Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[O:28])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:32]2[CH2:31][CH2:30][N:29]([C:27]([N:24]3[CH2:25][CH2:26][N:21]([C:18]4[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=4)[CH2:22][CH2:23]3)=[O:28])[CH2:34][CH2:33]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(N1CCNCC1)N1CCN(c2ccncc2)CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A solution of 4-trifluoromethylphenylsulphonyl chloride (6.62 g) in dichloromethane (5 mL) was added dropwise over 10 minutes to a stirred solution of 1-[1-(4-pyridyl)piperazin-4-ylcarbonyl]piperazine (5.7 g) (prepared as in Example 1) in dichloromethane (50 mL) containing triethylamine (6 mL) at 20° C. The reaction mixture was stirred for 2 hours at 20° C. The organic phase was washed with water (3×100 mL) and saturated brine solution (2×100 mL) dried and evaporated. The residue was purified by chromatography on silica gel, eluting with a mixture of dichloromethane: methanol (95:5) to give, as a sandy-coloured solid, 1-(4-trifluoromethylphenylsulphonyl)-4-[1-(4-pyridyl)piperazin-4-ylcarbonyl]piperazine (6.0 g): NMR (CDCl3): 3.08(t, 4H), 3.30-3.40 (m, 8H), 3.40-3.45(t, 4H), 6.63(d, 2H), 7.82(d, 2H), 7.90(d, 2H), 8.30(d, 2H); EI-MS m/z 484(M+H).
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1N.[BrH:18]>S(=O)(=O)(O)O.C(O)(=O)C.O>[Cl:5][C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1[Br:18]
Reactant: Br
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)Oc1ccc(Br)c(Cl)c1
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (16.31 g) in concentrated sulphuric acid was added dropwise to a solution of 2-chloro4-trifluoromethoxyaniline (50 g) in acetic acid, while maintaining the temperature below 10° C. The mixture was stirred at 5°-10° C. for 0.5 hours then added slowly to a mixture of cuprous bromide (33.9 g) in aqueous hydrobromic acid (200 ml) and ice. The mixture was stirred at room temperature for 0.5 hours and left to stand overnight. The mixture was diluted with water and extracted with dichloromethane, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-chloro4-trifluoromethoxybromobenzene (63.64 g) as a brown oil which was not further purified.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)cn1
Yield: 66 %

Procedure:
A mixture of the 4,5-dihydro-imidazole of step 2 (6.2 g, 15.5 mmol) and p-toluenesulfonic acid monohydrate (1.6 g, 8.4 mmol) in toluene (550 ml) was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture (8.2 g) was chromatographed on silica gel using ethyl acetate/acetone (98/2) to give pure 2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine (3.9 g, 66%) as a white solid: mp (DSC) 163° C. Anal Calc'd. for C17H14N3SO2F3 : C, 53.54, H, 3.70, N, 11.02, S, 8.41. Found: C, 53.12, H, 3.56, N, 11.00, S, 8.50.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH:31]2[CH2:33][CH2:32]2)[C:9]([F:30])([CH:13](O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)C(O)=O)=[CH:4][CH:3]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>N1C(C)=CC(C)=CC=1C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH:31]2[CH2:33][CH2:32]2)/[C:9](/[F:30])=[CH:13]/[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(C(O)Cc1ccc(F)c(Oc2ccccc2)c1)[C@H](c1ccc(Cl)cc1)C1CC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1cc(C)nc(C)c1
Product: F/C(=C\Cc1ccc(F)c(Oc2ccccc2)c1)[C@H](c1ccc(Cl)cc1)C1CC1
Yield: 69.8 %

Procedure:
A solution of crude (2R,3S or 2S,3R)-2-[(S)-(4-chlorophenyl)(cyclopropyl)methyl]-2-fluoro-4-(4-fluoro-3-phenoxyphenyl)-3-hydroxybutanoic acid (Diastereomer E) (0.72 g, 1.5 mmol), tosyl chloride (0.58 g, 3.0 mmol) and collidine (20 ml) is heated at 170° C. for 2 hours. The mixture is concentrated in vacuo and the residue chromatographed on silica gel eluting with ether:hexane (5:95) to yield the title compound as a colorless liquid (0.43 g, 69% from diasteriomer B), [α]D=+35.8 (C=0.0438, CHCl3) which is characterized by 1HNMR and 19FNMR spectral analyses.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:44]=2)[C:42]#[N:43])O1>>[C:42]([C:41]1[CH:44]=[C:37]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=3)=[O:8])[CH:22]=2)[CH:38]=[N:39][CH:40]=1)#[N:43]
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)c(F)c3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 198.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.05 min, m/z=488.3 [M+H]+, m/z=486.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.75 (s, 1H) 1.81-1.92 (m, 1H) 2.87 (d, J=11.25 Hz, 1H) 3.15-3.27 (m, 2H) 3.33-3.44 (m, 1H) 4.21 (br. s, 1H) 4.87 (d, J=3.42 Hz, 1H) 7.51-7.64 (m, 2H) 7.98 (dd, J=13.20, 2.20 Hz, 1H) 8.08 (d, J=2.20 Hz, 1H) 8.40 (t, J=1.96 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.90 (d, J=1.96 Hz, 1H) 9.03 (d, J=1.96 Hz, 1H) 10.31 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C(Cl)CCCCCCBr
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCCCBr)c(Cl)c1Cl

Procedure:
The title compound is prepared following substantially the same procedure described in Example 13, Step A, using the following substances: 2,3-dichloroanisole (89 g., 0.5 mole), 7-bromoheptanoyl chloride (127 g., 0.56 mole), aluminum chloride (74 g., 0.56 mole) and methylene chloride (500 ml.). This procedure affords 107 g. (58%) of 2,3-dichloro-4-(7-bromoheptanoyl)anisole which after recrystallization from cyclohexane melts at 57° C.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([S:12](=[O:39])(=[O:38])[NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]=[C:24]3[C:27]3([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:30][CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+].O>C(O)C>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:27]2([C:24]3[C:25]4[C:20](=[CH:19][CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:13][S:12]([N:9]5[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]5)(=[O:38])=[O:39])[CH:26]=4)[CH2:21][CH2:22][N:23]=3)[CH2:30][CH2:29][CH2:28]2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)N1CCN(S(=O)(=O)NCCOc2ccc3c(c2)C(C2(c4ccc(Cl)cc4)CCC2)=NCC3)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)N1CCNCC1
Yield: 100 %

Procedure:
4-(2-{1-[1-(4-Chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yloxy}-ethylsulfamoyl)-piperazine-1-carboxylic acid ethyl ester (450 mg, 0.782 mmol, example 54, procedure 1) and a 10% solution of potassium hydroxid in ethanol (20 ml) were heated under reflux for 15 h. The solvent was reduced and water was added to the residue. The mixture was extracted with dichloromethane. The combined organic layers were washed with sodium chloride, dried with potassium sulphate and evaporated. The residue was purified by column chromatography with silica gel using dichloromethane/methanol 3%→5% as the eluent to give the desired product as a yellow oil (394 mg, 0.782 mmol, 61%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10]1[C:11](=[O:22])[C:12]2[C:17]([C:18](=O)[C:19]=1Cl)=[CH:16][CH:15]=[CH:14][CH:13]=2.C([OH:25])C>>[O:22]=[C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[N:1]=[C:2]3[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]3[C:19]=2[C:10]1=[O:25]
Reactant: CCO
Reactant: Cc1cccnc1N
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Product: Cc1cccn2c3c(nc12)-c1ccccc1C(=O)C3=O
Yield: 52 %

Procedure:
4.76 g (44 mmol) of 2-amino-3-methylpyridine in solution in 50 mL of ethanol are added to a suspension of 10 g (44 mmol) of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene in 150 mL of ethanol that is brought to reflux. After 48 h of reflux, the reaction mixture is evaporated to dryness and purified on a flash column (support: silica; conditioning: heptane; eluent: dichloromethane) to produce 6 g of 5,6-dihydro-5,6-dioxo-11-methyl-naphtho[1',2':4,5]imidazo[1,2-a]pyridine in the form of orange crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:11][NH2:12])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:18]>CCO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:11]([NH2:12])=[O:18])[N:3]=1
Reactant: NSc1nc(N)nc2nc[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: Nc1nc(S(N)=O)c2[nH]cnc2n1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
2-Aminopurine-6-sulfenamide 2 (182 mg, 1 mmol) was suspended in EtOH (100 mL) and cooled to 0° C. m-Chloroperoxybenzoic acid (85%, 200 mg, 1 mmol) was added portionwise during 1 h with stirring, and stirring continued for additional 30 min. After filtration, the filtrate was concentrated to half the volume in vacuo. Ethyl ether (50 mL) was added and allowed to stand in a refrigerator overnight. The precipitate was collected by filtration and washed with ether to obtain 115 mg (58%) of the desired compound, mp. >250° C., : UV λmax (pH 1) 332 nm (ε 4,600) 240 nm (sh): λmax (pH 7) 326 nm (ε 4,500): λmax (pH 11) 326 nm (ε 4,200), 283 nm (ε 2,800): IR(KBr): 1140 (SO) cm-1 : 1H NMR (DMSO-d6): δ 6.59 (br s, 2,--SONH2, exchangeable in D2O), 6.57 (br s, 2, NH2, exchangeable in D2O), 8.12 (s, 1, C8H), 12.50 (br s, 1, NH, exchangeable in D2O). Anal. Calcd for C5H6N6OS (198.21): C, 30.30: H, 3.05: N, 42.40: S, 16.18. Found: C, 30.02: H, 2.82: N, 42.64: S, 15.97.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:19][C:20]1[C:21]([C:26]2[N:30]([CH:31]([CH3:33])[CH3:32])[N:29]=[CH:28][CH:27]=2)=[N:22][CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:19][C:20]2[C:21]([C:26]3[N:30]([CH:31]([CH3:33])[CH3:32])[N:29]=[CH:28][CH:27]=3)=[N:22][CH:23]=[CH:24][CH:25]=2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cccc1O
Reactant: CC(C)n1nccc1-c1ncccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1nccc1-c1ncccc1COc1cccc(O)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
A mixture of 2,6-dihydroxybenzaldehyde (1.96 g, 14.2 mmol, 2 eq.) and Cs2CO3 (7.5 g, 21.3 mmol, 3 eq.) in DMF (180 mL) was stirred at rt for 30 min. To this mixture was added 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (1.93 g, 7.1 mmol, 1 eq.) at rt. The mixture was continued to stir at rt O/N, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (920 mg, 37%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J=4.8, 1.5 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.49-7.34 (m, 2H), 6.59 (d, J=8.5 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H), 6.29 (d, J=8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J=6.7 Hz, 1H), 1.50 (d, J=6.6 Hz, 6H). LRMS (M+H+) m/z 338.1
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:9][CH:10]=3)[N:5]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4]=2[CH:3]=1.[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:9][CH:10]=3)[N:5]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(-c2ccc3c4ccc(Br)cc4n(-c4ccccc4)c3c2)c(-c2ccccc2)c1
Reactant: OB(O)c1ccccc1-c1ccccc1
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: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3c4ccc(-c5ccccc5-c5ccccc5)cc4n(-c4ccccc4)c3c2)c(-c2ccccc2)c1
Temperature: 110 °C
Yield: 57.6 %

Procedure:
A mixture of 3 g (5.9 mmol) of 2-bromo-7-(5-methoxybiphenyl-2-yl)-9-phenyl-9H-carbazole, 1.5 g (7.7 mmol) of biphenyl-2-ylboronic acid, 0.12 g (0.1 mmol) of tetrakis(triphenylphosphine)palladium, 15 ml of 2M Na2CO3, 20 ml of EtOH and 60 ml toluene was degassed and placed under nitrogen, and then heated at 110° C. for 8 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum. The residue was purified by column chromatography on silica(hexane-dichloromethane) afforded a white solid (2 g, 3.4 mmol, 58%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)[C:5]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:4]=2[O:3]1.[C:23]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][C:2]1([CH3:22])[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]([CH3:23])[C:11](=[O:15])[CH:10]=2)[C:5]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:4]=2[O:3]1
Reactant: CC1(C)N=C(Oc2cc[nH]c(=O)c2)c2cc(C#N)ccc2O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1ccc(OC2=NC(C)(C)Oc3ccc(C#N)cc32)cc1=O
Reaction time: 2 h

Procedure:
A mixture of 295 mg of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-4-pyridyloxy)-6-cyano-2H-1,3-benzoxazine, 20 ml of acetone, 400 mg of K2CO3 and 0.2 ml of dimethyl sulfate is boiled for 2 hours. The mixture is filtered and subjected to customary work-up to give 2,2-dimethyl-4-(1-methyl-2-oxo-1,2-dihydro-4-pyridyloxy)-6-cyano-2H-1,3-benzoxazine.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH3:40])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH3:40])[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 84.4 %

Procedure:
To a mixture of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate (0.70 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 mL) and the mixture was heated under reflux for 2 hrs. 1N Hydrochloric acid (5 mL) and water were added to the reaction mixture and the precipitated crystals were collected by filtration to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylic acid as crystals (0.56 g, yield 84%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 167-168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[OH-:10].[Cs+]>C(OCC)(=O)C.CCCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: COc1cccc(Br)c1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cccc(O)c1
Yield: 85 %

Procedure:
Following general operating mode B, 3-methoxybromobenzene (127 μL, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of an oil with a yield of 85% (eluent: ethyl acetate/heptane 10:90).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd].[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:9]1
Reactant: c1ccc(CN2CCC(N3CCCCC3)C2)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: C1CCN(C2CCNC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
550 mg 10% Pd/C are added to a solution of 5.50 g (22.5 mmol) 1-(1-benzyl-pyrrolidin-3-yl)-piperidine in 200 mL MeOH. The reaction solution is stirred for 5 h at RT and 3 bar H2. 550 mg palladiumhydroxide are added and the reaction is stirred for a further 6 h at RT and 3 bar H2. The catalyst is suction filtered and the solvent is eliminated i.vac.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][NH:29][C:30]([CH:32]1[O:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[N:34]([C:42]([C:44]2[S:45][CH:46]=[C:47]([CH2:50][N:51]([S:53]([C:56]3[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=3)(=[O:55])=[O:54])[CH3:52])[C:48]=2[Cl:49])=[O:43])[CH2:33]1)=[O:31])(C(C)(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[Cl:49][C:48]1[C:47]([CH2:50][N:51]([S:53]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH3:52])=[CH:46][S:45][C:44]=1[C:42]([N:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[O:37][CH:32]([C:30]([NH:29][CH2:28][CH2:27][OH:26])=[O:31])[CH2:33]1)=[O:43]
Reactant: CN(Cc1csc(C(=O)N2CC(C(=O)NCCO[Si](C)(C)C(C)(C)C)Oc3ccccc32)c1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(Cc1csc(C(=O)N2CC(C(=O)NCCO)Oc3ccccc32)c1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 46 %

Procedure:
A solution of tetrabutylammonium fluoride in THF (1.0M, 1.0 ml, 11.0 mmol) was added to a solution of N-(2-tert-butyldimethylsilyloxyethyl)-4-(3-chloro-4-(N-(4-chlorobenzenesulphonyl)-N-methylaminomethyl)thiophene-2-carbonyl)benzomorpholine-2-carboxamide (65 mg, 0.093 mmol) in THF (4.0 ml) and stirred for 1 h. The mixture was reduced, taken up in ethyl acetate, washed with 1N hydrochloric acid and brine, filtered and reduced. Chromatography (95% 60-80 petroleum ether/5% EtOAc) afforded 4-(3-chloro-4-(N-(4-chlorobenzenesulphonyl)-N-methylaminomethyl)thiophene-2-carbonyl)-N-(2-hydroxyethyl)-benzomorpholine-2-carboxamide as a white solid (25 mg, 46%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8](=[O:18])[C:7]=2[CH:19]=1)#N.[OH-:20].[Na+].C(O)C.Cl.[OH2:26]>>[O:13]=[C:12]1[CH2:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[S:8](=[O:18])[C:7]2[CH:19]=[C:3]([C:1]([OH:26])=[O:20])[CH:4]=[CH:5][C:6]1=2
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1ccc2c(c1)S(=O)c1ccccc1CC2=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)S(=O)c1ccccc1CC2=O

Procedure:
780 Mg. 3-cyano-10,11-dihydro-11-oxodibenzo[b,f]thiepin 5-oxide is refluxed for four hours in a mixture of 50 cc. 10% aqueous sodium hydroxide and 50 cc. ethanol. The reaction mixture is diluted with water, acidified with hydrochloric acid, filtered and dried under vacuum in the oven at 70° C. The solid is recrystallized from a mixture of dimethylformamide and methanol to yield 360 mg. of the pure acid, m.p. 273° C. dec.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:23])[CH2:19][CH2:20][C:21]#[CH:22]>C(#N)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:23][CH2:18][CH2:19][CH2:20][C:21]#[CH:22])#[N:2]
Reactant: C#CCCCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CC#N
Product: C#CCCCN=C(NC#N)NCCSCc1[nH]cnc1C
Reaction time: 96 h

Procedure:
A mixture of N-cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-S-methylisothiourea (3.00 g., 0.0111 mole) and 4-pentyn-1-amine (3.69 g., 0.0445 mole) in 60 ml. of acetonitrile was stirred at reflux for 24 hours, and then allowed to stand at room temperature for 96 hours. The solvent and excess amine were removed under reduced pressure and the residual yellow gum was purified by chromatography on 50 g. of 100-200 mesh silica gel, using gradient elution with methylene chloride/methanol (99:1-96:4). The middle fractions indicated by TLC to be pure were combined and evaporated to give 1.91 g. of yellow gum which was crystallized at -15° C. from 18 ml. of ethyl acetate. The resulting white solid (1.25 g.) was recrystallized at -15° C. from 10 ml. of acetonitrile to give 1.063 g. of product; m.p. 99°-103° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]5[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(OC2CCCCC2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OC5CCCCC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-cyclohexyloxy-pyridine.