Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[S:43][C:5]2[C:6](=[O:42])[N:7](COCC[Si](C)(C)C)[C:8]3[C:9]([CH3:33])=[CH:10][C:11]([O:31]C)=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C@@H:20]([CH3:30])[CH2:21][NH:22]C(=O)OC(C)(C)C)=[CH:16][CH:15]=4)[C:13]=3[C:4]=2[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:22][CH2:21][C@@H:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:13]3[C:4]4[CH:3]=[C:2]([F:1])[S:43][C:5]=4[C:6](=[O:42])[NH:7][C:8]=3[C:9]([CH3:33])=[CH:10][C:11]=2[OH:31])=[CH:15][CH:16]=1)[CH3:30]
Reactant: COc1cc(C)c2c(c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1)c1cc(F)sc1c(=O)n2COCC[Si](C)(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(O)c(-c2ccc([C@@H](C)CN)cc2)c2c1[nH]c(=O)c1sc(F)cc12
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 2-(4-(2-fluoro-8-methoxy-6-methyl-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (60 mg, 0.096 mmol) in CH2Cl2 (1 mL) at 0° C. was added BBr3 (1.0 M in methylene chloride, 1.0 mL, 1.0 mmol) and the reaction was stirred at that temperature for 1 h and quenched by pouring onto water or ice-water. The resulting mixture was concentrated and the residue was dissolved methanol (2 mL) and treated with NH4OH (2 mL). The resulting mixture was stirred at rt for 2 h and purified by preparatory HPLC (C18 silica, acetonitrile/water (with 0.05% TFA) gradient). The desired fractions were combined, concentrated and the residue was dissolved in aqueous HCl, concentrated and dried under high vacuum to afford the desired product as a hydrochloride salt: 1H NMR (500 MHz, CD3OD) δ 7.55 (dd, J=7.9, 1.7 Hz, 1H), 7.46 (dd, J=7.8, 1.8 Hz, 1H), 7.32 (dd, J=23.9, 7.9 Hz, 2H), 7.10 (s, 1H), 5.46 (d, J=2.9 Hz, 1H), 3.28-3.15 (m, 3H), 2.55 (s, 3H), 1.49 (d, J=6.3 Hz, 3H); ESI MS m/z 383 [C21H19FN2O2S+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:19]=[CH:18][C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[N:16][C:11]=2[CH:10]=1.S(=O)(=O)(O)N>NC1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:19]=[CH:18][C:12]2[N:13]=[C:14]([NH:17][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:15]=[N:16][C:11]=2[CH:10]=1
Reactant: Cc1cccc(C)c1-c1ccc2nc(N)nnc2c1
Agent: NS(=O)(=O)O
Solvent: Nc1ccccc1
Product: Cc1cccc(C)c1-c1ccc2nc(Nc3ccccc3)nnc2c1
Yield: 32 %

Procedure:
7-(2,6-Dimethyl-phenyl)-benzo[1,2,4]triazin-3-ylamine(24 mg, 0.096 mmol) was dissolved in aniline, sulfamic acid (18 mg, 0.19 mmol) was added. The mixture was reflux overnight. The final product was isolated by preparative HPLC. Yield: 32%. ESI-MS: [M+H]+, 327; 1H NMR (DMSO-d6): δ 2.05(s, 6 H), 7.09(t, J=7.35 Hz, 1 H), 7.18–7.25 (m, 3 H), 7.40(m, 2 H), 7.71(dd, J1=8.5 Hz, J2=1.9 Hz, 1 H), 7.84(d, J=8.5 Hz, 1 H), 8.00(d, J=7.6 Hz, 2 H), 8.11(d, J=1.9 Hz, 1 H).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9]>N1C=CC=CC=1>[C:2]([C:1]([O:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1)=[O:6])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
161.1 mmol (19.48 g) of pivaloyl chloride are added, at 0° C., to a solution of 107.8 mmol (15 g) of 4-nitrophenol in 250 ml of pyridine. The reaction mixture is stirred for 72 hours at ambient temperature. The reaction mixture is evaporated in vacuo and the oily residue is diluted with ethyl acetate and then washed with aqueous hydrochloric acid solution (0.1N) and then with 10% aqueous sodium chloride solution. The expected product is obtained by drying the organic phase and then concentrating.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.ClC1N=CN=C2C=1NC=N2.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:21]1([NH:20][C:9]2[N:1]=[CH:2][N:3]=[C:4]3[C:8]=2[N:7]=[CH:6][NH:5]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: c1ncc2[nH]cnc2n1
Agent: Clc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(Nc2ncnc3[nH]cnc23)cc1

Procedure:
The general procedure for the synthesis of purine derivatives is depicted in FIG. 1. The initial compound 6-chloropurine (1.0 eq.) was mixed with aniline (1.20 eq.) and K2CO3 (2.5 eq.) in 50.0 ml dioxane. The resultant mixture was charged in 100 mL round bottom flask with a stirring bar. The mixture was refluxed overnight and monitored by TLC. After the reaction finished, the solvent was removed and the remaining residue was extracted by ethyl acetate. After removing the solvent, the resultant crude product was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (5%) to provide pure titled compound.
Reaction SMILES: C([N:3](CC)CC)C.CS(Cl)(=O)=O.[Si:13]([O:20][CH:21]([CH2:40][CH2:41]O)[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[O:32])=[CH:26][C:25]=1[F:39])O)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[Si:13]([O:20][CH:21]1[CH2:40][CH2:41][NH:3][CH:22]1[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[O:32])=[CH:26][C:25]=1[F:39])([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:14])[CH3:15]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OC(CCO)C(O)c1ccc(NC(=O)c2ccccn2)cc1F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OC1CCNC1c1ccc(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
155 mg of triethylamine and 130 mg of methanesulfonyl chloride were added in order to a chloroform (8 ml) solution of 165 mg of N-(4-(2-((t-butyl(dimethyl)silyl)oxy)-1,4-dihydroxybutyl)-3-fluorophenyl)pyridine-2-carboxamide, with cooling with ice, and the reaction liquid was stirred at room temperature for 30 minutes. The reaction liquid was diluted with chloroform, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and 25 mg of sodium azide was added to a dimethylformamide (5 ml) solution of the resulting residue, and the reaction liquid was stirred at 40° C. for 2 hours. The reaction liquid was cooled, water was added to it, extracted with ethyl acetate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and 50 mg of sodium borohydride and 5 mg of copper sulfate pentahydrate were added in order to a methanol (10 ml) solution of the resulting residue, and the reaction liquid was stirred at 40° C. for 2 hours. The reaction liquid was cooled, aqueous saturated sodium bicarbonate was added to it, extracted with chloroform, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [C:1]([CH2:3][N:4]([CH2:9][CH2:10][C:11]#[N:12])[CH2:5][CH2:6][CH2:7][OH:8])#N.N>>[OH:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][CH2:11][NH:12][CH2:1][CH2:3]1
Reactant: N#CCCN(CC#N)CCCO
Agent: N
Product: OCCCN1CCCNCC1

Procedure:
hydrogenating the cyanomethyl-(2-cyano-ethyl)-(3-hydroxy-propyl)-amine in the presence of hydrogenation catalyst and ammonia to form 1-(3-hydroxy-propyl)-1,4-diazepane; and
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2([C:13]([OH:15])=O)[CH2:12][CH2:11]2)=[O:8])[CH:4]=[N:3][CH:2]=1.[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=2)=[C:19]([F:33])[CH:18]=1>>[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]([CH:28]([NH:30][C:13]([C:10]3([NH:9][C:7]([C:5]4[CH:4]=[N:3][CH:2]=[N:1][CH:6]=4)=[O:8])[CH2:11][CH2:12]3)=[O:15])[CH3:29])=[CH:26][CH:27]=2)=[C:19]([F:33])[CH:18]=1
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Reactant: CC(N)c1ccc(Oc2ccc(Cl)cc2F)cc1
Product: CC(NC(=O)C1(NC(=O)c2cncnc2)CC1)c1ccc(Oc2ccc(Cl)cc2F)cc1
Yield: 29 %

Procedure:
Analogously to Example (1e) the title compound was prepared from 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and 1-[4-(4-chloro-2-fluoro-phenoxy)-phenyl]-ethylamine.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C(#N)C.C(=O)=O.C([Li])CCC.CON(C)[C:24](=[O:27])[CH2:25][CH3:26]>O1CCCC1>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:24](=[O:27])[CH2:25][CH3:26]
Reactant: c1cc2sccc2cn1
Reactant: CCC(=O)N(C)OC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCC(=O)c1cc2cnccc2s1
Temperature: -78 °C
Reaction time: 14 h
Yield: 82.7 %

Procedure:
To a stirring mixture of thieno[3,2-c]pyridine (1.0 g) in anhydrous tetrahydrofuran (50 mL) at −40° C. (acetonitrile-dry ice bath) was added a solution of n-butyllithium (1.6 M, 4.7 mL) in hexanes. The mixture was cooled to −78° C. followed by the subsequent addition of a solution of N-methoxy-N-methyl-propionamide (0.97 g) in anhydrous tetrahydrofuran (10 mL). The cold bath was removed and the reaction mixture was allowed to warm gradually to room temperature. The mixture was stirred overnight (14 hours). The mixture was treated with saturated aqueous ammonium chloride (150 mL). The mixture was then extracted with ethyl acetate (500 mL), and the extract was washed with brine solution (100 mL). The organic phase was dried over anhydrous potassium carbonate and was concentrated under reduced pressure, reconstituted in chloroform, and concentrated again under reduced pressure to afford the orange-brown semisolid (1.17 g). The semisolid was purified by flash silica chromatography using an Analogix silica column (115 g silica), eluting with 0-30% ethyl acetate/heptane, then 30-60% ethyl acetate/heptane. Concentration of fractions containing product gave 0.49 g of product. Starting material (0.45 g) was also isolated by evaporation of appropriate fractions.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])([OH:16])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:26].[K+].[K+].OO>CS(C)=O>[CH2:1]([N:8]1[CH2:9][CH:10]2[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]([NH2:21])=[O:26])([OH:16])[CH:13]([CH2:12][CH2:11]2)[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(C2(O)C3CCC2CN(Cc2ccccc2)C3)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1cccc(C2(O)C3CCC2CN(Cc2ccccc2)C3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 570.8 %

Procedure:
3-(3-Benzyl-8-hydroxy-3-aza-bicyclo[3.2.1]oct-8-yl)-benzonitrile (1.86 g, 5.84 mmol) in DMSO (30 mL) with potassium carbonate (0.121 g, 0.88 mmol) was charged with 30% aqueous hydrogen peroxide (2.98 mL, 29.2 mmol) and allowed to stir at room temperature for 2 h (or until judged complete by TLC). The reaction was cooled in an ice bath then quenched with water (50 mL) causing the product precipitate as white solids. The mixture was acidified to pH 1 with 1N HCl (25 mL) to dissolve the product and the aqueous layer was washed with ether (2×30 mL). The ether extracts were back extracted with water (1×30 mL). The combined acidic aqueous layers were neutralized to pH 8 with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc (3×50 mL), washed with 50% saturated aqueous NaCl solution (3×50 mL) then dried by azeotroping with THF (3×100 mL) yielding a white solid (1.69 g, 86%). 1H NMR (400 MHz, CD3OD) δ 7.96 (t, J=1.5 Hz, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.64 (d, J=7.4 Hz, 1H), 7.41–7.15 (m, 6H), 3.56 (br s, 2H), 2.88 (m, 2H), 2.61 (m, 2H), 2.46 (br, s, 2H), 1.76 (m, 2H), 1.35 (m, 2H); APCI MS m/z 337.2 (M+1)+; mp 210–214° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH:28]1[C:32]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)=[N:31][N:30]=[N:29]1>>[NH:31]1[C:32]([C:33]2[CH:39]=[CH:38][C:36]([NH:37]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:35][CH:34]=2)=[N:28][N:29]=[N:30]1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(-c3nnn[nH]3)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-tetrazol-5-yl-aniline
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:25])([F:24])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.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:9][C:10]([F:24])([F:25])[C:11]1[CH:12]=[C:13]([C:2]2[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
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: C1CCOC1
Product: O=Cc1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)o1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of 5-bromofuran-2-carbaldehyde (2.54 g, 14.5 mmol), [3,5-bis(trifluoromethyl)phenyl]boronic acid (3.93 g, 15.2 mmol), tetrakis(triphenylphosphine)palladium (0.59 g, 0.51 mmol) and 2M sodium carbonate solution (36 mL, 72 mmol) in THF (150 ml) was stirred under an argon atmosphere for 16 hr. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate filtration, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate), and the obtained solid was disrupted in hexane to give the title compound (4.46 g, yield>99%) as a pale-yellow solid. LC/MS (ESI+) m/z: 309 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:28]=[CH:27][C:26]([F:29])=[CH:25][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1.C(N(CC)CC)C>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:28]=[CH:27][C:26]([F:29])=[CH:25][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)=[CH:19][C:18]=3[F:24])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(NCc1ccc(O)cc1F)c1cc(F)cnc1Oc1ccc2c(c1)OCO2
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(OCc2ccccn2)cc1F)c1cc(F)cnc1Oc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 100 mg (0.25 mmol.) 2-(benzo[1,3]dioxol-5-yloxy)-5-fluoro-N-(2-fluoro-4-hydroxy-benzyl)-nicotinamide [Prepared analogous to preparation 35 by substituting 2-chloro-5-fluoro-nicotinic acid (EP 0634413 A1)], 10 mL DMF and 175 mg (1.25 mmol.) potassium carbonate was added a solution of DMF (5 mL) containing 82 mg (0.5 mmol.) 2-chloromethyl-pyridine hydrochloride (Aldrich) and 1 equivalent of triethyl amine. The resulting mixture was stirred for 3 days at room temperature. Reaction mixture was poured into ice water (200 mL) and the resulting solid was filtered, washed with cold water and dried in vacuo to afford desired product.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[H-].[Na+].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19]>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CBr)cc1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 49.6 %

Procedure:
Using 0.22 g of 4-(methylthio)benzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.15 g of 2-(4-(methylthio)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (34)).
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:10]3=[N:11][CH:12]=[C:13]([NH2:15])[CH:14]=[C:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:15][C:13]1[CH:14]=[C:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:16][C:10]2=[N:11][CH:12]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1cnc2[nH]c(-c3ccccc3)nc2c1
Solvent: c1ccncc1
Product: O=C(Nc1cnc2[nH]c(-c3ccccc3)nc2c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 mg 2-phenyl-3H-imidazo[4,5-b]pyridin-6-ylamine (0.38 mmol,) in 4 ml dry pyridine were cooled to −40° C. and treated with 92 mg (1.1 equivalents) 2-chlorobenzoyl chloride. The cooling bath was removed an the mixture stirred for 1 hr at room temperature. The solvent was evaporated and the residue purified by chromatography on silica in methanol/dichloromethane mixtures. Yield 35 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1)=[O:4].[CH3:23][CH:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][C:9]=1[N:10]([C:30]([C@H:27]1[CH2:28][CH2:29][C@H:24]([CH3:23])[CH2:25][CH2:26]1)=[O:31])[CH:11]1[CH2:12][CH2:13][S:14][CH2:15][CH2:16]1)=[O:4]
Reactant: CC1CCC(C(=O)Cl)CC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC1CCSCC1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCSCC1

Procedure:
Amidation of 5-phenyl-3-(tetrahydro-thiopyran-4-ylamino)-thiophene-2-carboxylic acid methyl ester (0.2 g, 0.6 mmol) and 4-Methyl-cyclohexanecarbonyl chloride was carried out as described for example 19, step 2 gave 3-[(trans-4-methyl-cyclohexanecarbonyl)-(tetrahydro-thiopyran-4-yl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.208 g, 75.7%). NMR 1H (CDCl3, 400 MHz): 7.68-7.62 (m, 2H), 7.5-7.4 (m, 3H), 7.04 (s, 1H), 4.68-4.58 (m, 1H), 3.86 (s, 3H), 2.9-1.2 (m, 16H), 0.78 (d, 3H), 0.76-0.56 (m, 2H).s
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10]3([CH2:21][O:20][C:19]4[CH:22]=[C:23]5[C:27](=[CH:28][C:18]3=4)[CH2:26][CH2:25][O:24]5)[C:9]2=[O:29])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[F:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]3([CH2:21][O:20][C:19]4[CH:22]=[C:23]5[C:27](=[CH:28][C:18]3=4)[CH2:26][CH2:25][O:24]5)[C:9](=[O:29])[NH:8]2)=[CH:12][CH:13]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cc(F)ccc2C12COc1cc3c(cc12)CCO3
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1Nc2cc(F)ccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 6′-fluoro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (71%) as a colorless solid: mp 249-251° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ10.74 (s, 1H), 7.18-7.13 (m, 1H), 6.79-6.42 (m, 2H), 6.55 (s, 1H), 6.42 (s, 1H), 4.74 (ABq, 2H), 4.52 (t, J=9.0 Hz, 2H), 2.99 (t, J=9.0 Hz, 2H); MS (ES+) m/z 298.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:16]([N:18]1[C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[NH:1][C:19]1=[O:20])[CH3:17]
Reactant: CCN=C=O
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCn1c(=O)[nH]c2cc(C(=O)OC)ccc2c1=O
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of dimethyl 2-aminoterephthalate (4.18 g), ethyl isocyanate (2.58 ml) and triethylamine (1.0 ml) in toluene (20 ml) was heated at 70° C. for 15 hr. After concentration, methanol (50 ml) and concentrated hydrochloric acid (10 ml) was added and the mixture was stirred at room temperature for 5 hr. After concentration, the residue was washed with water (50 ml) and methanol (50 ml) and dried to give the object compound (2.23 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH:30]2[CH2:32][CH2:31]2)[C:16]2[C:21](=[O:22])[O:20][C:19]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:18]=3[C:17]=2[OH:29])[CH:10]=1)(=[O:7])=[O:6].[Na+].[I-:34]>C(Cl)Cl>[I:34][CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH:30]2[CH2:32][CH2:31]2)[C:16]2[C:21](=[O:22])[O:20][C:19]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:18]=3[C:17]=2[OH:29])[CH:10]=1)(=[O:7])=[O:6]
Reactant: [I-]
Reactant: O=c1oc2c(c(O)c1C(c1cccc(NS(=O)(=O)CCCCl)c1)C1CC1)CCCCCC2
Agent: [Na+]
Solvent: ClCCl
Product: O=c1oc2c(c(O)c1C(c1cccc(NS(=O)(=O)CCCI)c1)C1CC1)CCCCCC2
Temperature: 25 °C

Procedure:
To 96 mg (2 mmol) of the title compound of Example 331 is added 34 mg of NaI and 2 ml of methylene chloride. The reaction mixture is heated at reflux for 18 hours. The solution is cooled to room temperature and evaporated to dryness under vacuum. The residue is distributed between water and methylene chloride, the organic solution is washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give the title compound as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH2:9][CH2:10][CH3:11])[C:6](Cl)=[O:7].[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C>ClCCl>[CH3:16][N:17]([C:6](=[O:7])[CH:5]([O:4][C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[Br:1])[CH2:9][CH2:10][CH3:11])[O:18][CH3:19]
Reactant: CCCC(Oc1ccccc1Br)C(=O)Cl
Reactant: CNOC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(Oc1ccccc1Br)C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
5.5 g (18.9 mmol) of 2-(2-bromophenoxy)pentanoic acid chloride, 2.03 g (20.8 mmol) of N-methyl-O-methylhydroxylamine and 190 ml of dichloromethane are placed in a 500 ml round-bottomed flask. The solution is cooled to 0° C. and 5.8 ml (41.6 mmol) of triethylamine are slowly added. The solution is stirred for 1 hour at room temperature and then concentrated under vacuum. 100 ml of a molar hydrochloric acid solution are added to the residue and extraction is carried out with 3×100 ml of ethyl ether. The combined organic phases are dried over magnesium sulphate, filtered and concentrated under vacuum to give 6 g of N-methyl-O-methyl-2-(2-bromophenoxy)pentanohydroxamic acid in the form of a colourless oil; quantitative yield.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[Cl-].[Al+3:7].[Cl-].[Cl-]>>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Al+3:7].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Al+3:7]
Reactant: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Product: O=S(=O)([O-])[O-]
Yield: 1042.7 %

Procedure:
Concentrated sulphuric acid (8 g) was added to an aqueous solution of aluminium chloride (120 g). After standing, aluminium sulphate crystals precipitated from the over-saturated slurry obtained. The crystals were filtered off into a crystal cake (29 g), leaving a saturated solution of aluminium sulphate (97 g) as a mother liquor.