Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)=[CH:6][C:5]([C:19]([N:21]=[S:22]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[O:31])[O:29][CH3:30])=[O:23])=[O:20])=[CH:4][N:3]=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([NH2:48])[CH:43]=1>CN(C1C=CN=CC=1)C.ClCCCl.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]([N:21]=[S:22]([CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:29][CH3:30])=[O:31])=[O:23])=[O:20])=[CH:6][C:7]=1[C:8]#[C:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([NH:48][C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([O:41][CH3:40])[CH:43]=2)=[O:15])[CH:11]=1
Reactant: COc1cccc(N)c1
Reactant: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(C(=O)O)c2)c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)CCCCS(=O)(CCCCC(=O)OC)=NC(=O)c1cnc(N)c(C#Cc2cccc(C(=O)Nc3cccc(OC)c3)c2)c1
Temperature: 60 °C

Procedure:
The reaction mixture of 3-{[2-amino-5-({[bis(5-methoxy-5-oxopentyl)(oxido)-sulfanylidene]amino}carbonyl)pyridin-3-yl]ethynyl}benzoic acid (56 mg, 0.1 mmol, 1.0 equiv.), m-anisidine (13.4 μL, 0.12 mmol, 1.2 equiv.), DMAP (2.5 mg, 0.02 mmol, 0.2 equiv.) and EDC (29 mg, 0.15 mmol, 1.5 equiv.) in DCE (1 mL) in a sealed vial was stirred and heated at 60° C. for 3 hours. The resulting brown solution was diluted with EtOAc, washed with sat. aq. NaHCO3, aq. NH4Cl, and brine, and finally dried with anhydrous Na2SO4. The solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (from EtOAc-Hex 1:4 to 6:1) to yield Dimethyl 5,5′-[N-({6-amino-5-[(3-{[(3-methoxyphenyl)amino]carbonyl}phenyl)ethynyl]pyridin-3-yl}carbonyl)sulfonimidoyl]dipentanoate
Reaction SMILES: C([O:5][C:6](=[O:50])[C@H:7]([CH2:23][C:24](=[O:49])[NH:25][C@@H:26]1[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]1[O:28][C:29](=[O:31])[CH3:30])[NH:8][S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH3:20])=[C:14]([CH3:21])[C:13]=1[CH3:22])(=[O:11])=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl.CO>[CH3:20][O:19][C:15]1[CH:16]=[C:17]([CH3:18])[C:12]([S:9]([NH:8][C@H:7]([C:6]([OH:50])=[O:5])[CH2:23][C:24](=[O:49])[NH:25][C@@H:26]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]2[O:28][C:29](=[O:31])[CH3:30])(=[O:11])=[O:10])=[C:13]([CH3:22])[C:14]=1[CH3:21]
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)C(=O)OC(C)(C)C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)C(=O)O)c(C)c1C

Procedure:
Compound 15 (1.5 g) was hydrolyzed with trifluoroacetic acid and worked up as described for compound 19.Yield: 1.0 g. TLC analysis: Rf=0.07 (chloroform/methanol/glacial acetic acid 5:1:0.1 )
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[CH2:15][O:14][N:13]([C:16]3([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])[CH:20](SC4C=CC=CC=4)[CH2:19][C:18](=[O:28])[O:17]3)[C:12]2=[O:45])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[CH2:15][O:14][N:13]([C:16]3([C:29]([O:31][CH:32]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:20]=[CH:19][C:18](=[O:28])[O:17]3)[C:12]2=[O:45])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@H]1CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)OC(=O)CC2Sc2ccccc2)C1=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N[C@H]1CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)C=CC(=O)O2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
In 3 ml of dichloromethane was dissolved 60 mg of the Compound (50) obtained in Example 50. To the solution was added 20 mg of 3-chloroperbenzoic acid. The mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with an aqueous solution of sodium hydrogen carbonate and water, successively, followed by drying (Na2SO4). The solvent was then evaporated off, and the residue was dissolved in 1 ml of toluene. The solution was heated at 80° C. for 30 minutes, then the solvent was evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (1:1) to give 21 mg of the subject Compound (51) as colorless crystals. The IR and NMR spectra of this product were in agreement with those of the compound obtained in (a) above.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH2:23]Br)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[ClH:16].[Cl:16][C:17]1[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH2:23][N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([CH3:2])=[CH:15][CH:14]=3)[CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: Clc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(CC2CCN(CCOc3ccc(Cl)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-methylbenzyl)piperidine hydrochloride (600 mg, 2.66 mmol), 2-(4-chlorophenoxy)ethyl bromide (658 mg, 2.79 mmol) and K2CO3 (754 mg, 5.45 mmol) in CH3CN (50 mL) as colorless flakes (661 mg): mp 201-203° C.; 1H NMR (CDCl3) 1.60-2.12 (m, 5H), 2.31 (s, 3H), 2.58 (d, J=7.2 Hz, 2H), 2.63-2.82 (m, 2H), 3.20-3.50 (m, 2H), 3.58-3.70 (m, 2H), 4.53 (t, J=4.2 Hz, 2H), 6.80 (d, J=9.3 Hz, 2H), 7.00 (d, J=7.5 Hz, 2H), 7.09 (d, J=7.8 Hz, 2H), 7.24 (d, J=8.7 Hz, 2H), 12.60 (b, 1H).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>C(O)C>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: COCCN
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCCOC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 38, reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.41 g) and methoxyethylamine (1.04 g) in ethanol (15 ml) for 48 hours yielded the title compound, 0.38 g. m.p. 193-4° C. (recrystallized twice from methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][NH:19]C)[C:12]=2[F:21])[CH:9]=1)[C:5]#[N:6].[Cl:22][C:23]1[N:24]=[C:25]([CH2:31][CH3:32])[NH:26][C:27]=1[C:28]([OH:30])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:22][C:23]1[N:24]=[C:25]([CH2:31][CH3:32])[NH:26][C:27]=1[C:28]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:12]=1[F:21])=[O:30]
Reactant: CNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Reactant: CCc1nc(Cl)c(C(=O)O)[nH]1
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: CCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Yield: 58.1 %

Procedure:
4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-ethyl-1H-imidazole-5-carboxamide was prepared in a similar manner as described herein from 3-chloro-5-({6-chloro-2-fluoro-3-[(methylamino)methyl]phenyl}oxy)benzonitrile (0.713 g, 2.29 mmol), 4-chloro-2-ethyl-1H-imidazole-5-carboxylic acid (0.400 g, 2.29 mmol), HATU (1.133 g, 2.98 mmol), DIPEA (0.520 mL, 2.98 mmol) and DMF (12 mL). Purification was accomplished by silica gel chromatography (0-5% MeOH (2M NH3) in CH2Cl2) to afford the title compound (0.622 g, 58%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.09 (br. s., 1H), 7.81-7.84 (m, 1H), 7.48-7.53 (m, 2H), 7.45-7.47 (m, 1H), 7.33-7.40 (m, 1H), 4.54 (d, 2H), 2.60 (q, 2H), 1.18 (t, 3H). ES-LCMS: m/z 467.0, 469.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[C:32]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[N:26]=[C:25]3[CH3:33])=[CH:20][CH:19]=2)=[C:9]1[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C.[CH3:58][O:59][CH2:60][CH2:61]O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:61][CH2:60][O:59][CH3:58])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[C:32]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[N:26]=[C:25]3[CH3:33])=[CH:22][CH:23]=2)=[C:9]1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: COCCO
Reactant: CCOC(=O)C1=C(c2ccc(-n3c(C)nc4cnccc43)cc2)NC(C)=C(C(=O)O)C1c1ccccc1Cl
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(c2ccc(-n3c(C)nc4cnccc43)cc2)NC(C)=C(C(=O)OCCOC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (±)-4-(2-chlorophenyl)-1,4-dihydro-3-ethoxycarbonyl-6-methyl-2-[4-(2-methylimidazo[4,5-c]pyridin-1-yl)phenyl]pyridine-5-carboxylic acid (see Example 10) (270 mg, 0.5 mmol), 2,4,6-triisopropylbenzenesulphonyl chloride (377 mg, 1.25 mmol) and 4-dimethylaminopyridine (152 mg, 1.25 mmol) in dry dichloromethane (10 ml) was stirred under a nitrogen atmosphere at room temperature for 3 hours. 2-Methoxyethanol (1.0 ml) was added and the solution was stirred at room temperature for 20 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in excess 0.5M hydrochloric acid and washed with ether (2×30 ml). The aqueous solution was basified with excess saturated aqueous sodium bicarbonate and extracted with dichloromethane (4×30 ml). The combined organic extracts were dried (MgSO4), concentrated, and purified by flash chromatography on silica gel (eluting with 10:1 ethyl acetate/triethylamine) to give, after combination and evaporation of appropriate fractions, the title compound, (93 mg), m.p. 195°-196° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:14][O:15][C:16]([C:18]1[CH:22]=[CH:21][O:20][C:19]=1[CH2:23]Br)=[O:17]>>[CH3:14][O:15][C:16]([C:18]1[CH:22]=[CH:21][O:20][C:19]=1[CH2:23][O:10][C:9]1[C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Br:1])=[O:17]
Reactant: COC(=O)c1ccoc1CBr
Reactant: CCOc1cc(C=O)cc(Br)c1O
Product: CCOc1cc(C=O)cc(Br)c1OCc1occc1C(=O)OC

Procedure:
Alkylation of 3-bromo-5-ethoxy-4-hydroxy benzaldehyde (123 mg) with 2-bromomethyl-furan-3-carboxylic acid methyl ester (109 mg) was performed according to the method described in example 1a. Yield: 191 mg. MS-ESI: [M+H]+=383/385
Reaction SMILES: [NH:1]([C:3]([NH:5][CH2:6][C@H:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:14])[CH2:9][C@H:8]1[F:24])=[S:4])[NH2:2].[CH:25](OCC)(OCC)OCC.Cl>C(O)C>[F:24][C@H:8]1[C@@H:7]([CH2:6][NH:5][C:3]2[S:4][CH:25]=[N:2][N:1]=2)[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:14])[CH2:9]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(COC(=O)N2CC[C@H](CNC(=S)NN)[C@H](F)C2)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(COC(=O)N2CC[C@H](CNc3nncs3)[C@H](F)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of (±)-cis 4-methylbenzyl 4-{[(hydrazinocarbonothioyl) amino]methyl}-3-fluoropiperidine-1-carboxylate (180 mg, 0.51 mmol) in ethanol (10 mL) was treated with triethyl orthoformate (151 mg, 1.02 mmol) and concentrated HCl (0.01 mL) and stirred at room temperature, under nitrogen, for 18 h. After all solids had dissolved, the reaction mixture was heated to reflux for 1.5 hour, cooled to room temperature and the volatiles evaporated. The residue was partitioned between ethyl acetate and dilute sodium bicarbonate solution, the organic layer washed with brine, dried over sodium sulfate and solvent evaporated. The crude product was purified by gradient elution on silica gel (50% ethyl acetate: hexane to 20% methanol: ethyl acetate) to give the title compound as a white solid. The (−)-enantiomer was separated and the hydrochloride salt formed as described in Examples 1 and 2 Step 7.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C>[N:32]1([CH2:31][CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][CH:11]=[C:10]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:9]=3)=[CH:6][CH:7]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccc(-c2ccc(-c3ccccc3)nc2-c2ccc(O)cc2)cc1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(-c2ccc(-c3ccccc3)nc2-c2ccc(OCCN3CCCC3)cc2)cc1
Yield: 93.2 %

Procedure:
The 2-(4-hydroxyphenyl)-3-(4-methoxyphenyl)-6-phenylpyridine (2.0 g, 5 mmol), N-(2-chloroethyl)pyrrolidine hydrochloride (1.0 g, 5 mmol), and powdered K2CO3 (4.2 g, 30 mmol) were stirred in 200 mL methyl ethyl ketone and refluxed 20 h. The reaction mixture was worked up and the residue triturated with pet. ether, filtered, and dried in vacuo to give 2.1 g (84% yield) of an off-white solid: mp 100°-103° C.; 1H NMR (CDCl3) d 1.81-1.84 (m, 4H, pyrrolidine), 2.61-2.65 (m, 4H, pyrrolidine), 2.88-2.92 (t, 2H, J=6 Hz, NCH2), 3.83 (s, 3H, ArOCH3), 4.10-4.14 (t, 2H, J=6 Hz, OCH2), 6.81-6.87 (m, 4H, ArH), 7.15-7.18 (d, 2H, J=9 Hz, ArH) 7.42-7.50 (m, 5H, ArH), 7.73 (s, 2H, ArH), 8.13-8.16 (d, 2H, J=9 Hz, ArH); MS(FD) 450(M+). Anal. Calcd for C30H30N2O2 : C, 79.97; H, 6.71; N, 6.22. Found: C, 79.86; H, 6.09; N, 6.16.
Reaction SMILES: CI.[CH2:3]([C:5]1[S:6][C:7]2[CH:14]=[CH:13][C:12]3[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:11]=3[CH:10]([C:20]3[C:21](=[S:27])[NH:22][C:23](=[O:26])[NH:24][CH:25]=3)[C:8]=2[N:9]=1)[CH3:4].[C:28](=O)(O)[O-].[Na+]>C(O)C.O>[CH2:3]([C:5]1[S:6][C:7]2[CH:14]=[CH:13][C:12]3[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:11]=3[CH:10]([C:20]3[C:21]([S:27][CH3:28])=[N:22][C:23](=[O:26])[NH:24][CH:25]=3)[C:8]=2[N:9]=1)[CH3:4]
Reactant: O=C([O-])O
Reactant: CCc1nc2c(s1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=S
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CI
Product: CCc1nc2c(s1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)nc1SC

Procedure:
Methyl iodide (0.044 ml) was added to a stirred solution of the product from example 31 step (v) (0.250 g) and sodium bicarbonate (0.057 g) in ethanol (5 ml) and water (3 ml). After 3 h the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by trituration with ethyl acetate and isohexane.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1([CH3:24])[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[C:25]1([CH:31]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:32][CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH:31]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:32][CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][C:4]3([CH3:24])[CH2:8][C:7]4[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=4[O:5]3)[CH2:37][CH2:36]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCBr)O2
Reactant: c1ccc(C(OCCC2CCNCC2)c2ccccc2)cc1
Product: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCN1CCC(CCOC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 83 %

Procedure:
Using tert-butyl [2-(2-bromoethyl)-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl]carbamate and 4-(2-(diphenylmethoxy)ethyl]piperidine, the procedure of Reference Example 58 was otherwise repeated to provide the title compound. Yield 83%.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[C:10]([CH3:14])([CH3:13])[CH2:11]Cl.Cl.N1C=CC=CC=1.Cl.CCOCC>N1C2C(=CC=CC=2)C=CC=1>[Br:9][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:14][C:10]([CH3:11])([CH3:13])[C:4]=2[CH:5]=1
Reactant: COc1ccc(Br)cc1C(C)(C)CCl
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1(C)COc2ccc(Br)cc21
Reaction time: 3 h

Procedure:
2-(2-Methoxy-5-bromophenyl)-2-methyl-1-chloropropane (from example 5(a)) (120 g, 0.43 mole) was heated under reflux (163°-9° C.) with pyridine hydrochloride (220 g) in quinoline (220 g) with stirring for 3 hours. Addition to iced dilute hydrochloric acid and isolation through ether gave after distillation 73 g (75%) title product b.p. 62°-4° C. at 0.01 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:22]2[N:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[N:6][CH:7]=1.[CH2:28](B(O)O)[CH2:29][CH3:30].C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]([NH:9][C@@H:8]([C:22]2[N:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[C:5]2[CH:4]=[CH:3][C:2]([CH2:28][CH2:29][CH3:30])=[CH:7][N:6]=2)=[O:21])=[CH:13][CH:14]=1)([CH3:20])[CH3:19]
Reactant: CCCB(O)O
Reactant: CC(C)c1ccc(CC(=O)N[C@H](c2ccc(Br)cn2)c2cn(C)nn2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCCc1ccc([C@@H](NC(=O)Cc2ccc(C(C)C)cc2)c2cn(C)nn2)nc1
Yield: 49.7 %

Procedure:
N-[(S)-(5-bromopyridin-2-yl)(1-methyl-1H-1,2,3-triazol-4-yl)methyl]-2-(4-isopropylphenyl)acetamide (0.075 g, 0.18 mmol) was mixed with n-propylboronic acid (0.04 g, 0.44 mmol), PdCl2(dppf)2 (0.014 g, 0.019 mmol), Ag2O (0.10 g, 0.44 mmol) and K2CO3 (0.073 g, 0.53 mmol) and degassed. THF (3 mL) was added and the mixture was heated in microwave at 130 C for 30 min. The reaction mixture was diluted with EtOAc and filtered through Celite. The solvent was removed and the residue was purified by reverse HPLC to give 2-(4-isopropylphenyl)-N-[(S)-(1-methyl-1H-1,2,3-triazol-4-yl)(5-propylpyridin-2-yl)methyl]acetamide (0.035 g, 51%). ES-MS [M+1]+: 430.1. 1H NMR (CDCl3, 400 MHz) δ 1H NMR (CDCl3, 400 MHz) δ 8.29 (d, J=2.0 Hz, 1H), 7.58 (d, J=6.4 Hz, 1H), 7.45 (dd, J=2.4, 8.0 Hz, 1H), 7.40 (s, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.24-7.19 (ABq, 4H), 6.27 (d, J=7.2 Hz, 1H), 3.98 (s, 3H), 3.62 (s, 2H), 2.94-2.85 (m, J=6.8 Hz, 1H), 2.54 (t, J=7.6 Hz, 2 H), 1.66-1.56 (m, 2H), 1.24 (d, J=6.4 Hz, 6H), 0.93 (t, J=7.2 Hz, 3H). HRMS (ES) [M+1]+ calcd for C23H29N5O: 392.2445. Found: 392.2446.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:8])=[O:7])=[CH:4][CH:3]=1.[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O.C1(C)C(Cl)=CC=CC=1.FC1C=C(C=CC=1)C(Cl)=O.BrC1C=CC(C(Cl)=O)=CC=1.FC(F)(F)C1C=CC(C(Cl)=O)=CC=1.C(Cl)C1C(OC)=CC=CC=1.C1(C)C=CC(Cl)=CC=1.ClC1C=CC=CC=1C(Cl)=O.IC1C=CC(C(Cl)=O)=CC=1.IC1C=CC=CC=1C(Cl)=O.C(C1C=CC(C(Cl)=O)=CC=1)C.FC1C=CC=CC=1C(Cl)=O.[N+](C1C=CC=CC=1C(Cl)=O)([O-])=O>>[C:6]([Cl:8])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CCc1ccc(C(=O)Cl)cc1
Agent: COc1ccccc1CCl
Agent: O=C(Cl)c1ccc(Br)cc1
Solvent: Cc1ccccc1Cl
Solvent: Cc1ccc(Cl)cc1
Product: O=C(Cl)c1ccccc1

Procedure:
Substituting p-chlorobenzoyl chloride for benzoyl chloride in the above reaction yields p-chlorobenzoic acid, 2-tert-butylhydrazide; melting point 116°-122° C. Similarly, substituting p-fluorobenzoyl chloride, p-nitro-benzoyl chloride, o-toluyl chloride, m-fluorobenzoyl chloride, p-bromobenzoyl chloride, p-trifluoromethylbenzoyl chloride, o-anisyl chloride, p-toluyl chloride, o-chlorobenzoyl chloride, p-iodobenzoyl chloride, o-iodobenzoyl chloride, p-ethylbenzoyl chloride and o-fluorobenzoyl chloride, o-nitrobenzoyl chloride, for benzoyl chloride, yields respectively: p-fluorobenzoic acid, o-bromobenzoyl chloride, 2-tert-butylhydrazide; mp 136°-138° C.; p-nitrobenzoic acid, 2-tert-butylhydrazide; o-toluic acid, 2-tert-butylhydrazide; m-fluorobenzoic acid, 2-tert-butylhydrazide, mp 119°-120° C.; p-bromobenzoic acid, 2-tert-butylhydrazide; p-trifluoromethylbenzoic acid, 2-tert-butylhydrazide; anisic acid, 2-tert-butylhydrazide; p-toluic acid, 2-tert-butylhydrazide; o-chlorobenzoic acid, 2-tert-butylhydrazide; mp 68°-70° C.; o-iodobenzoic acid, 2-tert-butylhydrazide; p-ethylbenzoic acid, 2-tert-butylhydrazide; and o-fluorobenzoic acid, 2-tert-butylhydrazide; mp 58°-59° C.; o-nitrobenzoic acid, 2-tert-butylhydrazide; mp 116°-118° C.; o-bromobenzoic acid, 2-tert-butylhydrazide; mp 85°-87° C.; and N-methylanthranilic acid, 2-tert-butylhydrazide, mp 125°-129° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C[O-].[Na+]>CS(C)=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Following the general procedure of J. Polym. Sci., Polym. Chem. Ed. (1980), 18(10). 3069-80, 4-hydroxybenzoic acid, 1-chloro-4-nitro-benzene and sodium methoxide were heated in DMSO at 130° C. to afford the title compound.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[C:13]([CH:30]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[O:25][CH2:26][C:27](O)=[O:28].[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[C:13]([CH:30]=3)[CH2:14][CH2:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][C:17]=3[O:25][CH2:26][C:27]([N:34]1[CH2:35][CH2:36][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32][CH2:33]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1

Procedure:
The desired compound was prepared according to the procedure of Example D152 using {[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]oxy}acetic acid dihydrochloride and tert-butyl piperazine-1-carboxylate as the starting materials. LCMS for C23H25ClN5O3 (M+H)+: m/z=454.1. This material was used immediately in the next step.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.[CH3:24][C:25]([CH3:27])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[ClH:1].[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][CH:25]([CH3:27])[CH3:24])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: CC(C)=O
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 150 mg (0.40 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride and 48 μl (0.65 mmol) of acetone in 1.5 ml of 1,2-dichloroethane is adjusted to pH 4 using acetic acid. 254.8 mg (1.20 mmol) of sodium triacetoxyborohydride are added, and the mixture is stirred at RT for 6 h. The contents of the flask are concentrated under reduced pressure and purified by preparative HPLC. The product fractions are concentrated and the residue is dissolved in a 5:1 mixture of acetonitrile and 1N hydrochloric acid, then again concentrated and dried under high vacuum. 49 mg (29.4% of theory) of the title compound are obtained.