Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12](I)=[C:8]3[N:7]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:24]([C:26]1[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)#[CH:25]>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:25]#[C:24][C:26]4[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=4)=[C:8]3[N:7]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#Cc1cnc(N)nc1
Reactant: FC(F)(F)c1ccc(-c2cc(C3CC3)n3ncc(I)c3n2)cc1
Product: Nc1ncc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-iodo-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7 step 4) (215 mg, 0.5 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2 step 2) (60 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (59 mg, 28%). MS (ISP) 421.1 [(M+H)+].
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[CH:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)C=CC=CC=1.CC(C)([O-])C.[K+]>C1COCC1>[CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=[CH:19][CH2:20][CH:21]2[CH2:22][CH2:23][C:24](=[CH:27][CH2:28][CH3:29])[CH2:25][CH2:26]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(=O)CC1
Reactant: CCC=C1CCC(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC=C1CCC(CC=C2CCC(CCC)CC2)CC1
Temperature: -10 °C

Procedure:
57.0 g of 4-propylcyclohexanone and 25.0 g of triphenyl[2-(4-propylidenecyclohexyl)ethyl]phosphonium bromide were introduced into 150 ml of THF under nitrogen, and the mixture was cooled to -10° C. A solution of 5.61 g of potassium tert-butoxide in 100 ml of THF was then added dropwise with stirring, and the mixture was stirred at RT for a further 2 h. Conventional work-up gave 4-[2-(4-propylcyclohexylidene)ethyl]propylidenecyclohexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:26]4[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34]([CH2:36][CH2:37][NH2:38])=[O:35]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:26]4[O:30][C:29]([CH2:31][NH:38][CH2:37][CH2:36][S:34]([CH3:33])=[O:35])=[CH:28][CH:27]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)CCN
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1
Product: CS(=O)CCNCc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1

Procedure:
In an analogous manner to Example 1, 5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde and [2-(methanesulphinyl)ethyl]amine were converted into the title compound; δH [2H6]-DMSO 10.20 (1H, b), 9.11 (1H, s), 8.67 (1H, s), 8.59 (1H, s), 7.72 (2H, d), 7.53−7.30 (5H, m), 7.17−7.04 (3H, m), 6.52 (1H, d), 5.15 (2H, s), 3.87 (2H, s), 3.08−2.75 (4H, m), 2.55 (3H, s); m/z 514 (M+1)+.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][C:18]([NH:32]C(OC(C)(C)C)=O)([C:21](=[O:31])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>CO>[ClH:30].[ClH:1].[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][NH:22][C:21]([C:18]2([NH2:32])[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[O:31])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NCc2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(C(=O)NCc2ccc(Cl)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
A 4M solution of HCl in dioxane (7.7 ml, 31 mmol) was added dropwise to a solution of 4-tert-butoxycarbonylamino-4-(4-chloro-benzylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (96 mg, 0.20 mmol) in methanol (7.7 mL) and stirred at rt for 17 h. The solvents were concentrated to give 4-amino-piperidine-4-carboxylic acid 4-chloro-benzylamide dihydrochloride (71 mg, 0.20 mmol, 100%) that was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]2=[O:8])=[CH:11][CH:12]=1
Reactant: O=C1CCCCCC1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: O=C1CCCCCC1c1ccc(F)cc1
Temperature: 80 °C
Yield: 38.9 %

Procedure:
Step AAF (1): A mixture of cycloheptanone (1.0 g, 8.92 mmol), 1-bromo-4-fluorobenzene (0.874 g, 4.99 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.067 g, 0.116 mmol), sodium tert-butoxide (1.157 g, 11.68 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.049 g, 0.053 mmol) in THF (10 mL) was heated at 80° C. overnight. The crude product was purified by Prep-HPLC (Solvent A=10% MeOH-90% water-0.1% TFA, Solvent B=90% MeOH-10% water-0.1% TFA. Column: Phenomenex Luna 30×100 mm, S10, Flow rate: 40 ml/min, 45-100% B, 30 min) to obtain 2-(4-fluorophenyl)cycloheptanone (400 mg, 1.94 mmol, 22% yield). LC-MS (M+H)+=207.2. 1H NMR (400 MHz, methanol-d4) δ ppm 7.13-7.31 (m, 2 H) 6.91-7.08 (m, 2 H) 3.68-3.86 (m, 1 H) 2.58-2.76 (m, 1 H) 2.42-2.57 (m, 1 H) 1.85-2.13 (m, 5 H) 1.57-1.75 (m, 1 H) 1.35-1.57 (m, 2 H).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:23])=O>C1C=CC=CC=1>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[Cl:23])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccccc1)c1ccc(C2CCCCC2)cc1
Solvent: c1ccccc1
Product: ClC(c1ccccc1)c1ccc(C2CCCCC2)cc1
Temperature: 70 °C
Yield: 97 %

Procedure:
76 g (0.286 mol) of 4-cyclohexylphenylphenylcarbinol are introduced in portions into a mixture of 143 ml (2 mols) of thionyl chloride and 200 ml of benzene at 70° C. The reaction mixture is heated to 70° C. for 15 hours and then evaporated. The oil which remains is stirred with petroleum ether, whereupon it solidifies to a crystal sludge. 79 g (96% of theory) of 4-cyclohexylphenyl-phenylchloromethane of melting point 75° C. are obtained. ##STR7##
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[N:13]([CH:21]([CH3:23])[CH3:22])[N:12]=1.B(Br)(Br)Br.C1CCCCC=1>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[N:13]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:11]2[C:4]1[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccc(-c2nn(C(C)C)c3c(F)cccc23)c(OC)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CC(C)n1nc(-c2ccc(O)cc2O)c2cccc(F)c21
Yield: 82.2 %

Procedure:
Prepared according to Method D step C from 3-(2,4-dimethoxyphenyl)-7-fluoro-1-isopropyl-1H-indazole (0.213 g, 0.68 mmol), boron tribromide (0.513 mL, 5.0 mmol) and 1.0 mL of cyclohexene to give the product (0.160 g) as a white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[CH2:4][CH2:3]1.[Cl-].[CH3:19][O:20]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH:19]([C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[CH2:4][CH2:3]1)=[O:20]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(COc2cccc(F)c2F)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C[C@H]1CC[C@H](COc2cccc(F)c2F)CC1
Yield: 78.7 %

Procedure:
13.8 g of 1-((4-oxocyclohexyl)methoxy)-2,3-difluorobenzene was dissolved in 50 mL of THF, and 23.6 g of methoxymethyl triphenylphosphonium chloride was added thereto. To this solution, the THF (20 mL) solution containing 7.7 g of potassium-t-butoxide was added dropwise at an internal temperature of 10 to 25° C., and the solution was stirred for 30 nm. 10 mL of water was added thereto, and the solvent was evaporated under reduced pressure. Hexane and 50% methanol aqueous solution were added thereto, and the organic layer was fractioned. This organic layer was washed with 50% methanol aqueous solution and saturated saline, and subjected to column chromatography. After evaporating the solvent under reduced pressure, the residue was dissolved in 100 mL of THF, and 100 mL of 10% hydrochloric acid was added thereto, followed by reflux with heating for 3 hours. To the solution, water and ethyl acetate were added, and the organic layer was fractioned, washed with saturated saline, saturated sodium hydrogencarbonate, and saturated saline in this order, and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure. To the residue, 30 mL of methanol and 20% sodium hydroxide aqueous solution were added, and the solution was stirred with ice-cooling for 2 hours. To the solution, water and ethyl acetate were added, and the organic layer was fractioned, washed with saturated saline 3 times, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, to thereby obtain 11.5 g of 1-((trans-4-formylcyclohexyl)methoxy)-2,3-difluorobenzene.
Reaction SMILES: [CH2:1](I)[CH3:2].[Li]C(C)(C)C.CCCCC.[C:14]([N:33]1[CH:37]=[C:36]([CH:38]=[O:39])[N:35]=[CH:34]1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>CCOCC.C1COCC1>[C:14]([N:33]1[CH:37]=[C:36]([CH:38]([OH:39])[CH2:1][CH3:2])[N:35]=[CH:34]1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCI
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCOCC
Product: CCC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.6 %

Procedure:
In a 100 ml, three-necked flask fitted with a magnetic stirrer, under inert atmosphere, ethyl iodide (1.1 ml, 0.0136 mol) is dissolved in Et2O (25 ml). At −70° C., a 1.5 M solution of t-BuLi in pentane (17 ml, 0.026 mol) is added dropwise. The mixture is stirred 0.3 h at this temperature and 0.75 h at room temperature. A solution of 1-trityl-1H-imidazole-4-carbaldehyde x43 (2 g, 0.00591 mole) in THF (25 ml) is added dropwise at 0° C. The mixture is stirred for 1 h and poured onto ice. HCl is added until the pH is slightly acid (pH: 3-5) and the aqueous phase is extracted twice with Et2O. The combined organic phases are dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 95/4.5/0.5 (v/v/v)) to afford 1.21 g of 1-(1-trityl-1H-imidazol-4-yl)propan-1-ol x88.
Reaction SMILES: [F:1][C:2]([F:22])([P:14](=[O:21])([O:18]CC)[O:15]CC)[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13].C[Si](Br)(C)C.CO>C(Cl)Cl>[F:22][C:2]([F:1])([P:14](=[O:15])([OH:21])[OH:18])[C:3]1[C:4]([F:13])=[C:5]([F:12])[C:6]([F:11])=[C:7]([F:10])[C:8]=1[F:9]
Reactant: CCOP(=O)(OCC)C(F)(F)c1c(F)c(F)c(F)c(F)c1F
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: O=P(O)(O)C(F)(F)c1c(F)c(F)c(F)c(F)c1F
Yield: 67.4 %

Procedure:
Diethyl perfluorobenzylphosphonate (1.90 g, 5.97 mmol) was dissolved in dry CH2Cl2 (4 ml), stirred and TMSBr (3.66 g, 23.88 mmol) was added. The mixture was stirred for 2 hours at room temperature after which volatiles were removed on a rotary evaporator to give a thick yellow oil. MeOH (5 ml) was added and the suspension stirred for 90 minutes, after which the product was collected by filtration yielding white crystals (1.20 g, 77%).
Reaction SMILES: [P:1]([O-:63])([O:59][CH2:60][CH2:61]Br)([O:3][CH:4]([C@H:32]1[C@H:37]([O:38][C:39](=[O:58])[NH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:36][CH2:35][CH2:34][O:33]1)[C@H]1[C@H](OC(=O)NCCCCCCCCCCCCCCCCC)CCCO1)=[O:2].[CH3:64][N:65]([CH3:67])[CH3:66]>C(Cl)(Cl)Cl.C(O)(C)C.CN(C)C=O.C(=O)([O-])[O-].[Ag+2]>[P:1]([O-:63])([O:59][CH2:60][CH2:61][N+:65]([CH3:67])([CH3:66])[CH3:64])([O:3][CH2:4][C@H:32]1[C@H:37]([O:38][C:39](=[O:58])[NH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:36][CH2:35][CH2:34][O:33]1)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1C(OP(=O)([O-])OCCBr)[C@@H]1OCCC[C@H]1OC(=O)NCCCCCCCCCCCCCCCCC
Reactant: CN(C)C
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1COP(=O)([O-])OCC[N+](C)(C)C
Reaction time: 6 h

Procedure:
1.402 g of dl-[trans-3-(N-heptadecylcarbamoyloxy)tetrahydropyran-2-yl]methyl 2-bromoethyl phosphate (prepared as described in Example 1f) was dissolved in a 3:5:5 by volume mixture of chloroform, isopropanol and dimethylformamide, and 7.0 g of gaseous trimethylamine were introduced into the solution. The mixture was heated, under a nitrogen atmosphere, on an oil bath kept at 50° for 6 hours, whilst stirring, and was then cooled, after which 0.483 g of silver carbonate was added The mixture was heated under reflux for 1 hour, and then the solvent was distilled off. Methanol was added to the residue and insolubles were separated by filtration. The solvent was stripped from the resulting solution by evaporation under reduced pressure. The residue was purified by liquid chromatography [using 30 g of silica gel and a Lobar column (size B)], giving 0.930 g of the title compound as a white powder from the fractions eluted with a 32:7:1 by volume mixture of methylene chloride, methanol and water.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([OH:17])[CH:16]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.FC(F)(F)S(O[Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])(=O)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:16]=1)[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=Cc1cc(O)cc(OCc2ccccc2)c1
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1cc(C=O)cc(OCc2ccccc2)c1

Procedure:
Preparation takes place in analogy to Example 11 from 2.8 g (12.3 mmol) of 3-(benzyloxy)-5-hydroxybenzaldehyde (Example 3J), 1.67 g (24.5 mmol) of imidazole and 3.57 g (13.5 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[N:8][C:7]=1[C:14]1[S:15][C:16]([C:19]#[CH:20])=[CH:17][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[C:23](I)=[N:24][CH:25]=[CH:26][CH:27]=1.CCN(CC)CC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:1]([NH:5][C:6]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[N:8][C:7]=1[C:14]1[S:15][C:16]([C:19]#[C:20][C:23]2[C:22]([F:21])=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:17][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(-c2nc3sccn3c2NC(C)(C)C)s1
Reactant: Fc1cccnc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1c(-c2ccc(C#Cc3ncccc3F)s2)nc2sccn12
Reaction time: 20 h
Yield: 77.2 %

Procedure:
A solution of 450 mg (1.49 mmol) N-tert-butyl-6-(5-ethynylthiophene-2-yl)imidazo[2,1-b]thiazole-5-amine, 333 mg (1.90 mmol) 3-fluoro-2-iodo-pyridine, 38 mg (0.06 mmol) bis(triphenylphosphine)-palladium-(II)-chloride, 19 mg (0.07 mmol) copper-(I)-iodide and 389 μl (2.80 mmol) NEt3 in AE (21 ml) was heated to 50° C. while being stirred for 20 h. Concentration in a vacuum was subsequently performed and a CC (AE) carried out with the residue, whereby 456 mg (1.15 mmol, 77%) N-tert-butyl-6-(5-((3-fluoropyridine-2-yl)ethynyl)thiophene-2-yl)imidazo[2,1-b]thiazole-5-amine was obtained.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:2]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].CC(C)([O-])C.[K+].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[F:35])[C:27]([O:29]CC)=[O:28].O>CN(C=O)C>[C:12]([O:11][C:9]([N:1]([CH2:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[F:35])[C:27]([OH:29])=[O:28])[C:2]([O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[O:3])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1ccc(F)c(CBr)c1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cc(C(=O)O)ccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.7 %

Procedure:
1.56 g of di-tert-butyl iminodicarboxylate was dissolved in 20.0 mL of DMF, and 804 mg of potassium tert-butoxide was added under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction liquid was added dropwise a solution (10.0 mL) of 1.70 g of ethyl 3-(bromomethyl)-4-fluorobenzoate in DMF, followed by stirring at room temperature overnight. The reaction liquid was poured to water, followed by extraction with ethyl acetate, and the organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 2.59 g of 3-{[bis(tert-butoxycarbonyl)amino]methyl}-4-fluorobenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=3)[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reaction time: 4 h
Yield: 96.3 %

Procedure:
A mixture of the 6-methoxy-2-(4-nitropheyl)benzothiazoles 5 (22 mg, 0.077 mmol) and tin(II) chloride dihydrate (132 mg, 0.45 mmol) in boiling ethanol was stirred under nitrogen for 4 hrs. Ethanol was evaporated and the residue was dissolved in ethyl acetate (10 mL), washed with 1 N sodium hydroxide (2 mL) and water (5 mL), and dried over MgSO4. Evaporation of the solvent gave 19 mg (97%) of the product 6 as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([CH:9]([O:22][CH3:23])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])[C:5]([F:8])=[CH:6][CH:7]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([NH:1][C:2]1[C:3]([F:24])=[C:4]([CH:9]([O:22][CH3:23])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])[C:5]([F:8])=[CH:6][CH:7]=1)(=[O:27])[CH3:26]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(N)c1F
Reactant: CC(=O)Cl
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(NC(C)=O)c1F

Procedure:
In analogy to example 87.2 (RS)-2-(3-amino-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 30.5) was reacted with acetyl chloride to give (RS)-2-(3-acetylamino-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide as white foam.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][C:15]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2.[ClH:29].[CH3:30]COCC>>[ClH:29].[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[CH2:14][C:15]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOCC
Reactant: CN(C)CCc1[nH]c2ccccc2c1CC1(c2ccccc2)CCCCC1=O
Agent: Cl
Product: CN(C)CCc1c(CC2(c3ccccc3)CCCCC2=O)c2ccccc2n1C

Procedure:
The same procedure was used to methylate 37.5 g (0.1 mol) of 2({2-[2-(dimethylamino)ethyl]indol-3-yl}methyl)-2-phenylcyclohexanone. The residue obtained on evaporation of the ethereal extraction solvent was redissolved in ether and treated with ethereal hydrogen chloride. The crude hydrochloride salt was collected and recrystallized from 750 ml of isopropyl alcohol to give 25.8 g of product, mp 246°-247°dec.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]([CH:26]=[O:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29]([C:33]1[CH:38]=[CH:37][C:36]([Mg]Br)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[C:12]([CH:26]([C:36]3[CH:37]=[CH:38][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=3)[OH:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(O)c3ccc(C(C)(C)C)cc3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-2-cyclopentyl-4-iodo-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-tert.-butylphenylmagnesium bromide. The product is obtained as a diastereomic mixture, which is used directly in the next step.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:12]=3[N:11]=2)=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:12]3[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:13]=3[N:14]=2)=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCC1CCCCC1
Reactant: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a suspension of sodium hydride (0.40 g, 10 mmol, 60%) in dry N,N-dimethylformamide (10 ml) at 25° C. was slowly added a solution of 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (1.47 g, 5 mmol) in dry N,N-dimethylformamide (5 ml), and was allowed to stir for 0.5 h. A solution of bromomethyl-cyclohexane (0.81 g, 6 mmol; CAS Reg. No. 2550-36-9) in N,N-dimethylformamide (5 ml) was then added drop wise to the above solution, and further stirred for 16 h at 25° C. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride. The solvents were removed under reduced pressure. The crude material dissolved in ethyl acetate, washed with water, and then with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel (20% ethyl acetate/n-hexane) to afford the title compound as a brown solid (53%). MS (Turbo Spray): m/z=391.4 (M+H).