Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)(=[O:5])=[O:4]>C(OCC)(=O)C.[Pd]>[NH2:12][C:8]1[CH:7]=[C:6]([S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cccc(N)c1
Reaction time: 48 h
Yield: 56.6 %

Procedure:
A reaction vessel charged with the prepared N-methyl-3-nitro-benzenesulfonamide (4.2 g, 19.42 mmol) in 150 ml of ethyl acetate was further charged with 450 mg of 10% palladium on carbon. The reaction mixture was stirred under hydrogen atmosphere for 48 h, then was filtered through a pad of silica gel washing with EtOAc, and the filtrate was concentrated under reduced pressure. The free base was acidified to give 2.1 g, (˜11 mmol, 58% yield) of the title compound (a compound of formula (W) wherein R is methyl) as its HCl-salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.[OH-].[K+].Cl>CS(C)=O>[NH2:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[O:20])=[CH:11][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1cccc(O)c1
Reactant: O=C(Nc1cccc(Br)c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cccc(Oc2ccc(C(=O)Nc3cccc(Br)c3)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A solution of N-(3-Bromo-phenyl)-4-chloro-3-nitro-benzamide (from Example 16A) (0.71 g, 2.0 mmol), 3-aminophenol (0.22 g, 2.0 mmol) and powdered potassium hydroxide (0.23 g, 4.0 mmol) in Dimethyl sulfoxide (5 mL) was heated at 100° C. for 30 minutes. After cooling to room temperature the mixture was poured into ice water (100 mL) and the resultant solution adjusted to pH 5 with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3×50 mL), the combined extracts dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound (0.8 g, 93%).
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:16]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].CCOCC>C1COCC1.N1C=CC=CC=1>[CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5](=[O:13])[C:6]1[CH:7]=[CH:8][C:9]([O:12][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([O:26][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:35][CH:34]=2)=[CH:10][CH:11]=1
Reactant: CCC(C)COC(=O)c1ccc(O)cc1
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(C)COC(=O)c1ccc(OC(=O)c2ccc(OC(=O)OCc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 16 m moles (3.3 g) of the above 4-hydroxybenzoic acid 2-methylbutyl ester in 20 ml of THF and 40 ml of pyridine was cooled and a THF solution of 10 m moles (2.9 g) of the above 4-carbobenzoxyoxybenzoyl chloride was added dropwise. The mixture was returned slowly to room temperature, then stirred for 8 hours. After the reaction, the reaction mixture was ether extracted and concentrated, and then purified by column chromatography to obtain 2.9 g of 4-(4'-carbobenzoxyoxybenzoyloxy)benzoic acid 2-methylbutyl ester [m.p. 64.4°-65.4° C⟧ (yield: 63%)
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2)=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2)=[O:9]
Reactant: C=COCCONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (2-vinyloxyethoxy)-amide (1.85 g, 3.84 mmol) in methanol (40 mL) was added hydrochloric acid (3 mL, 1N, 3 mmol). The reaction mixture was stirred at room temperature for 1 hour, during which an off-white solid precipitated. The reaction mixture was concentrated in vacuo and the residue triturated with hot methanol/water (10 mL, 1:1). The product was collected by filtration and dried in vacuo to yield the title compound as an off white solid (1.26 g, 72%). LCMS (Method A): RT=8.28 min, [M+H]+=457. 1H NMR (DMSO-d6): 13.20 (1 H, s), 11.61 (1 H, s), 9.93 (1 H, s), 7.66 (1 H, dd, J=10.32, 1.95 Hz), 7.46 (1 H, d, J=8.81 Hz), 7.42 (1 H, dd, J=8.49, 1.84 Hz), 7.24 (1 H, s), 7.01 (1 H, d, J=8.78 Hz), 6.91 (1 H, t, J=8.65 Hz), 4.68 (1 H, s), 3.85 (2 H, dd, J=5.41, 4.48 Hz), 3.56 (2 H, t, J=4.85 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1>[Cl-].[Cl-].[Cl-].[Ti+3]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)c1
Agent: [Ti+3]
Agent: [Cl-]
Product: COc1cccc(N2CCN(Cc3ccc(N)cc3)CC2)c1

Procedure:
In the manner given in Example 1B, 1-(m-methoxyphenyl)-4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(m-methoxyphenyl)-4-[(4-aminophenyl)methyl]piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:33][O:34][N:35]([CH3:45])[C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][C:36]([N:35]([O:34][CH3:33])[CH3:45])=[O:44])[CH2:43][CH2:42]3)=[O:21])[C:10]([C:23]3[S:24][CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)CN1CCNCC1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)OC)CC1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 34) was reacted with N-methoxy-N-methyl-2-piperazin-1-yl-acetamide dihydrochloride to give 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-methoxy-N-methyl-acetamide in an analogous manner as described in example 1. LR-MS: 630.3 [(M+H)+].
Reaction SMILES: [CH:1](=[N:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[CH:1](=[N:8][N:9]=[C:10]([Cl:24])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NN=Cc1ccccc1)c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(C(Cl)=NN=Cc2ccccc2)cc1
Yield: 59 %

Procedure:
A mixture of N′-benzylidene-4-trifluoromethylbenzohydrazide (2.92 g), thionyl chloride (1.09 ml) and toluene (50 ml) was heated under reflux for 1 hr. After cooling, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1, volume ratio) and recrystallized from hexane to give N-benzylidene-4-trifluoromethylbenzenecarbohydrazonoyl chloride (1.85 g, yield 59%) as pale-yellow plate crystals. melting point: 95–96° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[CH2:16][C:17]([F:20])([F:19])[F:18])(=O)=O.FC(F)(F)C(O)=O.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[CH2:41][CH2:40][NH:39][CH2:38]2)=[CH:33][CH:32]=1>O1CCOCC1.ClCCl>[Br:30][C:31]1[CH:32]=[CH:33][C:34]([CH:37]2[CH2:41][CH2:40][N:39]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:38]2)=[CH:35][CH:36]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Brc1ccc(C2CCNC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)CN1CCC(c2ccc(Br)cc2)C1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
Diisopropylethylamine (0.26 ml, 1.489 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.13 ml, 0.902 mmol) were added to a stirred solution of 3-(4-bromophenyl)pyrrolidine 2,2,2-trifluoroacetate (254.5 mg, 0.748 mmol) in dioxane (3.0 ml). The reaction mixture was heated to 80° C. After 17 hours, the reaction mixture was cooled to room temperature and evaporated under reduced pressure to give a yellow residue. The residue was dissolved in dichloromethane and loaded onto a 5 g silica solid load cartridge. The residue was purified using an ISCO Rf and a 12 g silica column (CV=16.8 ml). The column was eluted as follows: 100% dichloromethane (3 CV), 0-3% MeOH/dichloromethane gradient (17 CV), 3% MeOH/dichloromethane (10 CV), 3-5% MeOH/dichloromethane gradient (15 CV), 5% MeOH/dichloromethane (5 CV) at 30 ml/min. The product fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil. LC-MS: calculated for C12H13BrF3N 307.02, 309.02 observed m/e: 308.05, 310.05 (M+H)+ (Rt 1.02/2 min).
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C@H:8]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][CH:9]1[OH:10])=[O:6])=[N+:2]=[N-:3].C(O[C:23](=[O:25])[CH3:24])(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:5]([O:10][CH:9]1[O:11][C@H:12]([CH2:17][O:18][C:23](=[O:25])[CH3:24])[C@@H:13]([O:16][C:12](=[O:11])[CH3:13])[C@H:14]([O:15][C:9](=[O:10])[CH3:8])[C@@H:8]1[NH:7][C:5](=[O:6])[CH2:4][N:1]=[N+:2]=[N-:3])(=[O:6])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=NCC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1OC(OC(C)=O)[C@@H](NC(=O)CN=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 190.8 %

Procedure:
A solution of 20 (25 mg, 0.095 mmol) in pyridine (2 mL) was cooled to 0° C. To this solution was added acetic anhydride (1.0 ml, 11 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight and allowed to warm to rt. The resulting light yellow solution was diluted with CH2Cl2 (100 mL) and washed with 1 N HCl (3×50 mL), sat. NaHCO3 (1×50 mL), water (1×50 mL) and sat. NaCl (1×50 mL). The combined aqueous layers were back extracted with 50 mL of CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluting with a gradient of 1:10 to 1:2 EtOAc/hexanes to afford 39 mg (95%) of a light yellow oil. IR (thin film): 3317, 2106, 1744, 1677, 1529 cm−1. 1H NMR (500 MHz, CDCl3): δ2.05 (app s, 6H), 2.10 (s, 3H), 2.12 (s, 3H), 3.82 (ddd, 1H, J=2.4, 4.5, 9.6), 3.93 (s, 2H), 4.13 (dd, 1H, J=2.4, 12.6), 4.29 (dd, 1H, J=4.5, 12.6), 5.15 (app t, 1H, J=9.6), 5.21 (app t, 1H, J=5.7), 5.78 (app t, 1H, J=4.5), 6.37 (d, 1H, J=5.7). 13C NMR (125 MHz, CDCl3): δ20.5, 20.5, 20.6, 20.6, 20.6, 20.8, 20.8, 51.2, 52.4, 52.5, 53.2, 61.4, 61.5, 67.4, 67.6, 69.8, 70.3, 72.0, 72.1, 72.9, 90.2, 92.1, 166.9, 168.6, 169.1, 169.2, 170.6, 170.8, 171.5. HRMS (FAB) m/z 437.1496 (MLi+C16H22LiN4O10 requires 437.1496).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[Cl:20][C:21]1[C:22]([C:27]2[N:31]=[CH:30][NH:29][N:28]=2)=[C:23]([NH2:26])[S:24][CH:25]=1>>[Cl:20][C:21]1[C:22]([C:27]2[N:31]=[CH:30][NH:29][N:28]=2)=[C:23]([NH:26][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[N:8][C:7]([C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:24][CH:25]=1
Reactant: O=C(O)Cn1c(=O)ccc2nc(C(F)(F)F)ccc21
Reactant: Nc1scc(Cl)c1-c1nc[nH]n1
Product: O=C(Cn1c(=O)ccc2nc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1nc[nH]n1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)-1,5-naphthyridin-1(2H)-yl)acetic acid (160 mg, 0.588 mmol) and 4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-amine (59 mg, 0.294) mmol) according to protocol A. Retention time (min)=5.046, method [7], MS(ESI) 455.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.30 (d, J=8.9 Hz, 1H), 8.21 (d, J=9.8 Hz, 1H), 8.09 (d, J=8.9 Hz, 1H), 7.20 (s, 1H), 7.13 (d, J=9.8 Hz, 1H), 5.36 (s, 2H).
Reaction SMILES: N.[CH:2]1(C(O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1>>[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: O=C(O)C1C=Cc2ccccc21
Agent: N
Product: C1=Cc2ccccc2C1
Reaction time: 1.25 h

Procedure:
Subsequently, as shown in FIG. 3C, the substrate 1 coated with photoresist 102 is put in heat-treatment furnace 105. In the furnace 105, the substrate 1 is heated in an ammonia gas atmosphere 106. The heat treatment is performed at a temperature of 95° to 120° C. for 75 minutes. At the photo-sensitized region, the indene carboxylic acid is crosslinked and alkali-insoluble indene is produced.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH3:26])=[C:20](I)[CH:19]=1>>[NH2:15][C:7]1[C:6]([C:4]([C:20]2[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([CH3:24])[C:21]=2[O:25][CH3:26])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1c(C)cc(F)cc1I
Product: CCSc1ncc(C(=O)c2cc(F)cc(C)c2OC)c(N)n1

Procedure:
The same procedure as described in Example 376 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 1-fluoro-3-iodo-4-methoxy-5-methyl-benzene (Example 382) to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-3-methyl-phenyl)-methanone. MS (M+H)+, 322.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:19]([CH3:22])=[N:20][N:21]=3)[C:13]=2[CH:12]=[C:11]1[C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28]I>CN(C=O)C>[CH2:3]([N:10]1[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:19]([CH3:22])=[N:20][N:21]=3)[C:13]=2[CH:12]=[C:11]1[C:23]1[CH:24]=[CH:25][N:26]([CH3:28])[N:27]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3ccccc3)n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(-c4ccn(C)n4)n3Cc3ccccc3)n12
Reaction time: 0.17 h

Procedure:
Sodium hydride (4.0 mg, 0.099 mmol, 60% in mineral oil) was added to a solution of 6-benzyl-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (6.5 mg, 0.020 mmol, from Example 62) in DMF (0.20 mL). After 10 minutes, methyl iodide (3.7 μL, 0.059 mmol, Aldrich) was added. After 15 minutes reaction time, the reaction was quenched with water. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) and the major isomer was isolated. Yield: (2.7 mg, 40%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.N1C=CN=C1.FC(F)(F)S(O[Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])(=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)cc(O)c2n1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1ccc2cc(F)cc(O[Si](C(C)C)(C(C)C)C(C)C)c2n1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
6-Fluoro-2-methylquinolin-8-ol (19.0 g, 107 mmol) was dissolved in methylene chloride (300 mL) and treated with 1H-imidazole (10.9 g, 160 mmol) and triisopropylsilyl trifluoromethanesulfonate (33.1 ml, 123 mmol). The reaction was stirred at ambient temperature for 13 hours. The reaction mixture was quenched with saturated NH4Cl and separated. The organic layer was washed twice with saturated NH4Cl, dried over Na2SO4 and concentrated in vacuo (35 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:8][S:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>O1CCCC1.O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][CH2:13][CH2:12][C:11]([NH:10][C:9]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][S:7][CH:8]=1)=[O:23]
Reactant: COC(=O)c1cscc1NC(=O)CCCOc1ccccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCOc1ccccc1Cl)Nc1cscc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
4-[4-(2-Chloro-phenoxy)-butyrylamino]-thiophene-3-carboxylic acid methyl ester (270 mg, 0.763 mmol) was added to a solution of lithium hydroxide monohydrate (71.1 mg, 1.68 mmol) in a mixture of tetrahydrofuran (7.4 mL) and water (7.4 mL) and the reaction mixture was stirred for 3 hours at room temperature. The tetrahydofuran was evaporated and the solution was neutralized by addition of a solution of hydrochloric acid (1N, 0.39 mL). The precipitate was filtered, washed with water and dried in vacuo to yield the title compound as a yellow solid (218 mg, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21]Cl)=[CH:13][CH:12]=3)=[O:5])[CH3:2].CCOCC.[CH2:28]([O:30][P:31]([O:35]CC)[O:32][CH2:33][CH3:34])[CH3:29]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21][P:31]([O:32][CH2:33][CH3:34])([O:30][CH2:28][CH3:29])=[O:35])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCCl)cc12
Reactant: CCOP(OCC)OCC
Solvent: CCOCC
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCP(=O)(OCC)OCC)cc12

Procedure:
460 mg of 6-(3-chloro-1-propinyl)-beta-carboline-3-carboxylic-acid-ethylester is stirred in 4 ml of triethylphosphite for 3 h at 120°-130° C. The mixture, after being cooled, is thoroughly stirred with ether and the ether-soluble part is chromatographed after evaporation on 50 g of silica gel using methylene-chloride/ethanol (10/2). 105 mg of 6-[3-diethoxyphosphoryl-1-propinyl]beta-carboline-3-carboxylic-acid-ethylester is obtained in the form of an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.[C-:23]#[N:24].[Na+]>CS(C)=O>[C:23]([CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1)#[N:24]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCl)no1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CC#N)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 3.82 g of 3-chloromethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole in 50 ml of dimethyl sulfoxide (DMSO) was added 0.75 g of sodium cyanide. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice-water. The resultant mixture was extracted with benzene and the extracts were washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene to yield 2.4 g of 3-cyanomethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole. It was recrystallized from ethyl acetate-diisopropyl ether to give colorless plates, m.p. 111°-112° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f35) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[O:11])=[CH:2]1.ClN1[C:32](=[O:33])[CH2:31][CH2:30]C1=O.BrCCCO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][O:12][C:10]([C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[N:1]3[CH2:30][CH2:31][CH2:32][O:33][C:2]=23)=[O:11])[CH2:15][CH2:16]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(OCC1CCN(Cc2ccccc2)CC1)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCC1CCN(Cc2ccccc2)CC1)c1c2n(c3ccccc13)CCCO2

Procedure:
(1-Benzyl-4-piperidyl)methyl indole-3-carboxylate was treated initially with N-chlorosuccinimide (1.5 equivalents) for 2 h, then with 3-bromo-1-propanol (2 equivalents) for 16 h, followed by anhydrous potassium carbonate in acetone, using the method described in Example 1b. The crude product was purified by chromatography on silica gel eluting with chloroform/ethanol (19:1) to afford the title compound (E15) as a beige solid following recrystallisation from chloroform/ether (47%) mp 158°-160° C.
Reaction SMILES: CC[O:3][C:4]([C@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])=[O:5].[OH-].[Li+].Cl.CCOC(C)=O.CCCCCCC.C(O)(=O)C>CO.O1CCCC1.O>[CH2:40]([O:39][C:37]([N:7]1[CH2:8][C@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[C@@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:11][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(=O)[C@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@@H](C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.370 g (2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1,2-dicarboxylic acid 1-benzyl ester 2-ethyl ester in 18 ml methanol-tetrahydrofuran-water 1:1:1 is cooled to 0° C. Lithiumhydroxide (0.050 g) is added and the mixture is left to warm to room temperature and stirred for 16 hours at this temperature. The mixture is acidified with 1M hydrochloric acid and extracted with dichloro-methane (2×). The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified via flash chromatography (SiO2 60 F) to provide the product as a light red wax. Rf=0.25 (EtOAc-heptane-acetic acid 20:10:1); Rt=4.95.