Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][O:12][C:10]2[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1F
Product: COC(=O)c1ccc(OCCCCc2ccccc2)cc1F
Yield: 97 %

Procedure:
Following the process described in example 18 (point A), starting from methyl 2-fluoro-4-hydroxybenzoate and 4-phenyl-1-butanol, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with hexane:ethyl acetate, 95:5 (97% yield).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14]>B(Br)(Br)Br>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14]
Reactant: COc1ccc2c(c1)C(C)(C)CCC2=O
Agent: BrB(Br)Br
Product: CC1(C)CCC(=O)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A stirred, cooled (−78° C.) solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 9, 0.8, 3 mmol) under argon was treated with a 1M solution of boron tribromide (10 mL). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was cooled to −780° C., quenched and diluted with saturated aqueous sodium bicarbonate solution and the aqueous phase was extracted with dichloromethane (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230-400 mesh) using 30% ethyl acetate in hexane as the eluent afforded the title compound (0.3 g, 52%) as a yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH2:11][O:10][C:9]2=[O:20])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:28][CH3:29]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:28][CH3:29])[CH:14]=3)[CH2:11][O:10][C:9]2=[O:20])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: O=C1OC[C@H](c2cccc(O)c2)N1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc([C@H]2COC(=O)N2c2ccc(Cl)cc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To (S)-3-(4-chlorophenyl)-4-(3-hydroxyphenyl)oxazolidin-2-one (0.07 mmol), K2CO3 (0.37 mmol) in DMF (0.5 mL) is added iodoethane (0.14 mmol) and the reaction stirred at 60° C. overnight, then cooled to room temperature, filtered through a Whatman 0.42 μM filter and purified by preparative HPLC (C-18, 10-90% ACN/water (0.05% TFA)). HPLC-MS calculated for C17H16ClNO3 (M+H+): 318.1, found 318.0.
Reaction SMILES: [Li][CH2:2]CCC.[F:6][C:7]1[C:12]([F:13])=[C:11]([O:14][CH2:15][CH2:16][CH3:17])[CH:10]=[CH:9][C:8]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[Se:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][CH:19]=1.CI.[Cl-].[NH4+].N>C(OCC)C>[F:6][C:7]1[C:12]([F:13])=[C:11]([O:14][CH2:15][CH2:16][CH3:17])[CH:10]=[CH:9][C:8]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[Se:25][C:26]([CH3:2])=[CH:27][CH:28]=2)=[CH:20][CH:19]=1
Reactant: CCCOc1ccc(-c2ccc(-c3ccc[se]3)cc2)c(F)c1F
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: CCCOc1ccc(-c2ccc(-c3ccc(C)[se]3)cc2)c(F)c1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2.0 ml (11.8 mmol) of TMP are initially introduced at −15° C. in 15 ml of diethyl ether, and 7.0 ml (11.1 mmol, 15% soln. in hexane) of n-BuLi are metered in. After 25 min, a solution of 3.5 g (9.3 mmol) of 2-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)selenophene in 35 ml of diethyl ether is metered in, and the mixture is stirred at RT for 45 min. The batch is cooled to −70° C., and 3.0 ml (48.2 mmol) of methyl iodide are added. The mixture is warmed to RT and stirred for 3 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added successively, and the mixture is briefly stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:toluene=1:1). The further purification is carried out by digestion in ethanol and recrystallisation from n-heptane/toluene (2:1). 2-(2′,3′-Difluoro-4′-propoxybiphenyl-4-yl)-5-methylselenophene is obtained as a solid having an m.p. of 143° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1.[CH:22]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[O:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)[C:30](Cl)=[O:31])[CH2:24][CH2:23]1.C1(C(C2CC2)OC2C=CC=CC=2C(Cl)=O)CC1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:22]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([C:30]([NH:1][CH:2]3[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]3[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[O:31])[CH:33]=[CH:34][C:35]=2[O:36][CH2:37][CH:38]2[CH2:39][CH2:40]2)[CH2:24][CH2:23]1
Reactant: O=C(Cl)c1ccc(OCC2CC2)c(OCC2CC2)c1
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1ccccc1OC(C1CC1)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C2CC(OC(C)=O)CCC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Reaction time: 16 h

Procedure:
590 mg of (±)-acetic acid (1RS,3RS,4RS)-4-amino-3-(3,4-dimethoxyphenyl)cyclohexyl ester (compound B1) are dissolved in a mixture of 6 ml of methylene chloride and 1.5 ml of pyridine and 10 mg of 4-dimethylaminopyridine are added. A solution of 595 mg of 3,4-dicyclopropylmethoxybenzoyl chloride in methylene chloride is added dropwise and the mixture is stirred for 16 h. Further 140 mg of dicyclopropylmethoxybenzoyl chloride and 10 mg of 4-dimethylaminopyridine are added to complete the reaction. The solvents are removed and the residue is purified by chromatography on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 5/4/1 as eluent. After concentration of the corresponding eluate fractions, 630 mg (59% of theory) of the title compound are obtained as a colourless foam.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:28])=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])C.[Li+].[OH-]>O1CCCC1>[CH:15]1([C:14]2[N:9]3[N:8]=[C:7]([CH3:28])[C:6]([C:4]([OH:5])=[O:3])=[C:10]3[N:11]=[CH:12][C:13]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1c(C)nn2c(C3CCCCC3)c(-c3ccc(F)cc3)cnc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nn2c(C3CCCCC3)c(-c3ccc(F)cc3)cnc2c1C(=O)O
Temperature: 25 °C
Reaction time: 60 h
Yield: 96 %

Procedure:
To a solution of 178 mg (0.46 mmol) of 7-cyclohexyl-6-(4-fluoro-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester in 9 mL of tetrahydrofuran was added 2.8 mL (2.8 mmol) of 1 M LiOH solution, and the mixture was heated at reflux for 15 h. Since analysis by TLC revealed that starting material was still present, 2.8 mL (2.8 mmol) of 1 M LiOH solution was added, and reflux was continued for 60 h. The reaction mixture was then cooled to rt, concentrated, diluted with water, acidified with 10% HCl solution to pH=2, and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, and evaporated to give 156 mg (96% yield, 90% purity) of 7-cyclohexyl-6-(4-fluoro-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (515) as a beige solid as indicated by 1H NMR; LC-MS—calcd for C20H20FN3O2 [M++H]+: 354.15, found: 354.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1I)[NH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[Na+].[Na+].[CH3:18][N:19](C)C(=O)C>[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:18]#[N:19])[NH:7][CH:6]=[CH:5]2
Reactant: Fc1cc2cc[nH]c2cc1I
Reactant: CC(=O)N(C)C
Agent: Cl[Pd]Cl
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Fe+2]
Solvent: ClCCl
Product: N#Cc1cc2[nH]ccc2cc1F

Procedure:
To a microwave reaction vessel was added 5-fluoro-6-iodo-1H-indole (1 g), potassium ferrocyanide (1.41 g), Na2CO3 (0.80 g), PdCl2(dppf)-CH2Cl2 adduct (0.31 g) and N,N-dimethylacetamide (DMA). The reaction vessel was then sealed and heated in Biotage Initiator using initial high to 140° C. for 2 hours. After cooling the reaction, the solvent was evaporated and the residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The insolubles were filtered, the organics were evaporated and the residue was chromatographed on silica gel to give the designed product 5-fluoro-1H-indole-6-carbonitrile (D151) (0.25 g). MS (ES): C9H5FN2 requires 160.0; found 161.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[N:17]=[C:18]([CH3:42])[C:19]([C:20]4[S:21][C:22]([C:31]5[N:35]=[CH:34][N:33](C6CCCCO6)[N:32]=5)=[C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:24]=4)=[C:13]3[CH:12]=2)[CH2:4][C:3]1=[O:43].[ClH:44].CCOC(C)=O>C1COCC1.CO>[ClH:44].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[N:17]=[C:18]([CH3:42])[C:19]([C:20]4[S:21][C:22]([C:31]5[N:35]=[CH:34][NH:33][N:32]=5)=[C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:24]=4)=[C:13]3[CH:12]=2)[CH2:4][C:3]1=[O:43]
Reactant: Cc1nn2ccc(OCCN3CCN(C)C(=O)C3)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nn2ccc(OCCN3CCN(C)C(=O)C3)cc2c1-c1nc(-c2ccccc2)c(-c2nc[nH]n2)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of 1-methyl-4-{2-[(2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-yl)oxy]ethyl}piperazin-2-one obtained above in THF (6 mL) and MeOH (2 mL), was added 2M hydrochloric acid (2 mL) and the mixture was stirred for 1 h at 60° C. To the mixture was added EtOAc (5 mL) and the resulting precipitate has been collected by filtration to obtain title compound (217 mg, 87%) as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][CH2:9][C:10]([O-:12])=O.[C:16]([NH:19][CH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O.ClC(Cl)C>[C:16]([NH:19][CH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:10](=[O:12])[CH2:9][CH2:8][C:7]([O:14][CH3:15])=[O:13])[CH:27]=2)[CH2:22]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCC1Cc2ccccc2C1
Reactant: COC(=O)CCC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: COC(=O)CCC(=O)c1ccc2c(c1)CC(CNC(C)=O)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.4 %

Procedure:
46.4 g of oxalyl chloride and 2 drops of dimethyl-formamide were added to 48.3 g of monomethyl succinate dissolved in 840 ml of dichloroethane. The mixture was stirred at room temperature for 5 hours. Then, under ice cooling, 34.6 g of 2-(acetylaminomethyl)indane dissolved in 280 ml of dichloroethane and 97.6 g of anhydrous aluminum chloride were added to the reaction mixture. After the mixture was stirred for 1 hour, the reaction mixture was poured into ice water. After the organic layer was collected by separation, washed with water and dried, the solvent was removed to obtain 51.8 g of 2-(acetylaminomethyl)-5-(3-methoxycarbonylpropionyl)indane. m.p.: 139° to 140° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:8]2([NH:16][S:17]([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C[O:34]C1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:8]2([NH:16][S:17]([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])=[O:19])[C:11]([O:13][CH2:14][CH3:15])=[O:34])=[CH:4][CH:3]=1
Reactant: C=C(OCC)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Yield: 61 %

Procedure:
To a solution of compound 9 (40 mg, 0.090 mmol) in anhydrous toluene (5 mL) was added Lawesson's reagent (40 mg, 0.099 mmol) under a nitrogen atmosphere, the mixture was heated at reflux for 12 h. After cooling down, the solvent was removed by evaporation in vacuo and the resulting residue was purified by column chromatography on silica gel (petroleum ether:EtOAc=3:1) to give compound 10 (30 mg, 73%) as a white solid. LC-MS tR=1.420 min in 2 min chromatography, MS (ESI) m/z 459.1 [M+H]+.
Reaction SMILES: O.[CH3:2][N:3]1[C:10]([NH2:11])=[C:9]([NH2:12])[C:7](=[O:8])[N:6]([CH3:13])[C:4]1=[O:5].[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)#[N:15].C(O)(=O)C>C(O)C>[OH2:5].[CH3:13][N:6]1[C:7](=[O:8])[C:9]2[NH:12][C:20]([C:19]3[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=3)=[N:11][C:10]=2[N:3]([CH3:2])[C:4]1=[O:5]
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: N#Cc1ccc(C=O)cc1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c(=O)c2[nH]c(-c3ccc(C#N)cc3)nc2n(C)c1=O
Temperature: 0 °C

Procedure:
1,3-Dimethyl-8-(4-cyanophenyl)xanthine hydrate was prepared by treatment of 1,3-dimethyl-5,6-diaminouracil hydrate (9.0 g, 52.9 mmol) with 4-cyanobenzaldehyde (6.9 g, 52.7 mmol) in ethanol (700 ml) in the presence of acetic acid (3 ml) at reflux for 5 hours. The reaction mixture was cooled to 0° C. and the resulting precipitate was collected. The crude iminouracil was dissolved in ethylene glycol dimethyl ether (700 ml) and treated with DEAD (11 ml) at reflux for 4 hours. The reaction mixture was cooled to 0° C. and the resulting precipitate was collected and recrystallized from 4:4:2 methanol:ethyl acetate:water. mp.>300° C. IR (KBr) 3412, 3320, 2965, 2936, 2877, 1680, 1604, 1512 cm-1. Anal. Calcd. for C14H11N5O2.H2O. C,56.18, H, 4.37; N, 23.40. Found: C, 56.20; H, 4.04; N,23.17.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH:19]=O)[CH2:15][C:16](=O)[CH3:17])=[C:10]([O:21][CH3:22])[CH:9]=1.C([O-])(=O)C.[NH4+:28]>C(OCC)(=O)C>[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:15]=[C:16]([CH3:17])[N:28]=[CH:19]2)=[C:10]([O:21][CH3:22])[CH:9]=1
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(N(C=O)CC(C)=O)c(OC)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
An acetic acid (255 mL) solution of 4-(formyl-(2-oxopropyl)amino)-3-methoxybenzoic acid methyl ester (118 g) and ammonium acetate (172 g) was heated under stirring at 140° C. for 1 hour. The reaction solution was neutralized with an ammoniac solution under ice-cooling after the reaction completed. Ethyl acetate was added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was filtered with a silica gel pad after dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. Tert-butylmethyl ether and heptane were added to the residue and the deposited solids were separated by filtering and washed with a 50% heptane solution of tert-butylmethyl ether. 68.4 g of the title compound was obtained by air-drying the obtained solids overnight. Furthermore, crystallization mother liquid was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system), and 22.3 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:10]=[N:11][C:12]([O:15]C)=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Sc2ccc(F)cc2)nn1
Agent: Cl
Product: O=c1ccc(Sc2ccc(F)cc2)n[nH]1
Yield: 64.6 %

Procedure:
A mixture of 3-(4-fluoro-phenylsulfanyl)-6-methoxy-pyridazine (250 mg), prepared by a procedure analogous to step A of Example 2, and concentrated hydrochloric acid was prepared and refluxed for 30 minutes. The mixture was then evaporated to dryness. The resulting residue was purified by silica gel chromatography (ethyl acetate as eluent) to afford the title compound (65%, 152 mg); mp, 99-101° C.
Reaction SMILES: N.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.[H][H]>CO.[Ni]>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][NH2:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: N#Cc1ccc2ccnc(N)c2c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ccc2ccnc(N)c2c1
Yield: 25.6 %

Procedure:
Liquid ammonia (210 mL) was added to a mixture of 4.2 g of 1-amino-isoquinoline-7-carbonitrile and 4.0 g of Raney-Ni in 210 mL of methanol in a steel vessel. hydrogen was pressed upon until an initial pressure of 100 atm. was obtained. This mixture was reacted for 16 hours at ambient temperature, the catalyst subsequently removed by filtration and the solvent pumped off. The residue was purified by silica chromatography (methanol/ammonia saturated methanol=85:15, 8:2) yielding 1.1 g (25%) of the title compound as a light yellow solid. M.p. 114-117° C.
Reaction SMILES: [CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[C:4]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[S:5][CH:6]=2)[O:2]1.O.NN.CCCCCC>C(O)C.[Pt]>[CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[C:4]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[S:5][CH:6]=2)[O:2]1
Reactant: O=[N+]([O-])c1ccc(-c2scc3c2OCCO3)cc1
Agent: [Pt]
Agent: NN
Solvent: O
Solvent: CCCCCC
Solvent: CCO
Product: Nc1ccc(-c2scc3c2OCCO3)cc1
Yield: 66 %

Procedure:
A solution of 1-(3,4-ethylenedioxythien-2-yl)-4-nitrobenzene (0.663 g, 2.52 mmol) in 95% ethanol (60 mL) containing platinum on sulfide carbon (50 mg) was added hydrazine hydrate (1.0 mL). The mixture was refluxed for 10 hours. After cooling, the mixture was filtered and the solvent was evaporated to give a solid. Addition of hexane followed by filtration gave 1-(3,4-ethylenedioxythien-2-yl)-4-aminobenzene. It was recrystallized from ethanol, 0.39 g, yield=66%, mp=98.5-99° C. IR (KBr; cm-1) 3433, 3352, 3032, 2924, 1624, 1520, 1428, 1365, 1288, 1170, 1071, 920 and 833. 1H NMR(CDCl3 ; δ in ppm): 3.604 (br, s, 2H), 4.208 (m, 4H), 6.176 (s, 1H), 6.651 (d, J=9.6 Hz, 2H) and 7.492 (d, J=9.6 Hz, 2H). 13C NMR(CDCl3 ; δ in ppm): 64.45, 64.59, 95.61, 115.10, 117.98, 123.60, 127.25, 136.61, 142.09 and 145.20. MS(EI) m/z (rel int): 233 [(M)+, 55%], 177 [(M+ --C3H4O), 6.6%], 149 [(M+ --C4H4O2, 11%] and 136 [(M+ --C5H5O2) 100%]. Anal. Calcd for C12H11NO2S: C, 61.78; H, 4.75; N, 6.00; S, 13.74. Found: C, 60.82; H. 4.87; N, 5.64; S, 12.86.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1.C(OCC)C>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([CH2:7][OH:8])=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(OC)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 6-methoxynicotinate (1.00 g, 5.98 mmol) in 20 mL of THF at 0° C. under an atmosphere of nitrogen was added lithium aluminum hydride (1.0 M in THF, 9.0 mL, 9.0 mmol) dropwise. After 30 min, the reaction was warmed to rt, and after 30 min, the reaction was recooled to 0° C., diluted with diethyl ether, and treated with water (0.34 mL), 15% aqueous sodium hydroxide (0.34 mL), and additional water (1.02 mL). The mixture was dried over magnesium sulfate and warmed to rt. After 15 min, the mixture was filtered through celite and concentrated in vacuo to provide (6-methoxypyridin-3-yl)methanol that gave a proton NMR spectra consistent with theory.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([OH:53])[CH2:37][N:38](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:32][C:31]=1[NH:54][S:55]([CH3:58])(=[O:57])=[O:56])C1C=CC=CC=1>>[OH:53][CH:36]([C:33]1[CH:34]=[CH:35][C:30]([OH:29])=[C:31]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH:32]=1)[CH2:37][NH:38][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 228) and N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Example 7) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83(t, J=7.2 Hz, 3 H), 1.20–1.40 (m, 2 H), 1.50–1.70 (m, 4 H), 1.95–2.10 (m, 2 H), 2.40–2.60 (m, 2 H), 2.94 (s, 3 H), 2.90–3.20 (m, 5 H), 3.62–3.75 (m, 2 H), 4.70–4.80 (m, 1 H), 5.95 (brs, 1 H), 6.85–6.95 (m, 3 H), 7.00–7.10 (m, 3 H), 7.24 (d, J=2.0 Hz, 1 H), 8.70 (brs, 1 H), 9.33 (brs, 1 H); MS (ES) m/z: 541.0 (MH+); HRMS Calcd. for C24H37N4O6S2 (MH+): 541.2155. Found: 541.2161.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][S:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CBr)c1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CSCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [3-(2-bromomethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.15 g, 0.36 mmol) and benzyl mercaptan (0.06 mL, 0.4 mmol) in 1,4-dioxane (10 mL) was added sodium hydride (60% in mineral oil; 0.05 g, 1.25 mmol), and the reaction was stirred for 1 hour at room temperature. After work-up, the crude material was purified by preparative HPLC to give the title compound.