NH:25][NH2:26])=[O:24])[O:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1
Reactant: NNC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Agent: NN
Solvent: O
Product: NNC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1

Procedure:
The title compound was prepared in the same fashion as that for compound 215 from ethyl 3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate and hydrazine hydrate. m/e+=387 (M+H+). 1H NMR (400 MHz, in DMSO-d6): δ 10.75 (1H, D, brs, NH), δ 8.70-8.68 (1H, D, dd, J=4.4, 2.0 Hz, ArH), δ 7.83-7.80 (2H, D, d, J=8.4 Hz, ArH), δ 7.75-7.71 (1H, D, dd, J=10.0, 5.2 Hz, ArH), δ 7.55-7.53 (2H, D, d, J=8.4 Hz, ArH), δ 7.47-7.42 (1H, D, dt, J=8.4, 2.4 Hz, ArH), δ 5.01-4.75 (2H, D, brd, NH2), δ 4.74 (2H, D, s, CH2).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].[C:22](OC)(=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[SH:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:21])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=[O:30])[N:20]=2)[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:10])([CH3:9])[CH3:11])=[O:4]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(Cc1ccnc(C#N)c1)C(=O)OCC[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(Cc1ccnc(-c2nc(=O)c3ccccc3s2)c1)C(=O)OCC[Si](C)(C)C
Yield: 53.6 %

Procedure:
2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-(2-cyano-4-pyridyl)propionate (0.68 g, 2.2 mmol) and methyl thiosalicylate (0.60 g, 3.6 mmol) were dissolved in toluene (2.5 ml), and triethylamine (0.56 ml, 4.0 mmol) was added thereto. The reaction mixture was refluxed for 16 hrs and subjected to a silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected and concentrated to give the titled compound (0.52 g, 53%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:29][CH2:28][C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Product: O[C@H](CNCc1ccc(C(F)(F)F)cc1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole, 4-(trifluoromethyl)benzylamine, and ethanol essentially as described above in Example 112. Purity by LC/MS=95%, [M+H]+=461.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH:9]([N:11]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[CH:1]1([CH2:7][CH2:8][CH:9]([NH2:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CCC1CCCCC1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(N)CCC1CCCCC1
Temperature: 25 °C
Yield: 36.8 %

Procedure:
A solution of 4.60 g 2-(3-cyclohexyl-1-methylpropyl)-1H-iso indole-1,3(2H)-dione and 7.26 g of hydrazine hydrate in 60 mL ethanol was heated to 70° C. The white precipitation was filtered off after cooling to room temperature. The mixture was washed with water and evaporated. 920 mg (37%) of a colourless oil were obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:18]([C:19]3[CH:41]=[CH:40][C:22]4[C:23]5[N:24]([CH:28]=[C:29]([C:31]6[N:35]([CH:36]([CH3:38])[CH3:37])[N:34]=[C:33]([CH3:39])[N:32]=6)[N:30]=5)[CH2:25][CH2:26][O:27][C:21]=4[CH:20]=3)=[CH:17][CH:16]=[N:15]2)[CH2:9]1)C1C=CC=CC=1.Cl.O1CCOCC1>CO.[Pd]>[CH:36]([N:35]1[C:31]([C:29]2[N:30]=[C:23]3[C:22]4[CH:40]=[CH:41][C:19]([C:18]5[N:14]([CH:10]6[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]6)[N:15]=[CH:16][CH:17]=5)=[CH:20][C:21]=4[O:27][CH2:26][CH2:25][N:24]3[CH:28]=2)=[N:32][C:33]([CH3:39])=[N:34]1)([CH3:38])[CH3:37]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4ccnn4C4CCCN(Cc5ccccc5)C4)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4ccnn4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9-(1-(1-benzylpiperidin-3-yl)-1H-pyrazol-5-yl)-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (500 mg, 0.0009 mol) was dissolved in Methanol (10 mL). 4.0 M of Hydrogen chloride in 1,4-Dioxane (0.5 mL, 0.002 mol) was added. 10% Palladium on Carbon (0.1:0.9, Palladium: carbon black, 120 mg, 0.00011 mol) was added under a stream of Nitrogen. The reaction mixture was vac/flushed with H2 (balloon) and stirred overnight at room temperature. LCMS show reaction is complete. The reaction mixture was filtered and concentrated to dryness to give 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-(piperidin-3-yl)-1H-pyrazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:26]1([C@@H:32]2[CH2:34][C@H:33]2[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:26]1([C@@H:32]2[CH2:34][C@H:33]2[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCNC(=O)[C@@H]1C[C@H]1c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCCCNC(=O)[C@@H]1C[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
2.4 g (16.1 mmol) 3-(3-pyridyl)-acrylic acid and 5.3 ml (38.0 mmol) TEA are suspended in 80 ml abs. dichloromethane and cooled to ca. 0° C. under moisture exclusion. 2.9 g (18.9 mmol) 88% HOBT and 3.6 g (18.8 mmol) EDC are added and the mixture is stirred for 30 min under ice cooling. 5.3 g (17.0 mmol) 4-(trans-2-phenyl-cyclopropyl-carbonylamino)-butylamine are dissolved in 30 ml abs. dichloromethane and added drop-wise under ice cooling. The mixture is stirred overnight at RT without further cooling. The formed precipitate is filtered off and crystallized from 120 ml isopropanol. Colorless crystals with MP. 194-196° C. Yield 4.2 g (71%).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].[CH3:12][NH:13][NH2:14]>C1(C)C=CC=CC=1>[F:1][CH:2]([F:11])[C:3]1[CH:4]=[C:5]([OH:6])[N:13]([CH3:12])[N:14]=1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)C(F)F
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)F)cc1O
Yield: 73.9 %

Procedure:
To a solution of 208.6 g (1257 mmol) of ethyl 4,4-difluoro-3-oxobutanoate (VII-1) in 1000 ml of toluene was added 57.8 g (1257 mmol) of methylhydrazine by dropwise addition with cooling. After 90 min under reflux the reaction mixture was cooled down and concentrated. After 1500 ml of diethyl ether had been added, the reaction mixture was stirred and the insoluble material was filtered off. The filtrate was concentrated to obtain 137.5 g (74% of theory) of 3-(difluoromethyl)-1-methyl-1H-pyrazol-5-ol (IX-1) as a reddish orange solid which was used in the next reaction step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](Cl)=[O:13])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][NH2:18].C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:13])[N:17]([CH3:16])[NH2:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)Cl
Reactant: CNN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of crude carbamoyl chloride 1 (9.35 g) in dry THF (40 ml) was added to an ice-cold solution of methylhydrazine (3.46 g; 4.00 ml; 0.075 mol) and triethylamine (6.33 g; 8.73 ml; 0.063 mol) in dry THF (40 ml). Stirring was continued at room temperature for 18 hours. The reaction mixture was filtered and evaporated, giving a light yellow solid. Recrystallization from hexane - chloroform gave 2 (6.62 g; 0.0272 mol; 68%) as a white solid, mp 89°-92°, TLC (silica gel; CH2CL2 --CH3OH, 10:1) Rf=0.45. MS m/e 243 (M+) Analysis: Calculated for C11H21N3O3 ; C,54.30; H, 8.70; N, 17.27. Found: C, 54.45; H, 8.96; N, 17.29, NMR (CDCl3): δ1.42 (9H,S); 1.7-2.3(4H.S); 3.00 (3H,S); 3.4-3.8(2H,m); 3.8(2H.bs); 4.4(1H.m) 1R(CHCl3): 35-3300, 1730, 1630 cm-1 [α]D =-55.7°±0.5°.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:42])[F:43])[CH:34]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 40.0 mg (0.21 mmol) of 3-trifluoromethylphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 51 mg (89% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:17])[CH:15]=[CH2:16])=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:25][CH2:24]1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1([C:26]2[CH:31]=[CH:30][C:29]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:17])[CH:15]=[CH2:16])=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)[CH2:24][CH2:25]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=CC(O)c1c(C)noc1-c1ccc(Br)cc1
Product: C=CC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-prop-2-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:23])([CH:12]([F:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]>O1CCCC1.CO.[C].[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([CH:12]([F:22])[C:2]([F:23])([F:1])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCC(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(F)(F)C(F)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.8 %

Procedure:
To 10% palladium-carbon (40 mg), a solution of tert-butyl (2,2,3-trifluoro-3-(3-nitrophenyl)propyl)carbamate (C35, 80 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain tert-butyl (3-(3-aminophenyl)-2,2,3-trifluoropropyl)carbamate (C36, 88 mg).
Reaction SMILES: CN(C)/N=[C:4](\[C:24]([F:27])([F:26])[F:25])/[CH2:5][C:6]([NH:17][S@@:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[F:16])[CH2:7][F:8].Cl.C([O:32]CC)C>O.O1CCOCC1>[CH3:21][C:20]([S@:18]([NH:17][C@:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[F:16])([CH2:5][C:4](=[O:32])[C:24]([F:27])([F:26])[F:25])[CH2:7][F:8])=[O:19])([CH3:23])[CH3:22]
Reactant: CCOCC
Reactant: Cc1cccc(C(CF)(C/C(=N/N(C)C)C(F)(F)F)N[S@](=O)C(C)(C)C)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc([C@](CF)(CC(=O)C(F)(F)F)N[S@](=O)C(C)(C)C)c1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of (R)-N-((Z)-4-(2,2-dimethylhydrazono)-1,5,5,5-tetrafluoro-2-(2-fluoro-3-methylphenyl)pentan-2-yl)-2-methylpropane-2-sulfinamide (5.66 g, 13.24 mmol) in 10% water (5 mL) in dioxane (50 mL) was added hydrogen chloride, 1m in diethyl ether (26.5 ml, 26.5 mmol) and the resulting mixture was stirred at 40° C. for 1 h. The reaction was quenched with water, diluted with EtOAc and washed with water. The organic phase was dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-40% EtOAc/hexanes to afford a yellow oil as (R)-2-methyl-N-((S)-1,5,5,5-tetrafluoro-2-(2-fluoro-3-methylphenyl)-4-oxopentan-2-yl)propane-2-sulfinamide (3.80 g, 75% yield). MS m/z=385.9 [M+H]+. Calculated for C16H20F5NO2S: 385.11.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:24]([C:30]1[CH:36]=[CH:35][C:33]([OH:34])=[CH:32][C:31]=1[OH:37])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].Cl>C1(C)C(C)=CC=CC=1>[OH:34][C:33]1[CH:32]=[C:31]([OH:37])[C:30]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:36][C:35]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: CCCCCCc1ccc(O)cc1O
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: CCCCCCc1cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)cc1O
Temperature: 80 °C

Procedure:
To a 350 mL sulfonation flask equipped with a mechanical stirrer, condenser and a nitrogen atmosphere are charged 21.4 g (80 mmol) of 2-chloro-4,6-diphenyl-s-triazine, and 100 mL of xylene (mixture of isomers). To the beige suspension are added 11.3 g (85 mmol) of aluminum chloride in one portion. The mixture is warmed to ca. 80° C. for 45 minutes. 18.8 g (96 mmol) of 4-hexylresorcinol are then added in five portions over 40 minutes to the now homogeneous solution. The reaction mixture is heated at 90° C. for 24 hours. After cooling to room temperature, the contents of the flask are poured into 100 mL of 12% aqueous hydrochloric acid. The precipitate formed is removed by filtration, washed to pH 7 with water, rinsed with methanol and dried at 70° C. under vacuum. The title compound is obtained as a crude orange product (29.2 g) and melts at 209°-213° C. It can be used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:11][N:10]=[C:9]2[S:25][CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[C:29]([F:34])[C:28]=2[F:35])=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][NH2:14])=[CH:11][N:10]=[C:9]2[S:25][CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[C:29]([F:34])[C:28]=2[F:35])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
A solution of 2-((1-(4-fluorophenyl)-2-((2,3,6-trifluoro benzyl)thio)-1H-imidazol-5-yl)methyl)isoindoline-1,3-dione (29) (390 mg, 0.78 mmol) and hydrazine hydrate (76 μL, 1.57 mmol) in ethanol (8 mL) was refluxed overnight. The white precipitate was removed by vacuum filtration and washed with ethanol and concentrated in vacuo to obtain (1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazol-5-yl)methanamine (30).