Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O.[CH2:19]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>C(#N)C>[CH2:10]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][CH2:17][N:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:20][CH2:21][CH3:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCCNCCCC
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: C=O
Solvent: CC#N
Product: CCCCN(CCCC)CON(Cc1ccccc1)Cc1ccccc1

Procedure:
The procedure of Example I is repeated using 21.33 g of dibenzylhydroxylamine, 9.73 g of aqueous formaldehyde (37%) solution and 12.93 g of di-n-butylamine in acetonitrile to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:2].Cl[CH:23]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCN(CC)CC>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][N:18]([CH:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:17][CH2:16]1)[CH3:2]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)nc2ccccc21

Procedure:
A solution of compound 15 (2 mmols) and 21 (2 mmols) in methylene chloride (10 mL) and Et3N (0.3 mL) is stirred under an inert atmosphere. The solution is warmed and the course of the reaction is followed by TLC. When the reaction is complete, dil. aq. Na2CO3 is added to the solution, shaken, and the layers are separated. The aqueous layer is extracted with additional CH2Cl2, the combined organic extracts are washed with half-saturated brine, dried (Na2SO4), filtered and concentrated under reduced pressure giving the crude product. The desired compound 1-(2-ethoxyethyl)-2-[hexahydro-4-(4-chlorobenzhydryl)-1H-1,4-diazepin-1-yl]-1H-benzimidazole 25 is obtained by purification of the crude product with the use of HPLC.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[N+:13]([O-:15])=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: C1CCNC1
Product: COC(=O)c1ccc(CN2CCCC2)c([N+](=O)[O-])c1
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield by essentially following the procedures outlined in Example 34, Part A, from methyl 4-bromomethyl-3-nitrobenzoate (Part A, above) and pyrrolidine.
Reaction SMILES: [Cl-].[Li+].[Cu](C#N)C#N.[CH:8]1([Mg]Cl)[CH2:12][CH2:11][CH2:10][CH2:9]1.C(OCC)C.[C:20]([O:24][CH3:25])(=[O:23])[C:21]#[CH:22].[I:26]I>O1CCCC1>[CH3:25][O:24][C:20](=[O:23])/[C:21](/[I:26])=[CH:22]\[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: II
Reactant: C#CC(=O)OC
Reactant: Cl[Mg]C1CCCC1
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)/C(I)=C\C1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
A mixture of lithium chloride (8.48 g, 200 mmol, predried at 130° C. under high vacuum for 3 h) and copper cyanide (8.96 g, 100 mmol) in dry tetrahydrofuran (100 mL) was stirred at 25° C. under argon for 10 min to obtain a clear solution. The reaction mixture was then cooled to −70° C. and then slowly treated with a 2.0M solution of cyclopentylmagnesium chloride in diethyl ether (55 mL, 110 mmol). After the addition, the reaction mixture was allowed to warm to −30° C. where it was stirred for 5 min. The resulting reaction mixture was again cooled back to −70° C. and then slowly treated with methyl propiolate (7.99 g, 95 mmol). The reaction mixture was stirred overnight at −60° C. to −50° C. The reaction mixture was then slowly treated with a solution of iodine (34.3 g, 135 mmol) in dry tetrahydrofuran (30 mL), with the temperature kept at −70° C. to −60° C. After addition of the iodine solution, the cooling bath was removed, and the reaction mixture was allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then poured into a solution consisting of a saturated aqueous ammonium chloride solution (200 mL) and ammonium hydroxide (50 mL), and the organic compound was extracted into diethyl ether (3×100 mL). The combined organic extracts were successively washed with a saturated aqueous sodium thiosulfate solution (1×300 mL) and a saturated aqueous sodium chloride solution (1×300 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 20/1 hexanes/diethyl ether) afforded (E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (25.8 g, 97%) as a yellow oil: EI-HRMS m/e calcd for C9H13IO2 (M+) 279.9960, found 279.9961.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.Cl.[Cl:10][C:11]1[CH:36]=[CH:35][C:14]2[O:15][C:16]3[CH:34]=[CH:33][CH:32]=[CH:31][C:17]=3[C@@H:18]3[C@H:23]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21][CH2:20][N:19]3[C:13]=2[CH:12]=1>CC(C)=O>[Cl:1][C:12]1[C:13]2[N:19]3[CH2:20][CH2:21][CH2:22][C@@H:23]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[C@H:18]3[C:17]3[CH:31]=[CH:32][CH:33]=[CH:34][C:16]=3[O:15][C:14]=2[CH:35]=[CH:36][C:11]=1[Cl:10].[Cl:10][C:11]1[C:36]([Cl:1])=[CH:35][C:14]2[O:15][C:16]3[CH:34]=[CH:33][CH:32]=[CH:31][C:17]=3[C@@H:18]3[C@H:23]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21][CH2:20][N:19]3[C:13]=2[CH:12]=1
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CC(C)=O
Product: O=C(N[C@@H]1CCCN2c3c(ccc(Cl)c3Cl)Oc3ccccc3[C@H]12)C(F)(F)F
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)c(Cl)cc3Oc3ccccc3[C@H]12)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 7 %
Yield: 17 %

Procedure:
N-chlorosuccinimide (6.87 mg, 0.05 mmol) and 0.5 μL 1N HCl was added to trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (20 mg, 0.05 mmol) in 102 μL of acetone. The resulting mixture was stirred at room temperature for 18 h. No reaction was observed. The reaction was repeated under the same conditions. The resulting mixture was stirred at room temperature for 1.5 h. The organic layer was washed with saturated aq. sodium bicarbonate and water, dried (Na2SO4) and evaporated and the crude compound was purified by preparative HPLC to give trans-N-(6,7-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (3.6 mg, 17%) and trans-N-(7,8-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (1.6 mg, 7%). Data: (m/z)=431 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14].[N+:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1)([O-:17])=[O:16].[OH-:25].[K+]>CS(C)=O.O>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:21]2[CH:22]=[CH:23][C:18]([N+:15]([O-:16])=[O:25])=[CH:19][CH:20]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: [OH-]
Reactant: Oc1ccccc1-c1ccccc1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 80 °C
Yield: 76.7 %

Procedure:
18.62 g (0.1 mol) of 2,2'-dihydroxy-biphenyl and 28.22 g (0.2 mol) of p-nitrofluorobenzene are dissolved in 80 ml of dimethylsulphoxide in a sulphonation flask and the solution is warmed to 80° C. A solution of 13.2 g (0.2 mol) of 85% pure potassium hydroxide in 10 ml of water is then added dropwise, whilst stirring, and the reaction solution is subsequently further stirred for 3 hours at 100°-110° C. During this time a yellow precipitate forms and after the reaction mixture has cooled this is separated off by decanting off the supernatant liquor and is then washed several times with water. After drying, the crude product is recrystallised from ethanol. 32.86 g (77% of theory) of 2,2'-di-(p-nitrophenoxy)-biphenyl of analytical purity are obtained in the form of slightly yellowish crystals with a melting point of 158° C.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C@H:14]([C:22](O)=[O:23])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C@@H:59]([CH2:80][C:81]1[N:82]=[CH:83][NH:84][CH:85]=1)[C:60]([NH:62][C@@H:63]([CH2:73][CH:74]1[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]1)[C@@H:64]([OH:72])[CH2:65][C@@H:66]([CH:69]([CH3:71])[CH3:70])[CH:67]=[CH2:68])=[O:61].CCN(C(C)C)C(C)C>C(#N)C>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C@H:14]([C:22](=[O:23])[NH:58][C@H:59]([C:60](=[O:61])[NH:62][C@@H:63]([CH2:73][CH:74]2[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79]2)[C@@H:64]([OH:72])[CH2:65][C@@H:66]([CH:69]([CH3:70])[CH3:71])[CH:67]=[CH2:68])[CH2:80][C:81]2[N:82]=[CH:83][NH:84][CH:85]=2)[CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:12])=[CH:5][CH:6]=1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: O=C(NCCOc1ccc(-c2ccccc2)cc1)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)NCCOc1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.5 %

Procedure:
A solution of 103 mg of N-[[2-(4-biphenyloxy)ethyl ]carbamoyl]-3-phenyl-L-alanine and 113 mg of BOP in acetonitrile was added to 100 mg (0.256 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide 0.052 ml of Hunig base in 5 ml of acetonitrile, and the mixture was subsequently stirred at room temperature for 12 hours. Subsequently the reaction mixture was poured onto 1N hydrochloric acid/ice, extracted with ethyl acetate, the extracts were dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by chromatography on silica gel with a 10:1 mixture of methylene chloride and methanol, to obtain 90 mg (45%) of 1-[2-(4-biphenyloxy)ethyl]-3-[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]- carbamoyl]phenethyl]urea as an amorphous powder. MS: 777 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[C:10]([C:11]=1[OH:12])=[CH:9][CH:8]=[CH:7][N:6]=2.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.C(Cl)Cl>[OH-:12].[OH:12][C:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3](=[O:19])[C:2]=1[NH+:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: O=c1c(Br)c(O)c2cccnc2n1-c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1c([NH+]2CCCC2)c(O)c2cccnc2n1-c1ccccc1
Product: [OH-]
Temperature: 100 °C

Procedure:
A solution of 3-bromo-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (2 g) in a mixture of pyrrolidine (10 mL) and DMF (5 mL) was stirred and heated at 100° C. for 2 days. The resulting mixture was then cooled, diluted with CH2Cl2 (100 mL) and filtered. The solid was triturated with hot CHCl3, filtered, and dried to yield the desired product, m.p. 282°-284° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[C:8]1([CH2:13][CH2:12][C:11](=[O:14])[NH:10][C:9]1=[O:15])[CH2:7][CH2:6][C:5]2=[O:19].[CH:20](O)(C)C>>[CH3:20][N:10]1[C:11](=[O:14])[CH2:12][CH2:13][C:8]2([C:16]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:18][CH:17]=3)[C:5](=[O:19])[CH2:6][CH2:7]2)[C:9]1=[O:15]
Reactant: Cc1ccc2c(c1)C(=O)CCC21CCC(=O)NC1=O
Reactant: CC(C)O
Product: Cc1ccc2c(c1)C(=O)CCC21CCC(=O)N(C)C1=O
Yield: 80 %

Procedure:
Following the procedure noted in Example 5, 38.6 grams (0.15 M) of 2,3-dihydro-6-methylspiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione was methylated to give 32.5 grams (80%) of 1',6-dimethyl-2,3-dihydrospiro-[naphthalene-1(4H),3'-piperidine]-2',4,6'-trione, melting point 146°-147.5° C. from isopropyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:25]=[C:26]1[NH:31][CH2:30][CH2:29][CH2:28][N:27]1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[N:14]2[CH3:24])[CH2:10][CH2:11][N:35]2[CH2:36][CH2:37][CH:32]([N:27]3[CH2:28][CH2:29][CH2:30][NH:31][C:26]3=[O:25])[CH2:33][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CN1C(=O)c2c(O)cccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Product: CN1C(=O)c2c(O)cccc2C1C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 156.4 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(4-hydroxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.31 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.156 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.378 g); mp 225°-240° C.; MS: m/z=531(M+1); NMR(CD3SOCD3): 1.60 (m,2), 1.65 (m,2), 2.98 (s,3), 4.37 (broad,1), 4.76 (d,1, J=3.5), 6.82 (m,2), 7.37 (m,4). Analysis for C27H32Cl2N4O3.1.2 HCl.1.0 H2O: Calculated: C, 54.66; H, 5.98, N, 9.44; Found: C, 54.70; H, 5.76; N, 9.15.
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)=[CH:4][S:3]1.[NH2:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12>>[O:1]=[C:2]1[S:6][C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:14][CH:15]2[C:32](=[O:33])[N:17]3[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]4[S:25][CH:26]=[N:27][N:28]=4)[CH2:20][S:21][C@H:16]23)=[O:10])=[CH:4][S:3]1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CON=C(C(=O)O)c1csc(=O)s1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(=O)s1

Procedure:
2-(2-Oxo-1,3-dithiol-4-yl)-2-methoxyiminoacetic acid (anti isomer, 0.7 g.) was allowed to react with 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.06 g.) in a similar manner to that of Example 1 to give the captioned compound (0.85 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[NH:11][C:10](=[O:15])[CH:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>CN(C=O)C>[Br:23][C:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][C:10](=[O:15])[NH:11][C:12]=1[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(=O)[nH]1
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)cc(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 16.7 %

Procedure:
To a solution of 4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one (1.1 g, 5.0 mmol) in DMF (20 mL) was added NBS (1.07 g, 6.0 mmol) in small portions over 15 min. The reaction mixture was stirred at room temperature for 20 min. Analysis by HPLC/MS indicated the starting 4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one was consumed, and about 17% (based on the UV absorption) of the desired product had formed. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The resulting suspension was filtered, and the collected solid was washed with water, the dried in a vacuum oven at 50° C. for 16 h to afford 250 mg (17%) of the title compound as an off-white solid. HPLC/MS: retention time=3.35 min, [M+H]+=298.2.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6].[NH3:14]>[Cl-].[Na+].O>[NH2:14][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[C:5]#[N:6]
Reactant: N
Reactant: N#Cc1ccc(C(F)(F)F)c(F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)c(N)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A closed pressure tube charged with 3-fluoro-4-(trifluoromethyl)benzonitrile (10.0 g; 52.9 mmol) and liquid NH3 (60 mL) was heated for 6 days at 90° C. The tube was cooled to −60° C. and opened. The mixture was allowed to stir for 1 h at rt. The residue was treated with brine and extracted with EtOAc to give the crude sub-title compound (10.2 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=O)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cc(CN2CCOCC2)cc(Cl)c1F

Procedure:
was prepared according to Scheme C2 (step C) from (3-chloro-2-fluoro-5-formyl-benzyl)-carbamic acid tert-butyl ester (220 mg, 0.65 mmol), morpholine (57 mg, 0.65 mmol), acetic acid (0.056 mL, 0.9 mmol) and sodium triacetoxyborohydride (344 mg, 1.6 mmol) in THF (8 mL). TLC, Rf (EtOAc)=0.44; MS (LC-MS): 359.0 [M]+.
Reaction SMILES: [Cl:1][O-:2].[Na+:3].[S:4]([O-:8])([O-:7])(=[O:6])=S.[Na+].[Na+]>>[S:4]([O-:8])([O-:2])(=[O:7])=[O:6].[Na+:3].[Na+:3].[Cl-:1].[Na+:3]
Reactant: [O-]Cl
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Product: O=S(=O)([O-])[O-]
Product: [Cl-]

Procedure:
However, as discussed above it is not desirable or necessary to consume all of the carbon dioxide of the gas stream 34 in this manner. What is desired is to convert all or most all of the sodium hydroxide of the fresh absorption liquor 33 to sodium carbonate and sodium bicarbonate in the upper portions of the packing 12 so that when it reaches the lower portions of the bed of packing 12 the reaction between sodium hydroxide and chlorine to form sodium chloride and sodium hypochlorite is minimized. If there is any sodium hypochlorite formed it reacts with the sodium thiosulfate to form sodium sulfate and sodium chloride with the consumption of base. The desired reaction in the lower portions of the bed of packing 12 is the reaction between sodium thiosulfate and chlorine to form sodium sulfate and sodium chloride with the consumption of base. Most preferably, almost all of the thiosulfate of the fresh absorption liquor 33 is consumed in the bed of packing 12 so that very little remains in the contacted absorption liquor 36.
Reaction SMILES: [N:1]1([C:11]([O:13]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:23]1[C:28]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:27][CH2:26][NH:25][CH2:24]1.Cl.C(N(CC)CC)C.O>ClCCl>[N:1]1([C:11]([N:25]2[CH2:26][CH2:27][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH2:23][CH2:24]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCC2(C=Cc3ccccc32)CC1)N1CCCc2ccccc21
Temperature: 150 °C
Yield: 85.1 %

Procedure:
0.4 g of 4-nitrophenyl 3,4-dihydroquinoline-1(2H)-carboxylate, 0.357 g of 4-spiroindene-piperidine hydrochloride, 0.28 ml of triethylamine and 2 ml of water are introduced into a 10 ml glass tube. The tube is sealed and then heated at 150° C. under microwave irradiation for 50 minutes. Dichloromethane is added. The organic phase is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a heptane/ethyl acetate gradient from 9/1 to 0/1. 0.393 g of 1′-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)spiro[indene-1,4′-piperidine] is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][N:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>O.ClCCl>[CH:17]1([C:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:28]([N:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[O:30])=[CH:3][C:4]=4[O:25][CH3:26])=[N:13][C:12]=3[N:14]([CH3:23])[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(N)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: C1COCCN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)N2CCOCC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 215.7 %

Procedure:
To a 3 ml dichloromethane suspension of 100 mg (0.283 mmol) of the compound obtained in Example 44, 28 mg (0.0944 mmol) of triphosgene and 79 μl (0.566 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 15 minutes. Then, 25 μl (0.283 mmol) of morpholine was added to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. After the washed layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=15/1) to obtain 95 mg (72%) of the captioned compound.
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH:7]([C:17]1[C:18]([CH3:40])=[N:19][O:20][C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([C:37](O)=[O:38])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH:43]1([S:46]([NH2:49])(=[O:48])=[O:47])[CH2:45][CH2:44]1>>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][CH:7]([C:17]1[C:18]([CH3:40])=[N:19][O:20][C:21]=1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([C:37]([NH:49][S:46]([CH:43]4[CH2:45][CH2:44]4)(=[O:48])=[O:47])=[O:38])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(=O)(=O)C5CC5)CC4)cc3)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C

Procedure:
Prepared according to the procedure described in Example 315 using 1-(4′-{4-[1-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid and cyclopropanesulfonamide.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH:29]1[CH2:34][CH2:33][CH:32]([C:35]#[N:36])[CH2:31][CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:34][CH2:33][CH:32]([C:35]#[N:36])[CH2:31][CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: N#CC1CCNCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C#N)CC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with piperidine-4-carbonitrile via General Procedure E to give 21.9 mg of 291 following reverse phase purification. MS (Q1) 472.2 (M)+