Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.[C:28](Cl)(=[O:38])[O:29][C@@H:30]1[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1.O>N1C=CC=CC=1>[C:22]1([C@H:3]([NH:2][C:28]([O:29][C@@H:30]2[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[O:38])[C:4]2[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=2)[O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1ccc(COc2cccc([C@@H](N)c3ccccc3)c2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a stirred solution of (S)-methyl 4-((3-(amino(phenyl)methyl)phenoxy)methyl)-benzoate hydrochloride (I13, 12.0 g, 31.3 mmol) in pyridine (100 mL) at 0° C. was added portion-wise (R)-quinuclidin-3-yl carbonochloridate (8.50 g, 37.5 mmol, prepared as previously reported for Int 6, Step 6). The reaction was stirred at 0° C. for 1 hour and then allowed to warm to RT for 16 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate (×3). The combined extracts were washed with brine, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude material was purified by chromatography on a KP-NH Biotage cartridge eluting with 0-20% methanol in ethyl acetate to afford the title compound (10.3 g, 66%).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[CH2:21]([O:20][C:18]([C:14]1[S:13][C:12]([C:10]2[S:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[CH:16][CH:15]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(-c2ccc(-c3cccs3)s2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccc(-c3ccccc3)s2)s1

Procedure:
This compound was prepared in a manner analogous to Example 69 using 2.0 grams (0.083 mole) of 5-phenyl-[2,2'-bithienyl], 3.2 ml (0.0083 mole) of n-buthyl-lithium (2.6M in hexanes), and 1.0 gram (0.0092 mole) of ethyl chloroformate in 50 ml of dry tetrahydrofuran The yield of 5'-(ethoxycarbonyl)-5-phenyl[2,2'-bithienyl]was 0.9 gram; m.p. 113-115° C.
Reaction SMILES: [CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:9]1[C:10]([CH3:14])([CH3:13])[C:11](=[O:12])[N:8]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Clc1ccccc1CBr
Reactant: CC1(C)NN(C2CCCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCCC2)N1Cc1ccccc1Cl

Procedure:
2-Cycloheptyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH2:32][CH2:33][CH:34]([F:36])[F:35])([CH2:27][CH2:28][CH:29]([F:31])[F:30])[C:24]([OH:26])=O)[CH:8]=2)[N:3]=1.[CH2:37]([NH2:39])[CH3:38]>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([CH2:27][CH2:28][CH:29]([F:31])[F:30])([CH2:32][CH2:33][CH:34]([F:35])[F:36])[C:24]([NH:39][CH2:37][CH3:38])=[O:26])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C(CCC(F)F)(CCC(F)F)C(=O)O)ccc2n1
Reactant: CCN
Product: CCNC(=O)C(CCC(F)F)(CCC(F)F)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1

Procedure:
(Preparation by reaction of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-(3,3-difluoropropyl)-5,5-difluoropentanoic acid [“A66”] with ethylamine);
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[O:19][N:18]=[C:17]([CH3:20])[N:16]=3)=[N:8][C:4]=2[CH:3]=1.[NH:27]1[C:35]2[C:30](=[CH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:34]=2)[CH:29]=[CH:28]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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>[C:21]([N:6]1[C:5]2[CH:25]=[CH:26][C:2]([C:32]3[CH:31]=[C:30]4[CH:29]=[CH:28][NH:27][C:35]4=[N:34][CH:33]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:19][N:18]=[C:17]([CH3:20])[N:16]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Cc1noc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2ccccc2-c2nc3cc(-c4cnc5[nH]ccc5c4)ccc3n2C(C)(C)C)n1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 10.2 %

Procedure:
To a solution of 5-bromo-1-tert-butyl-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-phenyl]-1H-benzimidazole (100 mg, 0.24 mmol) in DMF (5 mL) and H2O (1 mL) are added 7-azaindole-5-boronic acid pinacol ester (89 mg, 0.37 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol) and K2CO3 (34 mg, 0.24 mmol) at room temperature. The solution is heated to 120° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The mixture is stirred for 15 minutes and is filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×15 mL). The combined organic layer is (MgSO4), filtered and concentrated and the residue is purified by preparative HPLC to afford the title compound (11 mg, 10%) as a white foam. LCMS (ESMS): m/z 449.77 (M++1)
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([OH:17])[CH:9]=[C:10]([C:12]([Cl:16])=[C:13]([Cl:15])[Cl:14])[CH:11]=1)=[C:3]([Cl:5])[Cl:4].O[CH2:19][NH:20][C:21](=[O:24])[CH2:22][Cl:23].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:23][CH2:22][C:21]([NH:20][CH2:19][C:7]1[C:6]([C:2]([Cl:1])=[C:3]([Cl:5])[Cl:4])=[CH:11][C:10]([C:12]([Cl:16])=[C:13]([Cl:14])[Cl:15])=[CH:9][C:8]=1[OH:17])=[O:24]
Reactant: O=C(CCl)NCO
Reactant: Oc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCl)NCc1c(O)cc(C(Cl)=C(Cl)Cl)cc1C(Cl)=C(Cl)Cl
Temperature: 25 °C

Procedure:
A mixture of 0.352 g (1.0 mmol) of the product of Step D and 0.123 g (1.0 mmol) of N-hydroxymethyl-2-chloroacetamide was added in portions to a vigorously stirred solution of 0.9 mL acetic acid and 0.1 mL (98%) sulfuric acid at 0-10° C. The reaction mixture was allowed to warm to room temperature, and stirring was maintained for a total of 4 days. The reaction mixture was poured into ice-water, neutralized with saturated aqueous NaHCO3 solution and extracted into CH2Cl2. The organic extracts were combined, washed with brine, dried Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5-10% EtOAc in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12]3)[CH:6]=[CH:7][CH:8]=1.[BrH:21].BrBr.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[Br:21][CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:20])[F:1])[CH:4]=3)[CH:10]=2)[C:14]1=[O:18]
Reactant: O=C1CCc2cc(-c3cccc(C(F)(F)F)c3)ccc21
Reactant: Br
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccc(-c3cccc(C(F)(F)F)c3)cc2CC1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.79 g of 5-(3-trifluoromethylphenyl)indan-1-one are dissolved in 10 ml of glacial acetic acid. 5.5 μl of a 48% strength solution of hydrobromic acid in water are added and a solution of 0.362 ml of bromine in 5 ml of glacial acetic acid is then slowly added dropwise. The reaction mixture is stirred at room temperature for 3 hours and then poured into a mixture of 50 ml of water with 50 g of ice and 86 mg of sodium hydrogencarbonate. The aqueous suspension is extracted by shaking with 100 ml of dichloromethane, the organic phase is washed three times with 50 ml of water, dried over magnesium sulfate and concentrated, and the residue is chromatographed on silica gel using toluene/ethyl acetate 25/1. 2-Bromo-5(3-trifluoromethylphenyl)indan-1-one of melting point 96° C. is obtained. 2,2-Dibromo-5-(3-trifluoromethylphenyl)indan-1-one of melting point 210° C. (dec.) is isolated as a by-product.
Reaction SMILES: [Cl:1][C:2]1[C:20]([F:21])=[C:19]([Cl:22])[CH:18]=[C:17]([F:23])[C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]>O>[Cl:1][C:2]1[C:20]([F:21])=[C:19]([Cl:22])[CH:18]=[C:17]([F:23])[C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Solvent: O
Product: CCOC(=O)CC(=O)c1c(F)cc(Cl)c(F)c1Cl
Yield: 49.8 %

Procedure:
0.04 g of p-toluenetoluenesulphonic acid is added to an emulsion of 34.7 g of crude diethyl (2,4-di-chloro-3,6-difluorobenzoyl)-malonate in 40 ml of water. The mixture is heated at the boiling point for 3 hours, while stirring thoroughly, the cooled emulsion is extracted several times with methylene chloride, the combined CH2Cl2 solutions are washed once with saturated sodium chloride solution and dried with Na2SO4 and the solvent is distilled off in vacuo. Fractionation of the residue (33.9 g) in vacuo gives 13.9 g of ethyl (2,4-dichloro-3,6-difluorobenzoyl)-acetate of boiling point 110°-115° C./0.05 mbar, nD25 : 1,5241.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH3:8][S:9]([O:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCCO
Product: CC(C)CCCOS(C)(=O)=O

Procedure:
The title compound was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (620 mg, 63%) from 4-methyl-1-pentanol (511 mg, 5.00 mmol) and methanesulfonyl chloride (844 mg, 7.50 mmol). 1H NMR (CDCl3, 300 MHz) δ0.88 (d, 6H, J=4.7 Hz), 1.23-1.31 (m, 2H), 1.53-1.62 (m, 1H), 1.70-1.80 (m, 2H), 3.00 (s, 3H), 4.21 (t, 2H, J=6.6 Hz) ppm.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[CH:8]1([S:14][CH2:15][CH2:16][NH2:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Br[CH:19]([CH3:23])[C:20]([OH:22])=[O:21]>C(O)(C)(C)C>[CH:8]1([S:14][CH2:15][CH2:16][NH:17][C@H:19]([C:20]([OH:22])=[O:21])[CH3:23])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NCCSC1CCCCC1
Reactant: CC(Br)C(=O)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[C@H](NCCSC1CCCCC1)C(=O)O

Procedure:
To a stirred solution of 22.4 parts potassium tert-butoxide in 400 parts by volume of tert-butanol, under a nitrogen atmosphere, is added successively 19.62 parts of 2-(cyclohexylthio)ethylamine hydrochloride and 15.3 parts of 2-bromopropionic acid. The mixture is refluxed for 3 hours, then dried under reduced pressure. The material remaining is dissolved in 200 parts of water containing 10 parts of sodium hydroxide and extracted with ether. The aqueous solution is cooled in an ice bath and acidified to pH 5 with concentrated hydrochloric acid. The solid is collected by filtration and dried under reduced pressure to yield N-[2-(cyclohexylthio)ethyl] alanine.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=O)[O:3]1.[CH3:25][S:26]([NH2:29])(=[O:28])=[O:27]>>[OH:6][C:5]([C:4]([NH:29][S:26]([CH3:25])(=[O:28])=[O:27])=[O:3])=[CH:7][C:8]([N:10]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)[O:11][CH3:12])=[O:9]
Reactant: CON(Cc1ccc(C(=O)O)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CS(N)(=O)=O
Product: CON(Cc1ccc(C(=O)O)cc1)C(=O)C=C(O)C(=O)NS(C)(=O)=O
Yield: 95.1 %

Procedure:
Reaction of 4-({[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-benzoic acid (0.125 g, 0.37 mmol) with methanesulfonamide (0.053 g, 0.55 mmol) as described for compound 1 gave 0.131 g (95%) of the title amide as a white solid after recrystallization from acetonitrile; mp 119-124° C. 1H NMR (400 MHz, DMSO) δ: (ppm)); mixture of rotamers: 2.99 and 3.09 (3H, 2 S, SO2CH3), 3.42 and 3.54 (3H, 2 s, OCH3), 4.63 and 4.76 (2H, 2 s, NCH2), 6.14 (1H, s, CH), 7.17 (2H, m, aromatics), 7.69 (2H, m, aromatics). HRMS (ESI/pos) calculated for C14H17N2O8S, [M+H]+: 373.070563; found: 373.070061. Anal. calcd for C14H16N2O8S: C, 45.16; H, 4.33; N, 7.52; found: C, 45.22; H, 4.70; N, 8.12.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3](O)=[O:4].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C)C=O>[CH3:1][CH:2]([CH2:6][C:7]([F:10])([F:9])[F:8])[C:3]([Cl:14])=[O:4]
Reactant: CC(CC(F)(F)F)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(CC(F)(F)F)C(=O)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2-methyl-4,4,4-trifluorobutyric acid (172 g) in methylene chloride (150 mL) and N,N-dimethylformamide (3.5 mL) at 0° C., under nitrogen was added (dropwise) oxalyl chloride (125 mL). The mixture was allowed to warm to ambient temperature and stirred for 16 hours. After distillation of the solvent, distillation using a concentric tube distillation column (40 cm×15 mm) afforded 2-methyl-4,4,4-trifluorobutyryl chloride (about 99% purity, 79.87 g, 42%); bp 115.0°-116.0° C. (at atmospheric pressure, measured at room temperature as 763.27 mm Hg); GLC: tR =5.04 min; MS(CI): 139 (M+H-HCl).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:18][C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:17])OCC)[S:11][C:7]=2[CH:6]([C:19]#[N:20])[CH2:5]1)[CH2:2][CH3:3].[CH2:21]([NH:25][CH2:26][CH:27]=[O:28])[CH2:22][CH:23]=[CH2:24]>>[CH2:21]([N:25]([CH2:26][CH:27]=[O:28])[C:13]([NH:12][C:10]1[S:11][C:7]2[CH:6]([C:19]#[N:20])[CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:18][C:8]=2[N:9]=1)=[O:17])[CH2:22][CH:23]=[CH2:24]
Reactant: C=CCCNCC=O
Reactant: CCCC1Cc2nc(NC(=O)OCC)sc2C(C#N)C1
Product: C=CCCN(CC=O)C(=O)Nc1nc2c(s1)C(C#N)CC(CCC)C2
Temperature: 125 °C

Procedure:
Ethyl N-(5-propyl-7-cyano-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate (0.08 mol) and the dimethyl acetal of 2-but-3-enylaminoacetaldehyde (30 ml.) as charged into a glass reaction vessel equipped with a stirrer, reflux condenser and gas addition tube. The reaction mixture is blanketed with nitrogen gas and is heated 125° C. for a period of about 8 hours. After this time the reaction mixture is distilled to remove excess starting material. The residue is purified by elution chromatography using ethyl acetate as the eluant. The chromatographed solution is then stripped of solvent to yield the desired product dimethyl acetal of 2-[1-but-3-enyl-3-(5-propyl-7-cyano-4,5,6,7-tetrahydrobenzothiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]3)[CH:12]=2)[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3].[CH2:26](I)[CH3:27].C(N(CC)CC)C>CN(C)C=O>[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:26][CH3:27])[CH:16]([CH3:20])[CH2:15]3)[CH:12]=2)[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C)C3)cc21
Reactant: CCI
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CC1C
Yield: 48.1 %

Procedure:
A solution of 1.00 g of 1-ethyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid hydrochloride, 1.29 g of ethyl iodide and 1.09 g of triethylamine in 20 ml of N,N-dimethylformamide was heated at 70° to 80° C. for 1.5 hours. The solvent of the reaction mixture was evaporated and the residue was acidified with 50% aqueous acetic acid. The solution was neutralized with 20% aqueous sodium hydroxide and the precipitate was filtered. The precipitate was chromatographed on silica gel using chloroform-methanol (9:1) as eluent to give 0.47 g of the title compound as colorless crystalls, which was recrystallized from a mixture of chloroform and methanol as colorless needles, M.p. 203°-205° C.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N1CCC(OC2C=CC(C#N)=CC=2)C[CH2:24]1>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(=[O:5])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Reactant: N#Cc1ccc(OC2CCNCC2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1

Procedure:
Synthesized from 4-(4-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester (1.5 g) according to an analogous synthetic method to Example 215 described below, the total amount of 4-(piperidin-4-yloxy)benzonitrile crude product was dissolved in acetic anhydride (20 ml) and pyridine (20 ml), and the solution was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.1 g).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([O:27][CH3:28])[C:21]=1B(O)O>C(Cl)(Cl)Cl.ClCCl>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([O:27][CH3:28])[C:21]=1[Pb+3:17]
Reactant: COc1cc(C)cc(OC)c1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(C)cc(OC)c1[Pb+3]
Temperature: 40 °C
Reaction time: 1.25 h
Yield: 90 %

Procedure:
45.4 g of lead tetraacetate and 3.2 g of mercuric acetate are suspended in 150 ml of anhydrous chloroform and the mixture is heated to 40° C. under an argon atmosphere. A solution of 20 g of 2,6-dimethoxy-4-methylphenylboronic acid (prepared above) in 100 ml of chloroform is added dropwise to the reaction mixture at 40° C. The reaction mixture is left for 75 minutes at 40° C. and is then left to return to room temperature while stirring well. The reaction mixture is stirred at room temperature for 18 hours and is then diluted with 800 ml of dichloromethane. The solution is filtered over a bed of celite and the solvent is then evaporated to dryness in order to obtain yellow crystals of 2,6-dimethoxy-4-methylphenyllead triacetate, M.p.=172° C., Yield: 90%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[O:5])[CH3:2].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Temperature: 50 °C
Yield: 90 %

Procedure:
A mixture of 1H-imidazole-4-carboxylic acid ethyl ester (J.Het.Chem., 19, 253 (1982)) (584 mg, 4.17 mmol), 4-fluoronitrobenzene (588 mg, 4.17 mmol) and anhydrous sodium carbonate (487 mg, 4.59 mmol) in dry dimethylformamide (10 ml) was heated at 50° C. for 24 hours under nitrogen. After cooling to room temperature the mixture was poured into ice-cold water (60 ml) and the resulting solid collection by filtration, washed with water and dried under reduced pressure at 60° C. to give 1-(4-nitrophenyl)imidazole-4-carboxylic acid ethyl ester (980 mg, 90%) as an off-white solid, m.p. 198-200° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21](O)=[O:22])[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([C:21]([C:19]2[NH:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:5]5[NH:6][C:2](=[O:1])[S:3][C:4]=5[CH:10]=4)[C:13]=3[CH:20]=2)=[O:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1cc2c(Nc3ccc4[nH]c(=O)sc4c3)ncnc2[nH]1
Reactant: C1CCNCC1
Product: O=C(c1cc2c(Nc3ccc4[nH]c(=O)sc4c3)ncnc2[nH]1)N1CCCCC1

Procedure:
150 mg (458 μmol) 4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to example 30) were transformed in analogy to example 4 using piperidine to give after working up and purification 47.0 mg (26%) of the title compound.
Reaction SMILES: C([Si:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21]C=2)[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)CCC=C.[F:25][C:26]1[CH:27]=[C:28]([Mg]Br)[CH:29]=[CH:30][C:31]=1[F:32]>>[CH2:19]([Si@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[C:31]([F:32])[CH:30]=3)=[CH:16][CH:17]=2)[CH2:10][CH2:11]1)[CH2:24][CH:23]=[CH:22][CH3:21]
Reactant: C=CCCC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Reactant: Fc1ccc([Mg]Br)cc1F
Product: CC=CCC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 12 was repeated using 34.1 g of 4-(4-(4-pentenyl)-4-phenyl-4-silacyclohexyl)cyclohexanone and 3,4-difluorophenylmagnesium bromide, thereby obtaining the captioned compound.
Reaction SMILES: 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.[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([OH:53])=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH:54]([C:56](=[O:70])[CH2:57][CH:58]1[CH2:61][CH:60]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[CH2:59]1)[NH2:55]>CN(C=O)C>[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([NH:55][NH:54][C:56](=[O:70])[CH2:57][CH:58]1[CH2:61][CH:60]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:66])([CH3:67])[CH3:68])[CH2:59]1)=[O:53])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)NC1CC(CC(=O)NN)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
HATU (1.6 g, 4.3 mmol) and DIPEA (0.93 g, 7.2 mmol) were added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (1.0 g, 3.6 mmol), tert-butyl 3-(2-hydrazinyl-2-oxoethyl)cyclobutylcarbamate (0.97 g, 3.9 mmol) in DMF (10 mL) at. The reaction mixture was stirred at 0° C. for 1 hr. The mixture was quenched with saturated sodium chloride (50 mL) and the organic layer was separated. The water layer was exacted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (50% EtOAc/petroleum ether) to afford tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclobutylcarbamate (1.5 g, 88%). ESI-MS (EI+, m/z): 502 [M+H]+.