Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:15])[CH:5](P(OCC)(OCC)=O)[F:6])C.C([Li])CCC.[NH2:21][C:22]1[C:27]([CH:28]=O)=[CH:26][N:25]=[C:24]([S:30][CH3:31])[N:23]=1.[Cl-].[NH4+]>O1CCCC1.O>[F:6][C:5]1[C:4](=[O:15])[NH:21][C:22]2[N:23]=[C:24]([S:30][CH3:31])[N:25]=[CH:26][C:27]=2[CH:28]=1
Reactant: CSc1ncc(C=O)c(N)n1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc2cc(F)c(=O)[nH]c2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A solution of 1.74 g (10.33 mmol) of (diethoxy-phosphoryl)-fluoro-acetic acid ethyl ester in 20 mL of tetrahydrofuran is cooled to −78° C. and treated dropwise with 12.9 mL (20.65 mmol) of a 1.6 M solution of n-butyl lithium in hexanes. After stirring for 30 minutes at −78° C. the solution is treated with 1.74 g (10.33 mmol) of 4-amino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde (Example 3), allowed to warm to room temperature, and stirred overnight. The reaction is treated with saturated aqueous ammonium chloride, then water. The solid is collected by filtration and washed with diethyl ether to give 2.01 g (92%) of the product.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[N:31]1[CH2:37][CH2:36][C:35]([O:39][CH3:40])([CH3:38])[CH:34]([NH:41]C(=O)OC(C)(C)C)[CH2:33][CH2:32]1)=[O:23])=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:29]=[N:28][N:27]([CH3:30])[C:26]=1[N:31]1[CH2:32][CH2:33][CH:34]([NH2:41])[C:35]([O:39][CH3:40])([CH3:38])[CH2:36][CH2:37]1)=[O:23]
Reactant: COC1(C)CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CCC1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC1(C)CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)CCC1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a solution of tert-butyl N-(1-(4-((5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carbonyl)amino)-2-methyl-pyrazol-3-yl)-5-methoxy-5-methyl-azepan-4-yl]carbamate (0.12 g, 0.17 mmol) in MeOH (10 mL) was added HCl in dioxane (4 M, 10 mL, 0.04 mol). The reaction mixture was stirred at room temperature for 16 hr and concentrated under reduced pressure. Purification via preparative HPLC gave 485 as a pale yellow solid (64 mg, 74%). 1H NMR (400 MHz, d6-DMSO) δ 9.63 (s, 1H), 7.69 (s, 1H), 7.59-7.48 (m, 3H), 7.31-7.22 (m, 2H), 3.61 (s, 3H), 3.31-3.25 (m, 1H), 3.14-3.03 (m, 2H), 3.03 (s, 3H), 2.99-2.89 (m, 1H), 2.11-2.02 (m, 1H), 1.92-1.82 (m, 1H), 1.79-1.59 (m, 4H), 1.47 (dd, J=14.5, 6.2 Hz, 1H), 1.19 (s, 3H). LCMS (ES+) m/z 492 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:3]=1[CH:18]=O.CCN(CC)CC.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:3]=1[CH2:18][NH:30][CH:27]1[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: O=Cc1cc(CCNC(=O)CC(F)(F)F)ccc1Cl
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CC(F)(F)F)NCCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
A mixture of N-[2-(4-chloro-3-formyl-phenyl)-ethyl]-3,3,3-trifluoro-propionamide (175 mg, 0.596 mmol), Et3N (0.125 mL, 0.896 mmol) and cyclopropylamine (0.063 mL, 0.90 mmol) in MeOH (2.00 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (56.4 mg, 1.49 mmol) was added in portions. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc several times, and the combined org. extracts were washed with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 95:5) yielded the title compound (130 mg, 65%). LC-MS: tR=0.65 min; ES+: 335.12.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17](Cl)([Cl:20])(=[O:19])=[O:18]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:17]([Cl:20])(=[O:19])=[O:18])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Clc1cc(Br)cc(OCc2ccccc2)c1
Solvent: C1CCOC1
Product: O=S(=O)(Cl)c1cc(Cl)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Under N2 atmosphere, 2.23 g 1-benzyloxy-3-bromo-5-chloro-benzene was dissolved in 50 mL dry THF, and the mixture was cooled in an ice bath. Dropwise, 14.84 mL of a 1M solution of isopropyl magnesium chloride-lithium chloride complex was added, and the mixture was stirred at room temperature overnight. After cooling to −40° C., 2.41 mL of sulfuryl chloride was added in one portion (T raised to 10° C.), and the mixture was stirred for 15 minutes at room temperature. After cooling with an ice bath, the mixture was quenched with water and acidified with 1M aqueous HCl. The mixture was extracted with MTBE, and the organic phase was dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (PA→PA/Et2O 95:5) to yield 1.53 g (62%) of a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.14 (s, 2H), 7.30 (t, J=2 Hz, 1H), 7.34-7.47 (m, 5H), 7.50 (t, J=2 Hz, 1H), 7.62 (t, J=1.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12]([CH2:17][C:18]1([NH:26]C(=O)OC(C)(C)C)[CH2:23][O:22]C(C)(C)[O:20][CH2:19]1)[CH2:11][CH2:10]2.CC1(C)OCC(NC(=O)OC(C)(C)C)(CNC2C=CC(CCCCCCCC)=CC=2)CO1>>[NH2:26][C:18]([CH2:17][N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][CH2:5][C:4]3[CH:34]=[CH:35][CH:36]=[C:2]([F:1])[CH:3]=3)[CH:8]=2)[CH2:13]1)([CH2:23][OH:22])[CH2:19][OH:20]
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3cc(OCc4cccc(F)c4)ccc3C2)COC(C)(C)OC1
Agent: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Product: NC(CO)(CO)CN1CCc2cc(OCc3cccc(F)c3)ccc2C1
Yield: 21 %

Procedure:
When the product of Step E was substituted for tert-butyl 2,2-dimethyl-5-((4-octylphenylamino)methyl)-1,3-dioxan-5-ylcarbamate in Example 1, Step B, the identical process afforded the title compound in 21% yield, as a creamy solid. 1H-NMR (CDCl3) 2.31 (broad s, 6H); 2.69 (s, 2H); 2.73 (tr, J=6.5 Hz); 2.86 (tr, J=6.5 Hz); 3.47 (s, 4H); 5.03 (5, 2H); 6.78-6.81 (m, 3H); 6.96-7.02 (m, 1H); 7.12-7.25 (m, 2H, +CDCl3); 7.31-7.36 (m, 1H).
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:4]=[C:5]([C:13]([O-])=[CH:14][C:15](=O)[C:16]([O:18]CC)=[O:17])[CH:6]=[C:7]([O:9][CH:10]([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][NH2:53])[CH:47]=1>>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[N:52]([C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)[N:53]=[C:15]([C:16]([OH:18])=[O:17])[CH:14]=2)[CH:6]=[C:7]([O:9][CH:10]([F:11])[F:12])[CH:8]=1
Reactant: NNc1cccnc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Cl)cc(OC(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Cl)cc(OC(F)F)c2)n(-c2cccnc2)n1

Procedure:
350 mg (0.80 mmol) of the compound of Example 8A is reacted analogously to the synthesis of the compound of Example 20A with 128 mg (0.88 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 176 mg (60% of theory) of the title compound is obtained.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].COCCO>C(N(CC)CC)C>[NH2:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=[C:2]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([CH:18]3[CH2:19][CH2:20][CH2:21][O:17]3)=[O:23])[CH2:25][CH2:26]2)[N:11]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1CCCO1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: COCCO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
Sixty grams (0.25 M) of 2-chloro-4-amino-6,7-dimethoxyquinazoline and 56.8 grams (0.308 M) of N-(2-tetrahydrofuroyl)piperazine were added to a stirred solution of 500 grams of Methyl Cellosolve® (ethylene glycol monomethyl ether) and 37.9 grams of triethylamine. The reaction mixture was heated to and maintained at a temperature of between 115° to 120° C. for 8 hours, and then allowed to cool to room temperature overnight. The Methyl Cellosolve® ether was removed by vacuum distillation, the residue was taken up in 1920 ml of 45° C. filtered water, and the temperature of the solution was readjusted to 45° C. The pH was then adjusted to pH 2.5 with concentrated hydrochloric acid and the solution was mixed for 1 hour. The solution was then filtered and the pH adjusted to pH 8.3 with filtered ammonia water (28%). After heating for 1 hour at 65° C., the solution was cooled to 15° C. and held at a temperature of between 15°-20° C. for 16 hours. The resulting crystalline product was filtered, washed with cold water (15° C.) and dried in vacuo at 65° C. to yield 84 grams of anhydrous base.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:17](C(OC(C)(C)C)=O)[NH:18]C(OC(C)(C)C)=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:33]1[CH:34]=[N:35][N:36](C2CCCCO2)[CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][C:45](O)=O>>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:44]([CH3:45])=[N:18][N:17]=3)[C:11]=2[CH:10]=[C:9]1[C:33]1[CH:34]=[N:35][NH:36][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3cnn(C4CCCCO4)c3)n2Cc2ccccc2)n1
Product: Cc1nnc2ccc3c(cc(-c4cn[nH]c4)n3Cc3ccccc3)n12

Procedure:
di-tert-Butyl 1-{1-benzyl-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-5-yl}hydrazine-1,2-dicarboxylate (68 mg, 0.12 mmol, from Step 2) in AcOH (4 mL) was heated in the microwave to 180° C. for 9 minutes. The acetic acid was removed in vacuo, and the residue was reconstituted in MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (17 mg, 45%).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:12][C:11]2([CH2:17][CH2:16][N:15]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:14][CH2:13]2)[NH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C1COCC1>[CH2:28]([N:10]1[C:11]2([CH2:17][CH2:16][N:15]([C:18](=[O:24])[CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[CH2:14][CH2:13]2)[NH:12][C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:25])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCc1ccccc1
Reactant: CCC(CC)C(=O)N1CCC2(CC1)NC(=O)[C@H](Cc1ccccc1)N2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)C(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1

Procedure:
To a solution of 3-(S)-benzyl-8-(2-ethylbutyryl)-1,4,8-triazaspiro[4,5]decan-2-one (1.0 g, 2.9 mmol) in 40 mL of dry THF there was added sodium hydride (90 mg, 3.8 mmol) at room temperature and under a blanket of nitrogen. Following stirring over a period of 1 h at RT benzyl chloride (1.47 g, 11.6 mmol) was slowly added dropwise and the mixture was then heated over a period of 12 h under reflux. Following the addition of an aqueous saturated HCl solution (20 mL), the reaction mixture was isolated by filtration and the filtrate was extracted with EE (3×15 mL), and the combined organic phases were dried over Na2SO4. Following removal, by distillation, of the solvent, there was obtained the crude product as a yellow oil. Further purification was carried out by column chromatography. The product 1,3-(S)-dibenzyl-8-(2-ethylbutyryl)-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 1.1 g (52%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A mixture of 5 g of p-(p-fluorophenoxy)phenol, 5.1 g of ethyl 2-bromopropionate and 4 g of potassium carbonate is stirred at reflux temperature in 25 ml of acetone for 24 hours. After evaporation of the solvent the residue is taken up in 100 ml of diethyl ether and 100 ml of water. The ether phase is washed with semi-saturated and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The residue is purified by chromatography on silica gel with n-hexane/ethyl acetate (19:1) to yield pure ethyl 2-[p-(p-fluorophenoxy)phenoxy]-propionate; nD20 =1.5304.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32](=[O:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39]Br)=[C:35]([O:41][CH3:42])[CH:34]=1.[OH-].[Na+]>C1COCC1.CO>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:39][C:36]1[CH:37]=[CH:38][C:33]([C:32]([OH:43])=[O:31])=[CH:34][C:35]=1[O:41][CH3:42])=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1COc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)-quinolin-3-yl](phenyl)methanone and 4-Bromomethyl-3-methoxy-benzoic acid methyl ester following the procedure of Example 478 then hydrolysis using sodium hydroxide in THF:MeOH (1:2) at RT for 12 hr, the reaction mixture was acidified and concentrated. The crude residue was purified by reverse phase HPLC to provide the desired compound: mp 100-110° C.; MS (ES) m/z 555.8; HRMS: calcd for C32H22F3NO5+H+, 558.15228; found (ESI, [M+H]+), 558.154.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]#[N:10])=[N:4]1)[CH3:2].C([O-])(=O)C.[K+].[Br:16]Br>C(O)(=O)C>[Br:16][C:6]1[C:5]([C:9]#[N:10])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[CH3:8]
Reactant: BrBr
Reactant: CCn1nc(C#N)cc1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCn1nc(C#N)c(Br)c1C

Procedure:
1-Ethyl-5-methyl-1H-pyrazole-3-carbonitrile (2.98 g, 22.0 mmol) was treated with potassium acetate (4.93 g, 31.0 mmol) and bromine (3.87 g, 24.0 mmol) in glacial acetic acid (43 mL) according to the general method described in Part F of Examples 1-4. Methyl tert-butyl ether was used instead of dichloromethane in the extraction during the work-up. The organic layers were combined and concentrated under reduced pressure to yield 4-bromo-1-ethyl-5-methyl-1H-pyrazole-3-carbonitrile as a white solid.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.C(O)(=O)C>[Zn].O>[ClH:1].[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc2sc(C(=O)N[C@@H]3CN4CCC3CC4)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
422 mg (1.15 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzo-thiophene-2-carboxamide hydrochloride are suspended in 10 ml of a 1:1 mixture of acetic acid and water. 300.0 mg (4.59 mmol) of zinc are added, the mixture is then stirred at RT for 1 h. The reaction mixture is filtered through kieselguhr, and the filter cake is washed with methanol. The filtrate is concentrated under reduced pressure and the residue is purified by preparative HPLC. The product fraction is dissolved in 4M of HCl in dioxane, concentrated under reduced pressure and recrystallized from acetonitrile. 203 mg (47.3% of theory) of the title compound are obtained. The analytical data correspond to those of the enantiomeric compound from example 62.
Reaction SMILES: C([Mg]Cl)(C)C.[Br:6][C:7]1[CH:8]=[CH:9][C:10](I)=[N:11][CH:12]=1.[CH:14]1([C:17]([CH:25]2[CH2:27][CH2:26]2)=[N:18][S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])[CH2:16][CH2:15]1.[NH4+].[Cl-]>C1COCC1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]([CH:25]2[CH2:27][CH2:26]2)([CH:14]2[CH2:15][CH2:16]2)[NH:18][S@@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])=[N:11][CH:12]=1
Reactant: Brc1ccc(I)nc1
Reactant: CC(C)(C)[S@@](=O)N=C(C1CC1)C1CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)NC(c1ccc(Br)cn1)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (2 M in THF, 1.843 mL, 3.69 mmol) was added dropwise over 5 minutes to a cooled solution of 5-bromo-2-iodopyridine (0.999 g, 3.52 mmol) in THF (7.00 mL) under Ar(g) at 0° C. and then the reaction mixture was stirred for 1 hour. A solution of (R)—N-(dicyclopropylmethylidene)-2-methylpropane-2-sulfinamide (0.715 g, 3.35 mmol) in THF (3.00 mL) was added via syringe over 4 min at 0° C. to the reaction mixture. The reaction mixture was stirred at 0° C. for 1 hour and was warmed to room temperature. Saturated aqueous NH4Cl (15.0 mL) was added to the reaction and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated aqueous NaHCO3, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0.5-3% methanol in dichloromethane) to yield (R)—N-[(5-bromopyridin-2-yl)(dicyclopropyl)methyl]-2-methylpropane-2-sulfinamide as a yellow oil. MS APCI calc'd for C16H24BrN2OS [M+H]+ 371 and 373. found 371 and 373.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+]([O-])=O)=[C:5]([N+:10]([O-:12])=[O:11])[N:4]=[CH:3]1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O>[CH3:1][N:2]1[C:6]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([N+:10]([O-:12])=[O:11])[N:4]=[CH:3]1
Reactant: Oc1ccccc1
Reactant: Cn1cnc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cnc([N+](=O)[O-])c1Oc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A mixture of 17.2 g (0.1 mole) of 1-methyl-4,5-dinitroimidazole, 11.2 g (0.12 mole) of phenol and 4.4 g (0.11 mole) of NaOH in 200 ml of water was stirred for 1 hour at 50° C. Thereafter, the solution was diluted with a further 300 ml of water and was cooled. The precipitated crystals were filtered off under suction and recrystallized from water. 21.0 g (96%) of 1-methyl-4-nitro-5-phenoxyimidazole of melting point 116°-118° C. were obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:40][CH2:41][CH2:42][CH3:43]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:40][CH2:41][CH2:42][CH3:43])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCI
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 10.7 mg, 0.025 mmol) in DMF (1.0 ml) was reacted with K2CO3 (10.0 mg, 0.074 mmol) and 1-iodobutane (14.0 μl, 0.12 mmol) to yield the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[NH2:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([Cl:13])[N:7]=1.C(O)C>C(N(CC)CC)C>[NH2:5][C:6]1[N:11]=[C:10]([NH:4][CH2:3][CH2:2][OH:1])[CH:9]=[C:8]([Cl:13])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NCCO
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1nc(Cl)cc(NCCO)n1
Yield: 59.6 %

Procedure:
To 2-hydroxyethylamine (2.6 g, 42.7 mmol) were added 2-amino-4,6-dichloropyrimidine (7.0 g, 42.7 mmol), ethanol (150 ml) and triethylamine (6.6 ml), and the mixture was refluxed for one day. The solvent was distilled away under reduced pressure and the residue was washed with water, which was followed by recrystallization from chloroform to give yellow prism crystals (4.8 g, 59.6%), m.p. 143-146° C. (chloroform).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].C1(C)C(S([CH2:23][N+:24]#[C-:25])(=O)=O)=CC=CC=1.C[O-].[Na+]>CO>[CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH3:13])=[CH:6][C:3]=1[C:4]1[O:5][CH:25]=[N:24][CH:23]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc([N+](=O)[O-])c(C)cc1-c1cnco1
Temperature: 90 °C

Procedure:
To a mixture of 2,5-dimethyl-4-nitrobenzaldehyde (75 mg, 0.42 mmol) and toluenesulfonylmethyl isocyanide (TOSMIC) (98 mg, 0.5 mmol) in methanol (2 mL), was added sodium methoxide (68 mg, 1.26 mmol). The mixture was sealed and heated at 90° C. for 15 hr. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated. The 5-(2,5-Dimethyl-4-nitrophenyl)oxazole obtained was used in the next step without purification.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][OH:18])=[O:14].ClC(Cl)(Cl)C(=N)O[CH2:34][CH:35]=[CH2:36].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][O:18][CH:34]=[CH:35][CH3:36])=[O:14]
Reactant: COC(=O)[C@H](CO)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC=COC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluoromethanesulfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95°-97° C.