Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:30])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:28]#[N:29])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:30][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:28]#[N:29])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2c1CCCC2
Reactant: CCOC(=O)C1(N)Cc2ccc(C#N)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (306 mg, 1.74 mmol), 2-amino-5-cyano-indan-2-carboxylic acid ethyl ester (601 mg, 2.61 mmol), HATU (992 mg, 2.61 mmol) in anhydrous DMF (15 mL) is added DIPEA (431 μL, 2.61 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-80% EtOAc in heptane) to give a pure product (106) as white solid (473 mg, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1.[OH-].[K+].O.O.Br[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[Br:16]>CS(C)=O>[Br:16][C:15]([F:18])([F:17])[C:14]([F:20])([F:19])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[Br:16])[CH:3]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: Oc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(Br)C(F)(F)Oc1cccc(OC(F)(F)C(F)(F)Br)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 80 %

Procedure:
Into a 250 mL round-bottom flask were placed 18.72 g (0.17 mol) of 1,3-dihydroxybenzene (resorcinol) and 75 mL of DMSO. The solution was purged with nitrogen gas for one hour followed by adding 223.62 mL of 1.52M (0.34 mol) KOH-water water solution dropwise to the solution, with the reaction flask resting in an ice-bath. The reaction mixture was then heated at 100° C. for one day followed by distilling off most of the water from the reaction solution. The rest of reaction solvents were evaporated slowly under vacuum. The salt was dried at 120° C. under the vacuum line for at least two days. Then 75 mL of dry DMSO and 109.2 g (0.42 mol) of 1,2-dibromo tetrafluoroethane was transferred to the flask via a closed system. The mixture was stirred at 35° C. for 3 days. The reaction mixture was filtered to remove the KBr, then the reaction mixture was washed with acetone in a 500 mL separatory funnel and the organic layer was diluted with 150 mL of methylene chloride. The combined organic layer was washed first with 10% of sodium bicarbonate water solution, and then with 0.01N HCl and finally with distilled water until neutral. The solution was dried over sodium sulfate overnight. After the removal of the sodium sulfate by filtration and the evaporation of the solvents, the crude product was purified by distillation under reduced pressure with an oil bath at a temperature of 100-110° C. A total of 64 g (0.136 mol) of 1,3-di(2-bromotetrafluoro ethoxy)benzene was obtained in 80.4% yield, which had a boiling point of 76-80° C. (at 10−2 torr). The amount of hydrogen by-product in the product was about 5.4%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[N:21]1([NH:27][C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NN1CCCCC1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(NN4CCCCC4)n3)cc2s1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 9 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.3 mmol) and piperidin-1-amine (0.03 g, 0.3 mmol) in DMSO (0.03 g, 0.3 mmol) was heated under microwave (CEM) at 80° C. and 130 W (Powermax® off) for 20 min. Then, the mixture was diluted with 1 ml of DMSO and purified by HPLC (5-50% CH3CN in water) to give a light yellow solid (10 mg) as a TFA salt. MS (ESI pos. ion) Found m/z: 369, (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=O.N1CCCCC1.[CH2:19]([O:21][C:22](=[O:38])[CH2:23][C:24]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:25])[CH3:20]>C1C=CC=CC=1>[C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:24](=[O:25])/[C:23](/[C:22]([O:21][CH2:19][CH3:20])=[O:38])=[CH:1]/[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:32])([CH3:36])([CH3:37])[CH3:35]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(CC(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)/C(=C\c1ccc(CC(=O)O)cc1)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 33.6 %

Procedure:
To a solution of 4-formylphenylacetic acid (4.31 g, 26.3 mmol) in benzene (75 ml) and piperidine (0.95 ml, 9.5 mmol) was added tert-butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (8.1 g, 28.4 mmol). The solution was refluxed under a Dean-Stark trap for 8 h. The solvent was removed by rotary evaporation. The product was purified by silica gel column chromatography (silica gel/75% ethyl acetate in petroleum ether) giving A as an off-white solid (3.81 g, 34% yield). LCMS m/z 432 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=3)=[O:11])[CH:5]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)ccn1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: Cc1cc(C(=O)CC(c2cccc(-c3ccc(S(C)(=O)=O)cc3)c2)c2ccccc2C)ccn1

Procedure:
In analogy to example 22, from 3-(3-bromo-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (example 98, step 5) and 4-(methylsulfonyl)phenylboronic acid was prepared the title compound as light yellow foam, MS (ESI+): m/z=470.2 ([M+H]+).
Reaction SMILES: [I:1]Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[CH:11][C:6]=2[O:5][CH2:4]1>C(Cl)Cl.C(O)(=O)C>[I:1][C:9]1[C:10]([NH:12][C:13](=[O:15])[CH3:14])=[CH:11][C:6]2[O:5][CH2:4][O:3][C:7]=2[CH:8]=1
Reactant: ClI
Reactant: CC(=O)Nc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1I)OCO2
Reaction time: 8 h
Yield: 22 %

Procedure:
A 1.0 M solution of iodine monochloride in methylene chloride (72.6 mL) was added dropwise to a solution of N-(benzo[d][1,3]dioxol-5-yl)acetamide (10 g, 55.8 mmol) in methylene chloride (66 mL) and acetic acid (11 mL). The mixture was stirred under nitrogen overnight and then washed with saturated sodium thiosulfate (2×150 mL) and brine (150 mL). The methylene chloride solution was dried (MgSO4) and evaporated, and the residue was purified by column chromatography on silica gel (CH2Cl2/petroleum at 20/1) to obtain N-(6-iodobenzo[d][1,3]dioxol-5-yl)acetamide (3.7 g, 22%) as a white solid. LCMS: 306 [M+1]+; 1H NMR (DMSO-d6) δ 2.00 (s, 3H), 6.06 (s, 2H), 6.95 (s, 1H), 7.37 (s, 1H), 9.34 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[O:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:25]([CH3:29])[N:26]=[C:27]([CH3:28])[C:3]=12.C1C[O:33]CC1>C(N(CC)C(C)C)(C)C.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([NH:10][C:8]([C:7]2[C:2]([OH:33])=[C:3]3[C:27]([CH3:28])=[N:26][N:25]([CH3:29])[C:4]3=[N:5][CH:6]=2)=[O:9])=[O:12])=[CH:15][C:16]=1[C:21]([F:24])([F:23])[F:22]
Reactant: C1CCOC1
Reactant: Cc1nn(C)c2ncc(C(=O)NC(=O)Nc3ccc(F)c(C(F)(F)F)c3)c(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nn(C)c2ncc(C(=O)NC(=O)Nc3ccc(F)c(C(F)(F)F)c3)c(O)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of (4-chloro-1,3-dimethylpyrazolo[5,4-b]pyridin-5-yl)-N-({[4-fluoro-3-(trifluoromethyl)phenyl]amino}carbonyl)carboxamide (0.050 g) in THF (5 mL) was dissolved in a 1:3 mixture of N,N-diisopropylethylamine (DIPEA) and water (4 mL). The solution was stirred at room temperature for 24 h, concentrated, and the residue purified by column chromatography on silica-gel eluting with 3:1 EtOAc-MeOH to give the title compound as a white powder. 1H NMR (DMSO-d6) δ 2.46 (s, 3H), 3.75 (s, 3H), 7.45 (dd, J=9.9, 9.9 Hz, 1H), 7.81 (m, 1H), 8.11 (dd, J=6.6, 2.6 Hz, 1H), 8.58 (s, 1H), 11.51 (br s, 1H). MS (ESI) m/z 410.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH3:28]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH3:28])[N:16]([CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)c2nc(C)n(CCOCCNC(=O)N3CCOCC3)c2c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 4-morpholinecarbonyl chloride (370 μL) was added to a solution of 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (0.757 g) in chloroform (11 mL) and triethylamine (520 μL). The reaction mixture was stirred at ambient temperature for about 3 hours; then it was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was recrystallized from acetonitrile and dried in a vacuum oven at 60° C. for 24 hours to provide 0.7014 g of N-{2-[2-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}morpholine-4-carboxamide as a white powder, m.p. 205–207° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6].[Cl:12][C:13]1[S:17][C:16]([S:18](Cl)(=[O:20])=[O:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:6][S:18]([C:16]1[S:17][C:13]([Cl:12])=[CH:14][CH:15]=1)(=[O:20])=[O:19]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(=O)OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a solution of L-isoleucine methyl ester hydrochloride (1.82 g, 10 mmol) and 5-chlorothiophene-2-sulfonyl chloride (1.82 g, 10 mmol) was added triethylamine (4.18 mL, 30 mmol). The mixture was stirred at 60° C. overnight, then filtered and concentrated. The crude product was purified by flash chromatography over silica gel using 10% ethyl acetate in hexane to give 5-chlorothiophene-2-sulfonyl isoleucine methyl ester 2.53 g.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>CN(C)C=O>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][O:14][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: OCCOc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)OCCOc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A solution of 2.5 g of 2-[p-(p-fluorophenoxy)phenoxy]-ethanol in 25 ml of dimethylformamide is added dropwise during 20 minutes while stirring to a suspension of 0.5 g of sodium hydride (55% in oil) in 5 ml of dimethylformamide. The mixture is then allowed to stir at 40° C. for 4 hours, then treated dropwise with 1.18 g of dimethylcarbamoyl chloride and allowed to react at 40° C. for 16 hours. The cooled mixture is poured into 75 ml of ice/water and extracted three times with 50 ml of ethyl acetate each time. The extracts are washed three times with 50 ml of water each time, dried and evaporated. The residue is purified by chromatography on silica gel with n-hexane/ethyl acetate (85:15) to yield pure [2-[p-(p-fluorophenoxy)phenoxy]-ethyl]N,N-dimethylcarbamate; nD20 =1.5444.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:36][O:37][CH2:38][CH2:39]O)[CH:33]=[CH:34][CH:35]=1>C(Cl)Cl.[Al]>[Br:1][CH2:39][CH2:38][O:37][CH2:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=1
Reactant: COc1cccc(COCCO)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(COCCBr)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.3 %

Procedure:
A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) was added resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM (2.5 mL). The reaction was stirred at room temperature for 10 min. A solution of 2-({[3-(methyloxy)phenyl]methyl}oxy)ethanol (114 mg, 0.626 mmol) in DCM (1.5 mL) was added to the reaction, and the residual alcohol was transferred with additional DCM (1.5 mL). The reaction vessel was wrapped in aluminum foil and stirred at rt for 20 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (160 mg). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([CH:6]=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C([CH2:17][S:18]([CH2:21][S:22]([CH2:25][C:26](O)=O)(=[O:24])=[O:23])(=[O:20])=[O:19])(O)=O>C(O)(=O)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5](/[CH:6]=[CH:17]/[S:18]([CH2:21][S:22](/[CH:25]=[CH:26]/[C:5]2[C:4]([O:12][CH3:13])=[CH:3][C:2]([OH:1])=[CH:9][C:8]=2[O:10][CH3:11])(=[O:23])=[O:24])(=[O:19])=[O:20])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(O)cc(OC)c1C=O
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Solvent: CC(=O)O
Product: COc1cc(O)cc(OC)c1/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c1c(OC)cc(O)cc1OC
Yield: 62 %

Procedure:
A solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 62% yield. m.p. 148-150° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[N:7][CH:8]=1.C1CCN2C(=NCCC2)CC1.[CH:32]([S:35](Cl)(=[O:37])=[O:36])([CH3:34])[CH3:33]>ClCCCl>[C:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:20])[C:9]=1[C:5]1[CH:4]=[C:3]([CH2:2][NH:1][S:35]([CH:32]([CH3:34])[CH3:33])(=[O:37])=[O:36])[CH:8]=[N:7][CH:6]=1)#[N:19]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: CC(C)S(=O)(=O)NCc1cncc(-c2c(C#N)c3ccccc3n2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask is charged with 2-(5-aminomethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (130 mg, 0.5 mmol), DBU (304 mg, 2.0 mmol) and DCE (15 mL), and isopropylsulfonyl chloride (142 mg, 1.0 mmol) is added. The mixture is stirred at room temperature for 1 h and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 1:0 to 97:3) to give propane-2-sulfonic acid [5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (d, J=6.8 Hz, 6H), 3.18-3.26 (m, 1H), 3.79 (s, 3H), 4.37 (d, J=6.1 Hz, 2H), 7.34-7.38 (m, 1H), 7.41-7.46 (m, 1H), 7.70-7.79 (m, 3H), 8.08 (t, J=2.0 Hz, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 369.1389 [(M+H)+ Calcd for C19H21N4O2S: 369.1385].
Reaction SMILES: N[C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:3]1.N1CC[C@@H]([OH:30])C1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[OH:30][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:3]1
Reactant: O[C@@H]1CCNC1
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CC[C@@H](N)C3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCN3CC[C@@H](O)C3)cc2)cc1
Yield: 69 %

Procedure:
4′-{3-[(3R)-3-Aminopyrrolidinyl]propoxy}[1,1′-biphenyl]-4-carbonitrile (200 mg, 0.74 mmol), (3R)-3-pyrrolidinol (70 mg, 0.81 mmol), potassium carbonate (152 mg) and potassium iodide (183 mg) in 25 mL of 2-butanone were heated at 110° C. for 72 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (69 % yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[OH:21][C:22]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][C:23]=1[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:27][C:26]([NH:25][CH2:24][C:23]1[CH:33]=[C:34]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:35]=[CH:36][C:22]=1[OH:21])=[O:32])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)c(CNC(=O)OC(C)(C)C)c3)ccn2c1=O
Yield: 80.7 %

Procedure:
Methyl 8-(3-(((tert-butoxycarbonyl)amino)methyl)-4-hydroxyphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (65 mg, 0.22 mmol) and tert-butyl 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (93.3 mg, 0.27 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (85 mg, 100%).
Reaction SMILES: Br[CH2:2][CH:3]([N:10]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=2[N:12]=[C:11]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:28][C:29]1[CH:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:32]=[CH:31][N:30]=1.CCCCCCC>C(OCC)(=O)C>[CH3:38][O:37][C:35](=[O:36])[C:33]1[CH:32]=[CH:31][N:30]=[C:29]([O:28][CH2:2][CH:3]([N:10]2[C:14]3[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=3[N:12]=[C:11]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:34]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CBr)C3CCCCC3)c2cc1F
Reactant: COC(=O)c1ccnc(O)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 35 from 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Ex. 34, int.) and methyl 2-hydroxypyridine-4-carboxylate after a reaction time of 4 days at room temperature and using a gradient of n-heptane:ethyl acetate of 100:0 to 70:30. Light yellow solid (19%). MS: (Turbo Spray): m/z=526.2 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:14])[O:12][CH3:13].[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:15][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:14])[O:12][CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)NCc1cc(I)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NCc1cc(C#C[Si](C)(C)C)ccc1Cl

Procedure:
A mixture methyl [(2-chloro-5-iodo-phenyl)methyl]carbamate (i.e. the product of Step B) (3.0 g, 9.2 mmol), ethynyltrimethylsilane (1.94 mL, 13.8 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.032 g, 0.05 mmol), copper(I) iodide (0.018 g, 0.09 mmol), triphenylphosphine (0.024 g, 0.09 mmol) in tetrahydrofuran (18 mL) and triethylamine (18 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated onto silica gel (7 g) and then purified by medium pressure liquid chromatography (0 to 25% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as an oil (1.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[N:10][C:4]=2[CH:3]=1.[CH2:17]([O:19][C:20]1[C:21](=O)[C:22](=[O:27])[C:23]=1[O:24]CC)[CH3:18].C1(OC2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]([C:21]3[C:22](=[O:27])[C:23](=[O:24])[C:20]=3[O:19][CH2:17][CH3:18])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)N=Cc1ccccc1O2
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: C1COCCO1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOc1c(N2Cc3ccccc3Oc3ccc(Cl)cc32)c(=O)c1=O
Reaction time: 2 h

Procedure:
A mixture of 8-chloro-dibenz[b,f][1,4]oxazepine (2 g), 3,4-diethoxy-3-cyclobutene-1,2-dione (5 g), diphenylether (2 g) and dioxane (10 mL) was heated to reflux. After 2 hours, most of the dioxane was removed in vacuo and the precipitated title compound (0.75 g) was collected by filtration as yellow solid. The filtrate was treated with cold methanol when more of the title compound (1.2 g) precipitated. This material was used in Example 6 without further purification.
Reaction SMILES: [C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31](Cl)=[O:32])[C@H:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[ClH:11].[C:1]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:50][CH2:49]3)=[O:32])[C@H:14]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:16]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12h) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 721.4 [(M+H)+]