Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=1.Cl>FC(F)(F)CO.C(O)C.C(O)(C)C>[ClH:10].[Cl:17][C:13]1[N:12]=[C:11]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][CH2:6]2)[CH:16]=[N:15][CH:14]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C1CN(C2CC2)CCN1
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Solvent: OCC(F)(F)F
Product: Clc1cncc(N2CCN(C3CC3)CC2)n1
Yield: 36.1 %

Procedure:
Crude N-cyclopropylpiperazine (2.8 g) and 2,6-dichloropyrazine (3.0 g) are combined in 5 ml 2,2,2-trifluoroethanol and the mixture refluxed 4 hours under N2. The mixture is concentrated under vacuum and the residue partitioned between aqueous sodium carbonate and methylene chloride. The combined methylene chloride extracts are extracted with dilute hydrochloric acid which is made basic with sodium hydroxide. The crude base is extracted with methylene chloride and chromatographed on silica gel. Elution with CHCl3 gives fractions containing 2.4 g pure title base which is treated with hydrogen chloride in ethanol-isopropanol to give 2.0 g of the title salt, mp greater than 340° C. with decomposition at 245° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)C(C)C)(C)C.[NH:53]1[C:57]([CH2:58][NH2:59])=[N:56][N:55]=[N:54]1>CN(C)C=O.[Cl-].[NH4+]>[NH:53]1[C:57]([CH2:58][NH:59][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([CH:4]([NH:5][C:6]3[CH:7]=[CH:8][C:9]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=4)=[CH:10][CH:11]=3)[CH2:3][CH:2]([CH3:1])[CH3:31])=[N:23][CH:24]=2)=[N:56][N:55]=[N:54]1
Reactant: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Reactant: NCc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCc2nnn[nH]2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a solution of 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino) butyl)nicotinic acid (0.100 g, 0.233 mmol) in N,N-dimethylformamide (3.0 mL) was added 1,1′-carbonyldiimidazole (75.6 mg, 0.466 mmol) and N,N-diisopropylethylamine (181 mg, 1.40 mmol). The reaction was stirred for 30 minutes at 80° C. (1H-tetrazol-5-yl)methanamine (80.2 mg, 0.466 mmol) was added and the reaction continued to stir at 80° C. overnight. The reaction was diluted with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by preparative HPLC (column: Boston Analytics Symmetrix ODS-H 150×30 mm, 5 μm; modifier: formic acid 0.225%; gradient: 10 to 80% MeCN in water) gave N-((1H-tetrazol-5-yl)methyl)-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinamide (15.7 mg, 13%) as a light yellow solid. 1H NMR (400 MHz, CD3OD, δ): 9.35 (m, 1H), 8.98 (s, 1H), 8.15 (d, 1H), 7.72 (d, 4H), 7.50 (d, 1H), 7.35 (d, 2H), 6.64 (m, 3H), 4.75 (d, 2H), 4.55 (m, 1H), 1.75 (m, 2H), 1.55 (m, 1H), 0.95 (d, 3H), 0.85 (d, 3H). MS (M+1): 510.4.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[N:8]([CH3:11])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[S:5]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH:4]3[C:9](=[O:10])[N:8]([CH3:11])[C:7]4[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=4[S:5]3)[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: CN1C(=O)C(CCCl)Sc2ccccc21
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(CCN2CCN(c3ccc(F)cc3)CC2)Sc2ccccc21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To 15 ml of dimethylformamide were added 1.21 g of 2-(2-chloroethyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one, 1.08 g of 1-(4-fluorophenyl)piperazine, 0.69 g of potassium carbonate and 0.05 g of sodium iodide. The mixture was stirred at 100° C. for 4 hours. The reaction solution was poured into ice-water and extracted with dichloromethane. The dichloromethane layer was washed with water and dried (MgSO4). Then, the solvent was evaporated off. The residue was subjected to a column chromatography on silica-gel (130 g). From the eluate with hexane-ethyl acetate (1:1, v/v) was obtained 2-[2-[4(4-fluorophenyl)-1-piperazinyl]ethyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one as an oily substance. This product was treated with methanol saturated with hydrogen chloride to give crystals of its hydrochloride. The yield was 0.99 g (43.2%). Recrystallization from methanol-ether gave prisms, m.p. 202°-204° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:27])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:28]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:27])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:28])=[CH:6][CH:7]=1
Reactant: Cc1ccc(SCCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methylphenylmercapto)-butoxy]-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([S:14]SCC)[CH3:13].C(S)C>C(O)CC.CCCO.CCCO.CCCO.CCCO.[Zr].[Zr]>[CH2:12]([S:14][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[OH:11])[CH3:13]
Reactant: CCSSCC
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [Zr]
Solvent: CCCO
Solvent: CCS
Product: CCSc1cc(C(C)(C)C)ccc1O
Temperature: 194 °C
Yield: 48.3 %

Procedure:
To 4-t-Butylphenol (10.0 g, 0.067 moles) was added 2.8 g zirconium n-propoxide in n-propanol consisting of 21.6% zirconium (0.007 mole) and 10.8% free propanol. The mixture was distilled at atmospheric pressure removing 1.8 g of n-propanol. To the mixture was added ethyl disulfide (8.2 g, 0.067 moles). The mixture was heated under nitrogen while ethyl mercaptan was removed continuously by distillation. Heating under nitrogen was continued for a total of 142 hours during which temperature slowly increased to 194° C. The mixture was cooled, hydrolyzed by addition of water, and made acid with concentrated HCl. The mixture was extracted with ether. The ether extracts were dried over magnesium sulfate, filtered, and concentrated on a rotary flash evaporator. GC analysis of the concentrate indicated only two major components, 2.5 g of 4-t-butylphenol and 6.8 g of 2-ethylthio-4-t-butylphenol (49% yield).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:31][C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1.C(OCC)C>C1COCC1.O.C(Cl)Cl>[Cl:31][C:32]1[CH:33]=[C:34]([S:38]([NH:10][C:9]2[CH:8]=[C:7]([CH3:11])[N:6]=[C:5]3[S:12][C:2]([CH3:1])=[C:3]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[C:4]=23)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (Description 4) (100 mg, 0.352 mmol) in THF (2 mL), cooled in an ice bath, was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 1 h before the addition of 3-chlorobenzenesulfonyl chloride (0.124 mL, 0.879 mmol). The reaction mixture was then stirred at RT for a further 12 h. The reaction mixture was then diluted with water (15 mL) and the aqueous layer extracted with DCM (3×30 mL). The combined organic extracts were dried over a phase separating column and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-20% ethyl acetate in cyclohexane, afforded a solid which was dissolved in the minimum amount of DCM. Upon addition of diethyl ether, a solid precipitated out which was collected by filtration, washed with diethyl ether and dried, to afford the title compound (89 mg). LCMS (A) m/z: 459 [M+1]+, Rt 1.03 min (basic).
Reaction SMILES: CS([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)=O.[CH3:28][O-:29].[Na+].Cl>O1CCCC1>[CH3:28][O:29][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1
Reactant: C[O-]
Reactant: CS(=O)c1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
2-(Methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (60 mg) was suspended in tetrahydrofuran (2 ml), sodium methoxide (28% methanol solution, 200 mg) was added thereto under ice-cooling, and the mixture was stirred for 10 min. To the reaction mixture was added 1M hydrochloric acid (3 ml), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained white residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (39 mg) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7](C(C)=C)[C:6]1=[O:17].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O.CC(C)CC(=O)C>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:17])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 5 parts of 1-(3-chloropropyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazol-2-one, 3.9 parts of 4-(4-fluorophenyl)-4-piperidinol, 5.3 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed for 48 hours with water-separator. The reaction mixture is cooled to room temperature, water is added and the whole is alkalized with 15 parts of a sodium hydroxide solution 60%. The layers are separated and the organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is dissolved in 2-propanone. The solution is acidified with 2-propanol, previously saturated with gaseous hydrogen chloride, and the whole is stirred and refluxed for 15 minutes. The solvent is evaporated and the formed hydrochloride salt is dissolved in water. The free base is liberated in the conventional manner with a diluted sodium hydroxide solution. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is crystallized from methylbenzene. The product is filtered off and dried, yielding 2.5 parts of 1-{3-[4-(4-fluorophenyl)-4-hydroxy-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 135.4° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:50])[CH:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]5[CH2:35][O:34][C:33]([C:42]6[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=6[F:49])([CH2:36][N:37]6[CH:41]=[N:40][CH:39]=[N:38]6)[O:32]5)=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[N:6]1)[CH3:4].[CH:51](=O)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.S1C=CC=C1>CO.[Pd]>[F:49][C:43]1[CH:44]=[C:45]([F:48])[CH:46]=[CH:47][C:42]=1[C:33]1([CH2:36][N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[O:32][CH:31]([CH2:30][O:29][C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:14]4[CH:13]=[CH:12][C:11]([N:8]5[CH:7]=[N:6][N:5]([CH:3]([CH3:4])[CH:2]([NH:1][CH2:51][C:52]6[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=6)[CH3:50])[C:9]5=[O:10])=[CH:16][CH:15]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)[CH2:35][O:34]1
Reactant: CC(N)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Reactant: O=Cc1ccccc1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CC(NCc1ccccc1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O

Procedure:
A mixture of compound 37 (0.0029 mol) and benzaldehyde (0.0029 mol) in methanol (250 ml) was hydrogenated at 50° C. overnight with Pd on activated carbon 10% (2 g) as a catalyst in the presence of thiophene solution (2 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE and 2-propanol, filtered off and dried, yielding 1.1 g (48%) of [2S-[2α,4α(S*,R*)]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(phenylmethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one (compound 106; mp. 154.3° C.).
Reaction SMILES: C([O:5][C:6](=[O:39])[C@H:7]([NH:9][C:10]([C:12]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[C:26](=[O:32])[NH:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)=[O:20])[N:14]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:13]=1)=[O:11])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:28]1([NH:27][C:26]([C@@H:22]2[CH2:23][CH2:24][CH2:25][N:21]2[C:19](=[O:20])[CH2:18][O:17][C:15]2[N:14]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:13]=[C:12]([C:10]([NH:9][C@H:7]([CH3:8])[C:6]([OH:39])=[O:5])=[O:11])[CH:16]=2)=[O:32])[CH2:29][CH2:30][CH2:31]1
Reactant: C[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reaction time: 6 h

Procedure:
To a solution of 745 mg (R)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-propionic acid tert-butyl ester in 5 ml dichloromethane were added 1.6 ml TFA. After stirring for 6 h it was concentrated and codistilled twice with toluene to give the crude product. Yield: 770 mg
Reaction SMILES: [CH3:1][N:2]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3](=[O:26])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=[CH:23][C:24]#[N:25])=[CH:6]1.[Cl-].[NH4+].[N-:37]=[N+:38]=[N-:39].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:1][N:2]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:3](=[O:26])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=[CH:23][C:24]2[NH:39][N:38]=[N:37][N:25]=2)=[CH:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(CCc1ccccc1)C(=O)Cn1cc(C=CC#N)c2cc(OCc3ccccc3)ccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CCc1ccccc1)C(=O)Cn1cc(C=Cc2nnn[nH]2)c2cc(OCc3ccccc3)ccc21
Temperature: 100 °C

Procedure:
A suspension of 0.94 g (2 mmoles) of N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-cyanovinyl)indol-1-yl]acetamide, 0.56 g (10.45 mmoles)of ammonium chloride and 0.68 g (10.45 mmoles) of sodium azide in 20 ml of dimethyl-formamide is heated at 100° C. for 18 hours. The mixture is poured into ice water. Addition of ethyl acetate gives a precipitate which is collected and triturated in acetone to give N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-yl)vinylindol-1-yl]acetamide. (m.p. 203°-205° C.)
Reaction SMILES: C1(C)C=CC=CC=1.CC1(C)C(C)(C)OB([C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][CH2:19][C:20]3=[O:25])O1.Cl[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35].C([O-])([O-])=O.[Na+].[Na+]>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.CCOC(C)=O.O>[N+:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][CH2:19][C:20]2=[O:25])([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CC1(C)OB(c2cccc3c2CCC3=O)OC1(C)C
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCc2c1cccc2-c1ccccc1[N+](=O)[O-]
Yield: 91.1 %

Procedure:
Degassed toluene (0.5 L), borolan 88 (10 g, 39 mmol), 2-chloro-1-nitrobenzene (6.3 g, 40 mmol), Pd(PPh3)4 (3 g, 2.6 mmol) and 2M Na2CO3 (200 mL) were mixed under a rapid flow of argon, and the resulting mixture was refluxed overnight. Water (200 mL) and EtOAc (500 mL) were added. The aqueous layer was separated and extracted with EtOAc (2×500 mL), and the combined extracts dried over Na2SO4. The solvent was evaporated at reduced pressure and the crude product purified by column chromatography (20% EtOAc in hexanes) to give 9 g (91%) of the biphenyl intermediate 89 as a yellow solid.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1([C:9]([OH:25])([CH2:18][N:19]2[C:23]([SH:24])=[N:22][CH:21]=[N:20]2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:8][CH2:7]1.C(N(CC)CC)C>O1CCCC1>[Cl:5][C:6]1([C:9]([OH:25])([CH2:18][N:19]2[C:23]([S:24][C:3](=[O:4])[NH:2][CH3:1])=[N:22][CH:21]=[N:20]2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:8][CH2:7]1
Reactant: CN=C=O
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)Sc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
At room temperature, a solution of 0.3 ml (5 mmol) of methyl isocyanate in 5 ml of absolute tetrallydrofuran is added dropwise with stirring to a mixture of 1.72 g (5 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol, 0.1 ml of triethylamine and 20 ml of absolute tetrahydrofuran. After the addition, the reaction mixture is stirred at room temperature for 1 hour and then concentrated under reduced pressure. The crude product that remains is chromatographed over silica gel using a mixture of petroleum ether/ethyl acetate=1:1. Concentration of the eluate gives 1.3 g (65% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-[5-(N-methyl-carbamoylthio)-1,2,4-triazol-1-yl]-propan-2-ol in the form of an oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:11](=O)[CH2:10][C:9]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[CH2:13]2)[CH2:8]1.O>O1CCCC1.C1C=CC=CC=1>[NH:7]1[CH2:11][CH2:10][C:9]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([OH:21])[CH2:13]2)[CH2:8]1
Reactant: O=C1CC2(CN1)CC(=O)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccccc1
Product: OC1CC2(CCNC2)c2ccccc21
Reaction time: 20 h

Procedure:
17.1 g of lithium aluminium hydride in 300 cc of absolute tetrahydrofuran and 600 cc of absolute benzene are placed in a Soxhlet apparatus. 30 g of the spiro[indan-1,3'-pyrrolidin]-3,5'-dione to be reduced are placed in the Soxhlet apparatus in a Soxhlet capsule. Boiling at reflux is then effected for 20 hours, whereby the entire product is dissolved. The reaction mixture is subsequently cooled and carefully decomposed with 25 cc of water in 25 cc of tetrahydrofuran, the precipitate is filtered off and the filtrate concentrated. Spiro[indan-1,3'-pyrrolidin]-3 -ol is obtained as light yellow oil and is converted into its hydrogen fumarate by reacting with a solution of 17 g of fumaric acid in 400 cc of ethanol. M.P. 155°-158° (from ethanol/ether).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:14]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([CH2:36][OH:37])=[CH:33][C:32]=2[CH:38]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].N1C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:14]3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]2[O:35][C:34]([CH2:36][O:37][C:39](=[O:41])[CH3:40])=[CH:33][C:32]=2[CH:38]=1
Reactant: Cc1c(COc2ccc3oc(CO)cc3c2)oc2cccc(OCC3CCCN(Cc4cccnc4)C3)c12
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cc2cc(OCc3oc4cccc(OCC5CCCN(Cc6cccnc6)C5)c4c3C)ccc2o1

Procedure:
A solution of [5-[3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-ylmethoxy]-benzofuran-2-yl]-methanol (Example 50, 21 mg), acetic anhydride (100 μl) and pyridine (300 μl) was stirred at room temperature for one hour. The reaction mixture was dissolved in ethyl acetate and washed with saturated sodium hydrogencarbonate solution and water. The organic layer was washed with saturated ammonium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give acetic acid 5-[3-methyl-4-(1-pyridin-3-ylmethyl-piperidin-3-ylmethoxy)-benzofuran-2-ylmethoxy]-benzofuran-2-ylmethyl ester (22 mg) as a colorless oil. FAB-MS: m/z 555 (MH+); 1H-NMR (CDCl3): δ 1.25-2.23 (7H, m), 2.12 (3H, s), 2.23 (3H, s), 2.78 (1H, m), 2.97 (1H, br d, J=11 Hz), 3.47 (1H, d, J=13 Hz), 3.57 (1H, d, J=13 Hz), 3.86 (1H, dd, J1=9 Hz, J2=7 Hz), 3.94 (1H, dd, J1=9 Hz, J2=5 Hz), 5.09 (2H, s), 5.18 (2H, s), 6.55 (1H, d, J=8 Hz), 6.72 (1H, s), 7.00 (1H, dd, J1=9 Hz, J2=2.5 Hz), 7.04 (1H, d, J=8 Hz), 7.15 (1H, t, J=8 Hz), 7.16 (1H, d, J=2.5 Hz), 7.20 (1H, dd, J1=8 Hz, J2=5 Hz), 7.38 (1H, d, J=9 Hz), 7.66 (1H, br d, J=8 Hz), 8.48 (1H, br d, J=5 Hz), 8.53 (1H, br s).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([O:12][C:13](=[O:36])[NH:14][CH2:15][CH:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:33]=[CH:32][C:31](=[O:34])[CH2:30][CH2:29]3)=[C:24]([F:35])[CH:23]=2)[CH2:17]1)(C)(C)C.ClC(OC)=O>ClC(Cl)C.CC#N>[CH3:8][O:12][C:13](=[O:36])[NH:14][CH2:15][CH:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:29]=[CH:30][C:31](=[O:34])[CH2:32][CH2:33]3)=[C:24]([F:35])[CH:23]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Agent: COC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)NCC1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 1.5 h

Procedure:
TFA (1.5 mL) is added to a solution of {3-[3-fluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-carbamic acid tert-butyl ester (300 mg, 0.74 mmol) in dichloroethane (6.0 mL). This solution is stirred for 1.5 h. Removed solvent under vacuum, and the residue is dissolved in MeCN (3.0 mL). TEA (0.41 mL, 3 mmol) is added followed by methyl chloroformate (98 mg, 1 mmol). The mixture is stirred at r.t. for 16 h. Solvent is removed under vacuum, and the residue is purified by silica gel column chromatography (eluent: EtOAc) to afford the product as a yellow solid. Yield 100 mg (37%). MS (m/z): 364 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ7.62–7.30 (m, 4H), 4.98 (dd, J=7.7 Hz, 3.0 Hz, 1H), 4.80–4.65 (m, 1H), 4.11 (dd, J=6.86 Hz, 2H), 3.79–3.74 (m, 1H), 3.53 (s, 3H), 3.40–3.30 (m, 2H), 2.49–2.44 (m, 2H).