Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][CH2:49][C:50]([OH:52])=O)=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:43]=[CH:44][C:45]([NH:48][CH2:49][C:50]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:52])=[CH:46][CH:47]=1
Reactant: O=C(O)CNc1ccc(F)cc1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CNc3ccc(F)cc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure described for the parallel synthesis of C-17 amides above, using (4-fluorophenylamino)acetic acid as the reacting carboxylic acid. LCMS: m/e 681.7 (M+H)+, 6.62 min (method 3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc(Cl)n1)c1ccccc1
Yield: 93 %

Procedure:
6-Chloropyridin-2-amine (0.3 g, 2 mmol) was dissolved in DCM (20 mL) and then pyridine (0.57 mL, 7.0 mmol) was added to the mixture with stirring. Then, benzenesulfonyl chloride (0.36 mL, 2.8 mmol) was added into the mixture. The mixture was allowed to stir under inert atmosphere for 2 hours. The mixture was diluted with DCM and saturated NaHCO3, and then the aqueous layer was extracted with DCM three times. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (10-100% EtOAc/hexanes) to provide N-(6-chloropyridin-2-yl)benzenesulfonamide (0.5 g, 80% yield) as a colorless oil. MS (ESI pos. ion) m/z: 254 (MH+). Calculated exact mass for C11H8ClNO2S: 253.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1[O:43][CH3:44].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:42][O:41][C:38]1[CH:37]=[C:36]([O:43][CH3:44])[CH:35]=[CH:40][C:39]=1[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1
Reactant: COc1ccc(OB([O-])[O-])c(OC)c1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 m), 2,4-dimethoxyphenyl borate (116 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (6/0.6/0.6 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 7 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-(2,4-dimethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 48) (216 mg).
Reaction SMILES: [C:1]([C:3]1([CH3:14])[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)#[N:2].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:14][C:3]1([C:1]#[N:2])[CH2:6][NH:5][CH2:4]1
Reactant: CC1(C#N)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C#N)CNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-cyano-3-methylazetidine-1-carboxylate (30.0 mg, 0.15 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (2 ml) and the solution stirred at room temperature for 1 hr. The reaction was concentrated and dried under vacuum to give a viscous oil which was used crude in subsequent chemistry.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])=[CH2:2].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CCOCC>[C:17]([O:10][C:6]1[CH:5]=[C:4]([C:1]([CH3:3])=[CH2:2])[CH:9]=[CH:8][CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)c1cccc(O)c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=C(C)c1cccc(OC(C)=O)c1
Yield: 94.6 %

Procedure:
250 g (1.86 mol) m-isopropenylphenol and 15 mL (0.19 mol) pyridine were placed in a four-neck flask equipped with a stirrer, reflux condenser, addition funnel, and thermometer. While stirring with cooling on a water bath, 200 mL (2.12 mol) acetic anhydride was dripped in. The reaction mixture was then diluted with ether and washed with water to neutrality. Drying and distillation afforded 310 g (1.76 mol) of the target material. The yield was 94%. The properties of this product are reported below.
Reaction SMILES: [C:1]1([N:7]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([CH3:31])[C:15]([CH2:17][N:18]([C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=4)[CH2:19][CH2:20][CH2:21][CH3:22])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:41].C(=O)([O-])[O-].[NH4+:46].[NH4+]>C(O)C>[ClH:41].[C:1]1([N:7]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:8]([C:10]2[CH:33]=[CH:32][C:13]3[N:14]([CH3:31])[C:15]([CH2:17][N:18]([C:23]4[CH:24]=[CH:25][C:26]([C:29](=[NH:46])[NH2:30])=[CH:27][CH:28]=4)[CH2:19][CH2:20][CH2:21][CH3:22])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCN(Cc1nc2cc(C(=O)N(CCC(=O)OCC)c3ccccc3)ccc2n1C)c1ccc(C#N)cc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCCCN(Cc1nc2cc(C(=O)N(CCC(=O)OCC)c3ccccc3)ccc2n1C)c1ccc(C(=N)N)cc1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-(n-butyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].Cl[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1.O>CN(C=O)C>[OH:6][CH2:5][CH2:4][CH2:3][O:7][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1
Reactant: OCCCO
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCO)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
Sodium hydride (0.42 g, 10.61 mmol) was added to a solution of 1,3-propanediol (2.30 mL, 31.83 mmol) in DMF (22 mL) at 0° C. and the mixture was stirred at rt for 20 min. To the resultant heterogeneous mixture was added 6-chloronicotinonitrile (1.50 g, 10.6 mmol) in one portion. The mixture was stirred at rt for 18 h, poured into water, and filtered. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give the product (1.56 g, 83%) as a white solid. 1H NMR (CD2Cl2) δ 8.47 (d, 1 H), 7.82-7.79 (m, 1H), 6.84-6.82 (m, 1H), 4.53 (t, 2H), 3.75 (t, 2H), 2.06-1.99 (m, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH3:23])[CH2:8][CH2:7][N:6]([CH2:9][C@@H:10]([C:12]2[CH:21]=[CH:20][C:15]3[C:16](=[O:19])[O:17][CH2:18][C:14]=3[C:13]=2[CH3:22])[OH:11])[CH2:5]1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1>>[OH:11][C@H:10]([C:12]1[C:13]([CH3:22])=[C:14]2[C:15](=[CH:20][CH:21]=1)[C:16](=[O:19])[O:17][CH2:18]2)[CH2:9][N:6]1[CH2:7][CH2:8][C:4]([CH2:3][NH:2][C:25]2[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=2)([C:23]2[CH:14]=[CH:13][CH:12]=[CH:10][CH:9]=2)[CH2:5]1
Reactant: Cc1c([C@@H](O)CN2CCC(C)(CN)C2)ccc2c1COC2=O
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Product: Cc1c([C@@H](O)CN2CCC(CNc3ccc(C#N)cn3)(c3ccccc3)C2)ccc2c1COC2=O

Procedure:
6-((1-((R)-2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-phenylpyrrolidin-3-yl)methylamino)nicotinonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 18 starting from 5-[(R)-2-[3-(Aminomethyl)-3-methylpyrrolidin-1-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 7] and 6-chloropyridine-3-carbonitrile.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27]([OH:29])[CH3:28])[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:30])[CH:10]2[NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:7])[CH2:3][CH2:2]1.O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60]>C(N(CC)CC)C>[CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:27]([O:29][S:59]([CH3:58])(=[O:61])=[O:60])[CH3:28])[C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])[C:11](=[O:30])[CH:10]2[NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC1CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-hydroxyethylidene)acetate (904 mg) in a mixture (9.5 ml) of tetrahydrofuran and hexamethylphosphorotriamide (20:1) are added methanesulfonyl chloride (0.26 ml) and triethylamine (0.37 ml). After 2 hours, the reaction mixture is poured into ice water, and extracted with chloroform. The extract solution is washed with water, dried, and evaporated to give p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(1-methanesulfonyloxyethylidene)acetate (1.12 g). Yellow foam. IR: νmaxCHCl3 3426, 1785, 1722-1704br, 1640, 1601, 1160, 1175, 986 cm-1. NMR: δCDCl3 0.32-1.25m5H, 2.57s3H, 2.72s3H, 3.99d(7 Hz)2H, 4.55s2H, 5.33-5.99m4H, 6.82-7.62m7H 8.21d(8.5 Hz)2H.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14]O>C(Cl)(=O)C>[Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:14])=[O:8]
Reactant: CO
Reactant: COc1cc(O)c(Cl)cc1C(=O)O
Solvent: CC(=O)Cl
Product: COC(=O)c1cc(Cl)c(O)cc1OC
Temperature: 60 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of 5-chloro-4-hydroxy-2-methoxybenzoic acid (intermediate 52; 4.17 g; 13.69 mmol) in 123 ml of anhydrous methanol, 2.2 ml of acetyl chloride were added. The solution was stirred at 60° C. under nitrogen atmosphere for 18 hrs. The solution was evaporated under reduced pressure and the residue purified by preparative reversed-phase HPLC (Cl2CH2/EtOAc from 100/0 to 80/20), affording 2.2 g (75%) of a red solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br.[H-].[Na+].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])(=[O:3])[CH3:2]
Reactant: BrCCCCCCBr
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(CCCCCCBr)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
5.00 g (14.4 mmol) of Compound 27 obtained in Example 27 was dissolved in 150 ml of dimethylformamide under argon atmosphere, 10.9 ml of 1,6-dibromohexane and 575 mg of sodium hydride (60% oil dispersion) were added under ice-cooling and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:acetone=20:1) to give 6.11 g (83%) of 2-[4-[N-acetyl-N-(6-bromohexyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.Cl.N[C@@H](CCN1CC(OC2C=CC([Cl:48])=C(Cl)C=2)C1)CO>>[Cl:48][C:29]1[CH:28]=[C:5]([CH:4]=[CH:3][C:2]=1[Cl:1])[O:6][CH:7]1[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]2[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=2)=[O:18])[CH2:14][OH:15])[CH2:10]1
Reactant: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)n(C)n1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Product: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)c(Cl)c3)C2)n(C)n1

Procedure:
This compound is prepared in a manner analogous to that used to prepare 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 88 except using (S)-2-amino-4-[3-(3,4-dichloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[CH2:5][CH2:6][NH:7][CH2:8][CH:9]1[O:14][CH:13]([CH3:15])[CH:12]([CH3:16])[CH2:11][O:10]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:32][CH2:33][C:34](Cl)=[O:35]>O>[CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[CH2:5][CH2:6][N:7]([CH2:8][CH:9]1[O:14][CH:13]([CH3:15])[CH:12]([CH3:16])[CH2:11][O:10]1)[C:34](=[O:35])[CH2:33][Br:32])[CH3:2]
Reactant: O=C(Cl)CBr
Reactant: CCOC(CCNCC1OCC(C)C(C)O1)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(CCN(CC1OCC(C)C(C)O1)C(=O)CBr)OCC

Procedure:
N-(3,3-Diethoxypropyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and bromoacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)-α-bromoacetamide as the residue.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C[Si]([P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C)C>C1(C)C=CC=CC=1.CC#N.CC#N.Cl[Pd]Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccccc1I
Reactant: C[Si](C)(C)P(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: Brc1ccccc1P(c1ccccc1)c1ccccc1

Procedure:
According to the method described in a literature (S. E. Tunney and J. K. Stille, J. Org. Chem., 1987, 52, 748), (2-bromophenyl)diphenylphosphine was obtained by reacting 2-bromoiodobenzene and (trimethylsilyl)diphenylphosphine in toluene in the presence of dichlorobis(acetonitrile)palladium. Into a four-necked flask was weighed 10.00 g (29.3 mmol) of (2-bromophenyl)diphenylphosphine obtained in the above. The atmosphere of the reaction vessel fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen, and 100 mL of anhydrous tetrahydrofuran (hereinafter referred to as THF) was added thereto. Thereto was added dropwise 18.3 mL of n-butyllithium-hexane (1.6 M) solution at −78° C. over a period of 30 minutes, followed by 1 hour of stirring at the same temperature. The resulting mixed solution was added dropwise to a 25 mL THF solution of 4.83 g (29.3 mmol) of diethyl chlorophosphite (manufactured by Aldrich) at −78° C. over a period of 30 minutes. After the dropwise addition, a cooling bath was removed and the whole was further stirred at room temperature for 1 hour. After the reaction, THF was removed by evaporation, the residue was dissolved in 50 mL of diethyl ether, and insoluble matter was removed by filtration. The solvent was removed by evaporation and the residue was purified by active alumina column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (10.30 g, a pale yellow oily substance). Yield 92%.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:15]([C:22]([OH:24])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:28]2N(O)N=[N:31][C:29]=2[CH:30]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:29]1([NH:31][C:22]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:24])[CH2:30][CH2:28]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 185.7 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(3-methylbutyl)-1H-1,2,3-triazole-4-carboxylic acid (462 mg, 1.40 mmol) obtained in Example 97b), HOBt (95.4 mg, 0.700 mmol, 0.5 eq.) and cyclopropylamine (0.130 ml, 1.82 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 7.5 ml), WSC (328 mg, 1.68 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (40 ml) and washed with 2% aqueous sodium carbonate solution (×2), 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a grayish white powder (481 mg, 1.30 mmol, 93.0%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:12]=2[CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[N:9]2[C:25](=[O:28])[NH:26][N:27]=[C:8]2[N:7]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:6]=1[CH3:39])=[O:4].[CH3:40][Br:41]>CC#N>[Br-:41].[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C@H:10]2[N:9]3[C:25](=[O:28])[NH:26][N:27]=[C:8]3[N:7]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:36])[F:38])[CH:30]=3)[C:6]([CH3:39])=[C:5]2[C:3]([O:2][CH3:1])=[O:4])=[C:12]([CH2:19][CH2:20][CH2:21][N+:22]([CH3:40])([CH3:24])[CH3:23])[CH:13]=1)#[N:18]
Reactant: CBr
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2n[nH]c(=O)n2[C@@H]1c1ccc(C#N)cc1CCCN(C)C
Solvent: CC#N
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2n[nH]c(=O)n2[C@@H]1c1ccc(C#N)cc1CCC[N+](C)(C)C
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 12 (2.0 g, 3.70 mmol) in MeCN (10 mL) at 5° C. was added a 26% solution of methyl bromide in acetonitrile (10 mL) drop-wise. The mixture was allowed to warm to room temperature and stirred for 2 hours. The solvent was evaporated in vacuo. The resulting residue was taken up in 30% MeCN in water (30 mL) and freeze dried to yield a white solid (2.05 g).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[NH:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11]O.[CH2:13]([N:15](CC)[CH2:16]C)C>C(Cl)Cl>[CH3:13][N:15]([CH2:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][NH:6]1)[CH3:16]
Reactant: OC[C@@H]1CCCN1
Reactant: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CN(C)C[C@@H]1CCCN1
Temperature: -78 °C
Reaction time: 20 h

Procedure:
While cooling at −78° C., a solution of sulfuryl chloride (0.409 mL) in methylene chloride (30 mL) was added dropwise to a solution of (2S)-2-pyrrolidinemethanol (0.498 mL) and triethylamine (1.39 mL) in methylene chloride (30 mL) over a period of 10 minutes. The temperature of the resultant mixture was gradually returned to room temperature, followed by stirring of the mixture for 20 hours. The reaction mixture was partitioned between 1N aqueous hydrochloric acid and methylene chloride, and the organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure, and a solution of 2.0M dimethylamine in tetrahydrofuran (25 mL) was added to the residue, followed by stirring in a sealed tube at an external temperature of. 100° C. for 14 hours and 30 minutes, and then cooled in air. Trifluoroacetic acid (one droplet) was added thereto. The resultant mixture was further stirred in a sealed tube at an external temperature of 100° C. for 21 hours and then cooled in air. The solvent was removed at normal pressure, and 2N aqueous sodium hydroxide (50 mL) was added to the residue, followed by stirring at 100° C. for 15 hours. The resultant mixture was cooled in air. Diethyl ether was added thereto for partitioning the mixture, and the organic layer was dried over sodium sulfate anhydrate. After filtration, the solvent was removed at normal pressure, to thereby give (2S)-2-dimethylaminomethylpyrrolidine.