Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(c2ccc(O)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-((2,2-dimethylethyl)-dimethylsiloxy)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1) 75.0 mg (0.143 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.01 (2H, d, J=8.3 Hz), 7.59 (2H, d, J=8.4 Hz), 7.45 (2H, s), 7.20-7.17 (3H, m), 6.92-6.89 (2H, m), 5.97 (1H, t, J=4.7 Hz), 2.35 (2H, d, J=4.7 Hz), 1.34 (6H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.[O:17]1CCC[CH2:18]1.C([Li])CCC.[Cl-].[NH4+]>CCCCCC.CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:18]=[O:17])=[CH:12][CH:11]=1
Reactant: Brc1ccc(CCOC2CCCCO2)cc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(CCOC2CCCCO2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 11.3 g of 4-(2-(2-tetrahydropyranyloxy)ethyl)-1-bromobenzene and 100 ml of tetrahydrofuran was cooled to −78° C., to which 25.9 ml of 1.56 M solution of n-butyl lithium in n-hexane was added dropwise over 15 minutes. After stirring at −78° C. for 1 hour, 4.2 ml of N,N-dimethylformamide was added dropwise at the same temperature over 15 minutes. After further stirring at −78° C. for 1 hour, 100 ml of saturated aqueous ammonium chloride solution was added, and the stirring was further continued until the reaction mixture came to room temperature. The reaction mixture was extracted twice with 200 ml of ethyl acetate, and the ethyl acetate layers were combined, washed three times with saturated aqueous ammonium chloride solution, and washed with saturated aqueous sodium chloride solution. The combined ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a residue. This residue was subjected to silica gel chromatography, which afforded 7.20 g (yield, 78%) of 4-(2-(2-tetrahydropyranyloxy)ethyl)-benzaldehyde, nD24.5 1.5311.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].N1C=CC=CC=1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>ClCCl>[OH:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[NH:1][C:18](=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a solution of 2-amino-4-nitrophenol (10 g, 64.9 mmol) in dichloromethane (250 mL) under nitrogen at 0° C. was added pyridine (10.5 mL, 129.9 mmol) followed by butyryl chloride (7.05 mL, 68.2 mmol) over a period of 5 min. After 30 min at 0° C., the solution was left warming up to room temperature for 2 days. The organic layer was washed with aqueous copper sulfate solution and brine. Insoluble material from the aqueous layer was filtered off and washed with water to afford 4.95 g (34%) of the title compound.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][CH2:5][CH:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1)[CH2:7][CH3:8].Cl>C1COCC1.O>[CH3:4][CH2:5][CH:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1)[CH2:7][CH3:8]
Reactant: CCOC(=O)c1csc(C(CC)CC)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)c1nc(C(=O)O)cs1
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (2.07 g) was added to a solution of ethyl 2-(pentan-3-yl)thiazole-4-carboxylate (example 71, step c) (2.8 g) in a mixture of THF (80 mL) and water (20 mL). The resulting mixture was stirred overnight. The reaction was acidified with concentrated hydrochloric acid (6 mL) and the volatiles evaporated. The resulting aqueous mixture was saturated with sodium chloride and extracted with ethyl acetate (3×100 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a white solid. Yield 2.3 g
Reaction SMILES: N[CH:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:37].Cl>C(N(CC)CC)C>[O:37]=[C:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18][CH:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nncs3)CS[C@H]12
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CSc2nncs2)CS[C@@H]2C(=O)C(=O)N12

Procedure:
Benzhydryl 7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylate, trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid were reacted in the same manners as those of Examples 1-4 to give benzhydryl 7-oxo-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylate.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](NCCO)=[O:19].[Na].CCCCCCCCCC1C=CC([OH:40])=CC=1>>[C:18]([OH:19])(=[O:40])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCO
Agent: [Na]
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
(a-4) Mixture of 8 parts of stearic acid monoethanolamide (1:1) and 2 parts of sodium salt of nonylphenol-EO(4) sulfate
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[NH2:9][CH2:10][CH2:11][NH2:12].Cl>CO.O>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][NH:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:5]=1
Reactant: C=Cc1ccncc1
Reactant: NCCN
Agent: Cl
Solvent: O
Solvent: CO
Product: NCCNCCc1ccncc1

Procedure:
A solution of 4-vinylpyridine (52.5 g) in methanol (250 cm3) was added dropwise over 2 hours to a stirred solution of 1,2-diaminoethane in methanol (500 cm3) and water (500 cm3) under reflux in the presence of an excess of concentrated hydrochloric acid (pH1). After a further 1.5 hours the mixture was concentrated in vacuo and basified to pH9 with 4M sodium hydroxide solution. The solution was extracted with chloroform (4×150 cm3) and the dried (MgSO4) extracts were evaporated in vacuo to give an oil. Distillation gave N-[2-(4-pyridyl)ethyl]-1,2-diaminoethane as a colourless oil, b.p. 119°-122°/0.09 mm (27.0 g).
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C1(C([O:28][C:29]([C:31]2[N:32]3[CH:35]([CH2:36][CH2:37][C:38]=2[S:39][C:40]2[S:41][C:42]([NH2:45])=[N:43][N:44]=2)[C@@H:34]([NH:46][C:47](=[O:77])/[C:48](/[C:70]2[N:71]=[C:72]([NH2:76])[S:73][C:74]=2[Cl:75])=[N:49]\[O:50]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:33]3=[O:78])=[O:30])C2C=CC=CC=2)C=CC=CC=1>ClCCl>[NH2:76][C:72]1[S:73][C:74]([Cl:75])=[C:70](/[C:48](=[N:49]/[OH:50])/[C:47]([NH:46][C@H:34]2[C:33](=[O:78])[N:32]3[CH:35]2[CH2:36][CH2:37][C:38]([S:39][C:40]2[S:41][C:42]([NH2:45])=[N:43][N:44]=2)=[C:31]3[C:29]([OH:30])=[O:28])=[O:77])[N:71]=1
Reactant: Nc1nnc(SC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4nc(N)sc4Cl)C3CC2)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(SC2=C(C(=O)O)N3C(=O)[C@H](NC(=O)/C(=N\O)c4nc(N)sc4Cl)C3CC2)s1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of trifluoroacetic acid (10 mL), triethylsilane (5 mL) and dichloromethane (10 mL) was cooled to 0° C. and (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino]acetamido]-3-[5-amino-1,3,4-thiadiazol-2-ylthio]-8-oxo-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester from the previous step (2.3 g) was added in portions. The reaction mixture was stirred for 3 hours at 0° C., allowed to warm up to room temperature and evaporated to dryness. The residue was treated with diethyl ether (50 mL) and the solid that formed was filtered and dried to give 2.4 g of crude product. The crude product was purified on HP 20 initially with water elution until the pH was neutral, after which the product was eluted with acetonitrile:water 80:20. The solvent was evaporated to give the 0.65 g of the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid was prepared starting from 1-benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (3 g, 6.6 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 1.65 g (59%); off white powder; mp 191° C.; MS: 428 (M+H)+
Reaction SMILES: [Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([O:19]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:31])[C:27]([S:29][CH3:30])=[CH:28][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:1][C:2]1[N:6]([C@@H:7]2[O:24][CH2:23][C@@H:18]([OH:19])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Cl:31])[C:27]([S:29][CH3:30])=[CH:28][C:4]=2[N:3]=1
Reactant: CSc1cc2nc(Br)n([C@@H]3OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CSc1cc2nc(Br)n([C@@H]3OC[C@@H](O)[C@@H](O)[C@H]3O)c2cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
An ethanolic solution of 2-bromo-6-chloro-5-methylthio-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (0.057 g, 0.09 mmol) was deprotected in a modification of General Procedure VI with 0.044 g (0.41 mmol) of sodium carbonate in 0.5 ml of water. After stirring 1.5 h at ambient temperature, the mixture was treated as described in General Procedure VI. The product was dried overnight in vacuo to give 2-bromo-6-chloro-5-methylthio-1-beta-D-ribopyranosyl-1H-benzimidazole (0.042 g, 0.08 mmol, 98% yield). 1H NMR (DMSO-d6) δ7.79 (s, 1H), 7.49 (s, 1H), 5.61-5.59 (d, 1H), 5.16-5.12 (m, 2H), 4.86-4.84 (d, 1H), 3.98 (m, 3H), 3.68-3.65 (m, 2H), 2.49 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]=[C:11]([NH:23][NH2:24])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]#[N:28].CCOC(C)=O>CCO>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:27]([NH2:28])=[N:24][N:23]=[C:11]2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CBr
Reactant: CC(C)(C)OC(=O)NCc1cc(NN)ncc1-c1ccc(Cl)cc1Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cc2nnc(N)n2cc1-c1ccc(Cl)cc1Cl
Temperature: 65 °C
Yield: 51.3 %

Procedure:
A mixture of the crude [5-(2,4-dichloro-phenyl)-2-hydrazino-pyridin-4-ylmethyl]-carbamic acid tert-butyl ester (1.66 g) and BrCN (638 mg, 6.0 mmol) in EtOH (40 mL) was heated at 65° C. and stirred for 2 h30. The reaction mixture was cooled to RT, poured into AcOEt (100 mL) and washed with a 2.0 M aqueous Na2CO3 solution (2×50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM/MeOH 95:5→4:6) to yield the title compound (908 mg, 2.22 mmol, 74% over 2 steps) as a brownish solid. MS: 408 [M+1]+; HPLC: AtRet=1.62; TLC: RF 0.16 (DCM/MeOH 95:5).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)=[O:6].Cl[C:14]1[N:15]=[C:16]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][S:20][C:18]=2[N:19]=1>>[OH:1][CH2:2][CH2:3][NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:14]2[N:15]=[C:16]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:17]3[C:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][S:20][C:18]=3[N:19]=2)[CH2:8]1)=[O:6]
Reactant: O=C(NCCO)[C@H]1CCCNC1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Product: O=C(NCCO)[C@H]1CCCN(c2nc(NCc3ccccn3)c3c(-c4ccccc4)csc3n2)C1

Procedure:
(S)-Piperidine-3-carboxylic acid (2-hydroxy-ethyl)-amide was reacted with (2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine as in Example 6 above to give (S)-1-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-d]pyrimidin-2-yl}-piperidine-3-carboxylic acid (2-hydroxy-ethyl)-amide as a yellow foam (188 mg).
Reaction SMILES: C[O-].[Na+].Br[C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([I:13])[N:6]=1.[C:14]([O-])(O)=[O:15].[Na+].C(Cl)Cl>CN(C=O)C>[I:13][C:7]1[N:6]=[C:5]([O:15][CH3:14])[C:10]([O:11][CH3:12])=[CH:9][CH:8]=1
Reactant: COc1ccc(I)nc1Br
Reactant: O=C([O-])O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1OC
Temperature: 100 °C

Procedure:
Add NaOMe (1.4 equiv., 1.25 g, 23.14 mmol) to 2-bromo-6-iodo-3-methoxypyridine, 3 (4.95 g, 15.76 mmol) dissolved in DMF (10 mL), and stir the reaction medium, heating at 100° C. under N2 for 1 h. After cooling, the reaction mixture is shared between saturated NaHCO3 and CH2Cl2, and the organic phase is dried (MgSO4) and concentrated. Purification on SiO2 (EtOAc at 10%/heptane) gives 4 (3.13 g, 74.9% as a white solid: 1H NMR (CDCl3) δ 7.25 (d, 1H, J=7.8 Hz), 6.76 (d, 1H, J=8.1 Hz), 4.03 (s, 3H), 3.87 (s, 3H); m/z obs.=266 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Br:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: COc1ccc(CN)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cccc(Br)n2)cc1
Yield: 91.3 %

Procedure:
A solution of 2,6-dibromopyridine (14-1) (37.3 g, 157 mmol), 4-methoxybenzylamine (21.6 g, 157 mmol), and diisopropylethylamine (22.4 g, 173 mmol) in 1,4-dioxane (150 mL) was heated at reflux for 24 h. The reaction mixture was cooled, concentrated in vacuo, and the residue was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (125 mL). The organic layer was washed with water (100 mL) followed by brine (100 mL) and dried (Na2SO4). The organic layer was filtered, concentrated in vacuo, and purified by flash chromatography (silica, 10% to 40% EtOAc/hexanes) affording 42 g of amine 14-2 as a white solid in 91% yield. 1H NMR (300 Mz, CDCl3): δ 8 7.26-7.22 (m, 3H), 6.88-6.86 (m, 2H), 6.75-6.73 (d 1H), 6.27-6.25 (d, 1H), 4.98-4.96 (br s, 1H), 4.39-4.37 (d, 2H), 3.80 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][C:18]([CH:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[OH:22])=[CH:17][CH2:16]2)=[CH:10][CH:9]=1.[F:33][C:34]1[CH:35]=[C:36]([N:41]=[C:42]=[O:43])[CH:37]=[C:38]([F:40])[CH:39]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([O:22][CH:21]([C:18]2[CH2:19][CH2:20][N:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:9][CH:10]=3)[CH2:16][CH:17]=2)[C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)=[O:43])[CH:37]=[C:38]([F:40])[CH:39]=1
Reactant: OC(C1=CCN(Cc2ccc(Oc3ncccn3)cc2)CC1)c1ccc(C(F)(F)F)cc1
Reactant: O=C=Nc1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(F)cc(F)c1)OC(C1=CCN(Cc2ccc(Oc3ncccn3)cc2)CC1)c1ccc(C(F)(F)F)cc1
Yield: 30.2 %

Procedure:
This compound was prepared in a manner analogous to that of Step F of Example 2, using 0.44 gram (0.0010 mole) of {1-[(4-pyrimidin-2-yloxyphenyl)methyl](4-1,2,5,6-tetrahydropyridyl)}[4-(trifluoromethyl)phenyl]methanol, 0.21 gram (0.0014 mole) of 3,5-difluorophenylisocyanate, 0.14 gram (0.0014 mole) of triethylamine, and 0.05 gram (catalyst) of 4-dimethylaminopyridine in 15 mL of methylene chloride. The reaction product was purified with column chromatography on silica gel using 10% to 25% acetone/methylene chloride mixtures as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.18 gram of Compound 786, mp 85–92° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:23](=[O:25])[CH3:24])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(4-Nitrophenyl)piperazine (2.5 g, 12.1 mmol) was dissolved in dichloromethane (100 ml). Triethylamine (2.0 ml, 14.5 mmol) was added and the reaction was cooled to 0° C. Acetic anhydride (1.25 ml, 13.3 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. Saturated sodium bicarbonate was added and the reaction was extracted (×3) with dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to give 4-(4-nitrophenyl)-1-acetylpiperazine as a yellow solid (3.01 g,). GC/MS (EI, M+) m/z=249.
Reaction SMILES: I(Cl)(=O)=O.I([Cl:8])(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([C:34](=[O:36])[CH3:35])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[Cl:8][CH2:35][C:34]([C:28]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[CH:27]=1)=[O:36]
Reactant: COc1ccc(C(C)=O)cc1OC1CCCC1
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CCl)cc1OC1CCCC1
Yield: 36.5 %

Procedure:
Under a N2 flow, a solution of benzyltrimethylammonium dichloroiodate (78 g) in THF (250 ml) was added to a mixture of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone (26.3 g) in THF (250 ml) while stirring. The resulting reaction mixture was stirred for 16 hours at RT. The solvent was evaporated and the residue was redissolved in diethyl ether (300 ml). The mixture was added dropwise to a 5% Na2S2O4 solution (400 ml). The aqueous layer was extracted twice with diethyl ether (100 ml). The combined organic layers were washed twice with water (500 ml), dried (MgSO4), filtered and the solvent evaporated. The crude oil was crystallized from hexane. The precipitate was filtered off, washed with hexane and dried, yielding 11 g of 2-chloro-1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone. The filtrate was evaporated and the residue was crystallized from hexane. The precipitate was filtered off and dried, yielding 7.4 g (24.6%) of 2-chloro-1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone (interm. 1).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][S:15][C:9]=3[NH:10][C:11](=S)[CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([NH:21][NH2:22])(=[O:20])[CH3:19].O>C(O)C>[C:18]([NH:21][NH:22][C:11]1[CH2:12][N:13]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:17]=[CH:16][S:15][C:9]=2[N:10]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)NN
Reactant: S=C1CN=C(c2ccccc2)c2ccsc2N1
Solvent: O
Solvent: CCO
Product: CC(=O)NNC1=Nc2sccc2C(c2ccccc2)=NC1

Procedure:
1.5 g (0.00582 mol) of 1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepine-2-thione are heated to reflux for 4 hours under a nitrogen atmosphere with 1.3 g (0.0175 mol) of acetyl hydrazine in 120 ml of absolute ethanol. The solvent is evaporated and the crystals obtained are shaken with water in a separating funnel. After filtration under a vacuum, the product is recrystallized from ethyl acetate containing active carbon to give colorless crystals of 2-(2-acetylhydrazino)-5-phenyl-3H-thieno[2,3-e]-1,4-diazepine, melting point 194°-196° C. (transition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH:14]=O)[C:7](=[O:16])[CH:6]=[N:5]2.[NH2:17][CH2:18][C@@H:19]1[CH2:23][N:22]([C:24]2[CH:25]=[CH:26][C:27]3[O:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=3[N:33]=2)[C:21](=[O:35])[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][NH:17][CH2:18][C@@H:19]1[CH2:23][N:22]([C:24]3[CH:25]=[CH:26][C:27]4[O:28][CH2:29][C:30](=[O:34])[NH:31][C:32]=4[N:33]=3)[C:21](=[O:35])[CH2:20]1)[C:7](=[O:16])[CH:6]=[N:5]2
Reactant: O=CCCn1c(=O)cnc2cc(F)ccc21
Reactant: NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1COc2ccc(N3C[C@@H](CNCCCn4c(=O)cnc5cc(F)ccc54)CC3=O)nc2N1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 3-(6-fluoro-2-oxoquinoxalin-1(2H)-yl)propanal (0.1 g, 0.45 mmol), 6-[(4R)-4-(aminomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Examples 54, 0.11 g, 0.45 mmol) DMF (3 ml) and molecular sieve (4 A, 0.1 g) was stirred at room temperature for 20 minutes. The reaction mixture was cooled on ice and sodium triacetoxyborohydride (0.12 g, 0.54 mmol) was gradually added thereto. Then, the mixture was stirred at room temperature for 4 hours, a sodium hydrogen carbonate aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The obtained crude product was purified by thin layer chromatography (dichloromethane/methanol) to yield the title compound. 8 mg (2%).