Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:21](=[O:23])[NH:20][CH:19]=[N:18][C:17]=3[N:16]([CH3:24])[C:15](=[O:25])[C:14]=2[CH3:26])=[C:8]([F:27])[CH:7]=1>>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:21](=[O:23])[N:20]([CH2:2][CH2:3][OH:4])[CH:19]=[N:18][C:17]=3[N:16]([CH3:24])[C:15](=[O:25])[C:14]=2[CH3:26])=[C:8]([F:27])[CH:7]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Reactant: OCCBr
Product: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)n(CCO)cnc2n(C)c1=O

Procedure:
The title compound was prepared according to the procedure used for Example 9 by reaction of 2-bromoethanol with compound 9F. 1H NMR (400 MHz, MeOD) δ ppm 1.70 (s, 3H) 3.74 (s, 3H) 3.82 (t, J=5.05 Hz, 2H) 4.13 (t, J=5.05 Hz, 2H) 4.53 (s, 1H) 6.78 (t, J=8.72 Hz, 1H) 7.26 (dd, J=8.21, 1.39 Hz, 1H) 7.37 (dd, J=10.48, 2.15 Hz, 1H) 10.27 (s, 1H) [M+H] calc'd for C17H16BrFN4O3, 424; found, 424.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][O:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][C:19]=1[O:26][CH3:27]>C(O)C>[CH3:15][O:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:20][C:19]=1[O:26][CH3:27]
Reactant: COC(=O)c1ccc(CBr)cc1OC
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN2CCN(C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
To 100 mL of ethanol were added 10.0 g of 1-methylpiperazine and 20.2 g of triethylamine. To the mixture cooled with ice, 25 mL of a solution of 24.6 g of 4-(bromomethyl)-2-methoxy-benzoic acid methyl ester in ethanol was added dropwise. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated. To the residue, 75 mL of water and 250 mL of methylene chloride were added, and the organic layer was separated. The obtained organic layer was dried over Na2SO4 and concentrated. The residue was purified by amino-silica gel column chromatography (heptane/AcOEt system) to give 22.4 g of the title compound (85% yield).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1.NN>C(O)C.CCOCC>[F:36][C:34]([F:35])([F:37])[C:32]1[CH:31]=[C:5]([CH:4]=[C:3]([C:2]([F:39])([F:38])[F:1])[CH:33]=1)[CH2:6][O:7][CH2:8][C:9]1([CH2:18][CH2:19][NH2:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][O:10]1
Reactant: O=C1c2ccccc2C(=O)N1CCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Agent: NN
Solvent: CCOCC
Solvent: CCO
Product: NCCC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCc2ccccc21
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-(1-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-1,3-dihydroisobenzofuran-1-yl)ethyl)isoindoline-1,3-dione (250 mg, 0.455 mmol) in ethanol (2 mL) was added hydrazine (0.100 mL, 3.2 mmol). The resulting solution was heated to 45° C. and held there for 3 h. The reaction was cooled to room temperature, diluted with ether, and filtered to remove the precipitate which was discarded. Concentration of the mother liquor gave 175 mg (92%) as a colorless oil. 1H-NMR (CDCl3, 300 MHz) δ 7.74 (s, 1H), 7.63 (s, 2H), 7.28 (m, 2H), 7.21 (m, 1H), 7.16 (m, 1H), 5.11 (s, 2H), 4.61 (qAB, JAB=12.8 Hz, 2H), 3.65 (qAB, JAB=9.8 Hz, 2H), 2.73 (m, 1H), 2.54 (m, 1H), 2.13 (ddd, J=14.4, 8.6, 5.8 Hz, 1H), 2.00 (ddd, J=14.3, 8.6, 5.8 Hz, 1H), 1.55 (bs, 2H); 13C-NMR (CDCl3, 126 MHz) δ 141.4, 141.3, 139.9, 131.7 (q, J=33.6 Hz), 128.2, 127.5, 127.1, 123.4 (q, J=273 Hz), 121.7, 121.4, 121.1, 90.0, 76.8, 72.8, 72.0, 40.4, 37.4. Mass spec.: 420.14 (MH)+. Accurate mass spec.: m/z 420.1391 [MH]+, Δ=1.7 ppm.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH:19][CH2:16][CH:17]=[CH2:18])=[S:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCN
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Solvent: CCCCC
Product: C=CCNC(=S)NC1(N=NC(C)(C)C)CCCCC1

Procedure:
To 9.6 grams (.0416 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane cooled to 10° C. and stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 2.37 grams (.0416 moles) of allylamine. The reaction mixture became viscous, was diluted with pentane and stirred for 24 hours at room temperature. The pentane was stripped from the reaction mixture to leave an orange liquid weighing 11.3 grams (94% crude yield). The infrared spectrum of the product had a strong band at 1525 cm-1 and a sharp NH band at 3300 cm-1 and the isothiocyante band at 2040 cm-1 was very weak indicating a trace of the starting material was still present.
Reaction SMILES: [N+:1]1([O-])[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.CS([Cl:15])(=O)=O>CN(C=O)C>[Cl:15][C:6]1[CH:7]=[CH:8][N:9]=[C:4]2[NH:3][CH:2]=[N:1][C:5]=12
Reactant: [O-][n+]1c[nH]c2ncccc21
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: Clc1ccnc2[nH]cnc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
A 50 mL round bottom flask set up with a reflux condenser under nitrogen atmosphere was charged 4-azabenzimidazole N-oxide (1.2 g, 8.88 mmol) and 11 mL of DMF. This was heated to 50° C. and methanesulfonyl chloride (1.86 ml, 23.98 mmol) was added dropwise via syringe. The resulting mixture was heated to 80° C. and stirred at this temperature for 16 hours. This was cooled to room temperature and quenched with water (approximately 10 mL) and reaction mixture brought to pH 7 by adding 6N NaOH aqueous solution. The reaction was extracted four times with dichloromethane (50 mL). Some product was present in aqueous layer; this was concentrated and residue set aside. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep 40 g column, gradient elution 0-10% MeOH:DCM) to afford 7-chloro-3H-imidazo[4,5-b]pyridine (450 mg, 33.0% yield). MS [M+H]=154.2. Calc'd C6H4ClN3=153.56.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C@@H:10]1[CH2:13][C@H:12]([NH:14]C(=O)OC(C)(C)C)[CH2:11]1.Cl.C(OCC)C>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C@@H:10]1[CH2:11][C@H:12]([NH2:14])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](Oc2cccc(Cl)c2Cl)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N[C@H]1C[C@@H](Oc2cccc(Cl)c2Cl)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 197 %

Procedure:
To 1,1-dimethylethyl {cis-3-[(2,3-dichlorophenyl)oxy]cyclobutyl}carbamate (5.21 g, 15.68 mmol) was added hydrochloric acid in dioxane (4M, 40 mL, 160 mmol) and the reaction mixture stirred in a sealed vessel at room temperature for 1 hour. The mixture was diluted with dioxane (300 mL) and stirred for a further 5 hours. Diethyl ether (300 mL) was then added and the solid collected by filtration and dried under high vacuum overnight to give the title compound (4.149 g)
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[C:14]=2[C:15]#[N:16])=[C:6]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:5]=1[OH:32])(=[O:3])[CH3:2].C1CCCCC=1>C(O)C>[NH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:24]=[CH:25][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:32])[C:6]=2[CH2:26][CH2:27][C:28]([F:29])([F:30])[F:31])[C:14]=1[C:15]#[N:16]
Reactant: CC(=O)c1ccc(OCCCOc2cccc([N+](=O)[O-])c2C#N)c(CCC(F)(F)F)c1O
Solvent: C1=CCCCC1
Solvent: CCO
Product: CC(=O)c1ccc(OCCCOc2cccc(N)c2C#N)c(CCC(F)(F)F)c1O
Temperature: 25 °C

Procedure:
2.5 g of 10% Pd-on-charcoal are added to a solution of 10 g of 2-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-nitro-benzonitrile and 10 g of cyclohexene in 500 ml of ethanol and the mixture is refluxed for 30 minutes. After cooling to room temperature, it is filtered and freed from the solvent. Ether is added to the residue and the crystals which have separated out are filtered off. 2-Amino-6-{-3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-benzonitrile is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2ccc(C#N)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C#N)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 13 (367 mg, 0.82 mmol) is treated with 3-chlorobenzo-[b]thiophene-2-carbonyl chloride (226 mg, 0.98 mmol) using Method D to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C=O.O>[Si:19]([O:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a mixture of 5-hydroxyisatoic anhydride (1.6 g, 9.0 mmol) and imidazole (670 mg, 9.9 mmol) in N,N-dimethylformamide (10 mL) was added tert-butyldimethylsilyl chloride (1.42 g, 9.45 mmol). After stirring for 2 h, the reaction mixture was diluted with ice and water. After warming to room temperature, the resulting precipitate was filtered and washed with water and hexane. The solid was vacuum dried at 55° C./0.1 mm for 14 h to give 2.55 g (96%) of the title compound as a light gray solid; mp 198-200° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:32].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16]([Cl:32])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: ClCCl
Solvent: CO
Product: Cc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1

Procedure:
According to the general procedure (GP12), chlorination of 1-iodo-3-methyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (389 mg; 0.727 mmol) and purification by FC (DCM/MeOH=20/1) gave the product 1-chloro-3-methyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as an orange oil (33 mg; 0.074 mmol). LC-MS: tR=1.02 min.; [M+H]+=444.44 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH:9](=[N:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: Oc1ccc(N=Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
2.1 g (19.3 mmol) of 4-aminophenol was dissolved in 28 ml ethanol, and 1.9 ml (19.3 mmol) benzaldehyde was added. The mixture was heated to the reflux temperature and reacted for 1.5 h, Then, the reaction mixture was cooled to the room temperature and the solid separated out from the mixture was filtered by sucking. The filter cake was washed with a small amount of ethanol and dried to obtain 3 g of a yellow solid with the yield of 76.9%. m.p. 182-183° C.
Reaction SMILES: C([Li])CCC.[C:6]([N:13]1[CH2:16][C:15](=[O:17])[CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.[CH2:19]([O:26][C:27]1[CH:32]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:28]=1Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CCCCCC>[C:9]([O:8][C:6]([N:13]1[CH2:16][C:15]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:32][C:31]=2[O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([OH:17])[CH2:14]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: Brc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
In a 100 ml three-necked flask, 5 g of 2,4-bis(benzyloxy)-1-bromobenzene are dissolved in 60 ml of tetrahydrofuran. The mixture is cooled to −70° C. and then 11.4 ml of 2.5M n-butyllithium in hexane are added. The reaction medium is stirred at −70° C. for 1 hour, and then 2.8 g of 1-Boc-azetidine-3-one dissolved in 4 ml of THF are added dropwise. The reaction medium is stirred at −70° C. for 2 hours and then left at ambient temperature overnight. The reaction medium is poured into 40 ml of a 2M solution of hydrochloric acid and then extracted with 100 ml of ethyl acetate. The organic phases are combined, washed with 50 ml of water and then dried over magnesium sulphate and evaporated.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[S:7][C:8](C(O)=O)=[CH:9][C:5]=2[C:4]([CH3:13])=[N:3]1.N1C2C(=CC=CC=2)C=CC=1>[Cu]>[CH3:1][N:2]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]([CH3:13])=[N:3]1
Reactant: Cc1nn(C)c2sc(C(=O)O)cc12
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Cc1nn(C)c2sccc12
Temperature: 200 °C
Yield: 69 %

Procedure:
A mixture of 1,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (2 g, 10.19 mmol), copper (1.943 g, 30.6 mmol) and quinoline (10 mL, 85 mmol) were heated to 200° C. for 1 hour in a Biotage Initiator microwave. Following heating, the mixture was extracted with ethyl acetate (3×100 mL) and 3N HCl (200 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified via silica gel flash chromatography, eluting with a gradient of 10-40% EtOAc and hexane to give the title compound as a clear oil (1.07 g, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 9H), 3.83 (s, 3H), 6.98 (d, J=5.40 Hz, 1H), 7.09 (d, J=4.90 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C7H8N2S, 153. found, 153.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[H-].[Na+].[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1>CN(C)C=O>[N:30]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[C:4]([C:24]([F:27])([F:25])[F:26])[CH:3]=2)[CH:34]=[CH:33][CH:32]=[N:31]1
Reactant: O=C(c1ccc(F)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cccn2)cc1C(F)(F)F)N1Cc2cccn2Cc2ccccc21
Yield: 54.9 %

Procedure:
In the manner of Example 2, employing (4-fluoro-2-trifluoromethyl-phenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.20 g), pyrazole (0.25 g) and dimethylformamide (35 ml). The product (0.62 g) was obtained as a colorless amorphous solid, MS, m/z: 423.2 (M+H)+, 445.2 (M+Na)+, 845.3 (2M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6](Br)=[C:7]([CH2:15][CH2:16][O:17][CH3:18])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.C([Li])CCC.CCCCCC.[CH:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[C:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=1[CH:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:38]
Reactant: O=Cc1ccccc1
Reactant: COCCc1cc(OCOC)cc(OCOC)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCc1cc(OCOC)cc(OCOC)c1C(O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 51.7 %

Procedure:
3,5-Bis(methoxymethoxy)-2-bromo-1-(2-methoxyethyl)-benzene (5.3 g, 16 mmol) obtained in Example 1, Step 4 was dissolved in tetrahydrofuran (0.10 L). After the solution was cooled to −78° C., a 1.6 mol/L solution of n-butyllithium in hexane (30 mL, 48 mmol) was added thereto, followed by stirring for 5 minutes. Benzaldehyde (6.4 mL, 62 mmol) was added to the reaction mixture, followed by stirring for 1 hour. To the reaction mixture was added a saturated aqueous solution of ammonium chloride (30 mL), and the mixture was extracted with ethyl acetate (0.30 L). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain [2,4-bis(methoxymethoxy)-6-(2-methoxyethyl)phenyl]phenylmethanol (3.0 g, 53%). Then, [2,4-bis(methoxymethoxy)-6-(2-methoxyethyl)phenyl]phenylmethanol (3.0 g, 8.4 mmol) was dissolved in dichloromethane (50 mL), and Molecular Sieves 4 Å (7.9 g) and pyridinium dichromate (7.9 g, 21 mmol) were added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain 2,4-bis(methoxymethoxy)-6-(2-methoxyethyl)phenyl=phenyl=ketone (2.9 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.[H-].[Na+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])[CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1
Reactant: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(S(=O)(=O)c2ccccc2)c2[nH]c3ccc(Cl)cc3c21
Reaction time: 0.5 h

Procedure:
A solution of 6-chloro-4-oxo-1,2,3,4-tetrahydrocarbazole (109 mg, 0.5 mmol) in THF is treated with NaH (60 mg, 60% dispersion in mineral oil, 1.5 mmol), stirred for 30 min., treated with phenylsulfonyl chloride (132 mg, 0.5 mmol), shaken for 8 h and concentrated in vacuo. The resultant residue is dissolved in ethyl acetate, washed with water and reconcentrated in vacuo to afford the title product which is used as is in Example 134.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:32](=[O:33])[CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1

Procedure:
200 mg (0.551 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 39a with 88 μl (0.661 mmol) of phenylacetyl chloride and 108 μl (0.771 mmol) of triethylamine. The title compound ##STR90## is obtained (127 mg, 48%) as white foam. TLC:methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.56, FD-MS:M+ =480, 482; IR:3660, 3405, 1665, 1630 cm-1.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([C:22]2[N:27]=[CH:26][C:25]([C@H:28]3[C@H:30]([C:31]([O-:33])=[O:32])[C:29]3([CH3:35])[CH3:34])=[CH:24][N:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[C:36]([CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:41]=1)O)#[N:37]>CN(C)C1C=CN=CC=1.ClCCl>[CH:16]1([C:22]2[N:27]=[CH:26][C:25]([C@H:28]3[C@H:30]([C:31]([O:33][CH:38]([C:36]#[N:37])[C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([O:46][C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[N:41]=4)=[O:32])[C:29]3([CH3:35])[CH3:34])=[CH:24][N:23]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)n1
Reactant: CC1(C)[C@@H](C(=O)[O-])[C@@H]1c1cnc(C2CCCCC2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)n2)[C@@H]1c1cnc(C2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.7 %

Procedure:
Dicyclohexylcarbodimide (118 mg) was added to a stirred mixture of (±)-trans-3-(2-cyclohexylpyrimidin-5-yl)-2,2-dimethylcyclopropane carboxylate (150 mg), 1-cyano-1-(6-phenoxypyrid-2-yl)methanol (130 mg), 4-dimethylaminopyridine (5 mg) and dichloromethane (5 cm3) and the mixture stirred at the ambient temperature for 7 hours, and kept for a further 16 hours without stirring. The product was isolated by filtering through a silica column, eluting first with dichloromethane and then with a mixture of dichloromethane (20 parts by volume) and ethyl acetate (1 part by volume) to yield (RS)-1-cyano-1-(6-phenoxypyrid-2-yl)methyl (1RS, trans)-3-(2-cyclohexylpyrimidine-5-yl)-2,2-dimethylcyclopropane carboxylate, (248 mg) identified by n.m.r. as a 1:1 mixture of the two pairs of enantiomeric diastereomers.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.[CH3:28][N:29]([CH2:31][C:32](O)=[O:33])[CH3:30].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])[CH2:2]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)CN(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol), dimethylaminoacetic acid (47 mg, 0.455 mmol), HOAt (62 mg, 0.455 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (87 mL, 0.455 mmol) and 4-methylmorpholine (0.10 mL, 0.911 mmol) in anhydrous DCM (4 mL) was stirred at RT for 20 h. Volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) then triturated with diethyl ether affording 134 (55 mg, 30%). LCMS: RT 1.79 min [M+H]+ 448.1. 1H NMR (DMSO, 400 MHz): δ 8.23-7.93 (3H, m), 7.90-7.78 (1H, m), 7.68-7.58 (1H, m), 7.21-7.12 (2H, m), 4.80-4.69 (1H, br), 4.53-4.30 (1H, m), 4.22 (0.6H, bd, J=12.25 Hz), 4.03 (0.4H, bd, J=12.25 Hz), 3.85 (0.6H, t, J=12.08 Hz), 3.44-3.26 (1.4H, t, J=12.08 Hz), 3.21-3.10 (1H, m), 2.99 (0.4H, bd, J=13.04 Hz), 2.90-2.64 (1.6H, m), 2.44-2.26 (1H, m), 2.25-2.11 (6H, m), 1.85-1.58 (5H, m), 1.13-0.97 (1H, m). Signals split due to presence of rotamers