Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCCCCC.C([Li])CCC.C(OC([N:31]1[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32]1)=O)(C)(C)C.[Cl-].[NH4+]>C(OCC)C>[ClH:12].[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([C:33]2([OH:37])[CH2:34][CH2:35][CH2:36][NH:31][CH2:32]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: Cl
Product: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCCNC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 53.8 %

Procedure:
5-Bromo-2-chlorobenzotrifluoride (Aldrich Co., 2.0 g) was dissolved in diethyl ether (50 ml), and the mixture was cooled to −78° C. An n-butyllithium hexane solution (2.6 M, 3.2 ml) was added to the solution and the mixture was stirred for 10 min. 1-(tert-Butoxycarbonyl)-3-piperidone (Aldrich Co., 1.6 g) was added, and the mixture was gradually warmed to room temperature. After completion of the reaction, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with diethyl ether. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1-2:1)). The intermediate was dissolved in ethyl acetate, and a 4N hydrochloric acid-ethyl acetate solution (3 ml) was added. The mixture was stirred at room temperature for 3 hr. After completion of the reaction, the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give 3-[4-chloro-3-(trifluoromethyl)phenyl]piperidin-3-ol hydrochloride (655 mg, yield 27%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[N:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:41]=[C:42]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)[CH2:43][NH:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.O>[Br:10][C:11]1[N:16]=[C:15]([C:17]([N:62]2[CH2:61][CH2:60][N:59]([C:42](=[O:41])[CH2:43][NH:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:49][CH:48]=3)=[O:46])[CH2:64][CH2:63]2)=[O:19])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cccc(Br)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cccc(Br)n2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 25.2 %

Procedure:
DIPEA (149.8 mg, 0.2 mL, 1.15 mmol) was added to a stirred solution of 6-bromo-pyridine-2-carboxylic acid (52.03 mg, 0.25 mmol) in DMF (3 mL). HOBT (38.2 mg, 0.28 mmol) and EDCI (123 mg, 0.34 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.30 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 80% EtOAc in Hexane as eluent) to afford 32 mg (24.6% yield) of biphenyl-4-carboxylic acid {2-[4-(6-bromo-pyridine-2-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 93.11%. 1H NMR (CDCl3): δ 8.0-7.9 (d, 2H), 7.8-7.66 (m, 4H), 7.66-7.58 (m, 7H), 7.52-7.46 (t, 2H), 7.44-7.38 (m, 1H), 7.38-7.32 (m, 1H), 4.4-4.3 (dd, 2H), 3.92-3.74 (m, 6H), 3.7-3.6 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C([Sn](Cl)(CCCC)CCCC)CCC.[N-:30]=[N+:31]=[N-:32].[Na+].[C:34](Cl)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>[OH-].[Na+].CCCCCCC.O.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:32]([C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:31]=[N:30][N:15]=2)=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CCCCCCC
Product: Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
4'-Methylbiphenyl-2-nitrile (preparation described in European patent application 0253310, published on 20.01.88)(10.00 g, 51.7 mmol, 1 eq), tri-n-butyltin chloride (14.0 mL, 51.7 mmol, 1 eq), sodium azide (3.4 g 51.7 mmol, 1 eq), and xylene (50 mL) were mixed and refluxed for 64 h after which the reaction mixture was cooled to room temperature. 10.0N NaOH (6.10 mL, 0.061 mmol, 1.2 eq) and trityl chloride (14.99 g, 53.8 mmol, 1.04 eq) were then added and the mixture stirred for 24 h after which water (39 mL) and heptane (100 mL) were added. The resultant slurry was stirred at 0° C. for 1.5 h. The resultant solids thus obtained were filtered, washed with water (2×55 mL) washed once with 3:2 heptane/toluene (55 mL) and dried overnight under high vacuum to yield 19.97 g of a light yellow powder; mp 148.0°-155.0° C. (dec.). These solids were slurried in ethyl acetate (75 mL) and filtered to yield 15.0 g of a light yellow powder: mp 164.0°-165.5° C. (dec.). NMR (CDCl3) δ 7.91 (d, 1H, J=9 Hz); 7.53-7.18 (m, 13H); 7.02-6.84 (m, 9H); 2.25 (s, 3H). ##STR76##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:9]=1[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23].[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:9]=1[CH:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[OH:23]
Reactant: O=C(c1cccnc1)c1c(Cc2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1cccnc1)c1c(Cc2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 50 mg (0.1 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorobenzyl)-4-[(3-pyridyl)carbonyl]isoxazole in 15 mL of THF was added 21 mg (0.56 mmol) of sodium borohydride at room temperature. After 2 hrs, the solution was diluted with ethyl acetate, washed with saturated sodium chloride, and dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation. The crude product was purified by prep TLC to give 39 mg (0.088 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorobenzyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. 1H NMR (CDCl3): δ 3.91 (d, 1), 4.00 (d, 1), 6.97 (br s, 1), 7.64 (d, 1), 8.42 ppm (br m, 2). MS m/z: 445.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][NH2:4])[CH3:2].C(=O)(O)[O-:6].[Na+].[C:10]([C:15]1[C:16](=O)[CH2:17][CH:18]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([O:31][CH3:32])[O:29][CH3:30])=[CH:24][CH:23]=2)[CH2:19][C:20]=1[OH:21])(=O)[CH2:11][CH2:12][CH3:13]>CO>[CH3:32][O:31][CH:28]([O:29][CH3:30])[C:25]1[CH:24]=[CH:23][C:22]([CH:18]2[CH2:19][C:20](=[O:21])[C:15]([C:10](=[N:4][O:3][CH2:1][CH3:2])[CH2:11][CH2:12][CH3:13])=[CH:16][CH:17]2[OH:6])=[CH:27][CH:26]=1
Reactant: CCON
Reactant: CCCC(=O)C1=C(O)CC(c2ccc(C(OC)OC)cc2)CC1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCC(=NOCC)C1=CC(O)C(c2ccc(C(OC)OC)cc2)CC1=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
2.5 g of ethoxyamine, 2.1 g of sodium bicarbonate and 100 ml of methanol are added to 8.4 g of 2-butyryl-5-(4-dimethoxymethylphenyl)-3-hydroxycyclohex-2-en-1-one and the mixture is stirred for 10 hours at room temperature. After the mixture has been evaporated down, the residue is partitioned in methylene chloride/water, and the organic phase is separated off, dried and evaporated down. 7.5 g of 5-(4-dimethoxymethylphenyl)-2-(1-ethoxyiminobutyl)-3-hydroxycyclohex-2-en-1-one (compound No. 19 in the Table below) remain: ##STR5##
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].C1[O:10]C1.[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1.C(Cl)(=O)C>C(OCC)C.BrBr>[CH3:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH2:12][CH2:13][O:14][C:15](=[O:10])[CH3:11]
Reactant: C1CO1
Reactant: C1CCOC1
Reactant: Cc1ccsc1Br
Agent: BrBr
Solvent: CCOCC
Solvent: CC(=O)Cl
Product: CC(=O)OCCc1sccc1C
Reaction time: 20 h

Procedure:
A solution of 2-bromo-3-methylthiophene (35.4 g, 200 mmol, ALFA) in diethyl ether (200 mL) was added drop wise to Mg turnings (5.35 g, 220 mmol) over ˜30 min at such a rate as to maintain gentle reflux (at the beginning the reaction was initiated with 2 drops of Br2). After refluxing for 1 h, 2.0M ethylene oxide in THF (150 mL, 300 mmol) was added drop wise at 0° C. over 1 h and stirring was continued at rt for 20 h. After cooling to 0° C. acetyl chloride (22.8 mL, 320 mmol) was added drop wise at 0° C. over 15 min an the suspension was stirred at rt for 18 h. The reaction mixture was diluted with diethyl ether (200 mL) and washed with 1M HCl (200 mL) and 10% brine (200 mL). The aqueous layers were extracted with diethyl ether (100 mL) and the combined organic layers were dried (Na2SO4) and evaporated affording 49 g brownish oil which was purified by distillation affording 32.8 g (89.0%, GC 96.4%) colorless oil, bp ˜120° C./10 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C[O:17][C:18]([C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:19].C1COCC1.[Li+].[OH-]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:26][C:25]2[C:20]([C:18]([OH:19])=[O:17])=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1ncccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Prepared from 0.60 g (2.17 mmol) of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride and 0.30 g (1.97 mmol) of 3-amino-pyridine-2-carboxylic acid methyl ester in 3 mL pyridine using procedure x. The solvent was switched to THF, followed by the addition of 1 M aqueous LiOH and the mixture stirred for 1 h. The pH of the mixture was adjusted to neutral and the product was extracted with ethyl acetate. LC-MSD, m/z for C13H8ClF3N2O4S [M+H]+=380.9, 383.0; HPLC retention time: 1.8 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[NH2:14][C@H:15]([C:20]([O:22]C(C)C)=O)[C@H:16]([CH2:18][CH3:19])[CH3:17].[C:26]1([C@@H:36]([NH2:38])[CH3:37])C2C(=CC=CC=2)C=CC=1>>[CH:36]([N:38]([C:20](=[O:22])[C@H:15]([C@H:16]([CH2:18][CH3:19])[CH3:17])[NH2:14])[C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:13][CH:12]=1)([CH3:37])[CH3:26]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)C
Reactant: C=CCOc1ccc(C(=O)O)cc1
Reactant: C[C@H](N)c1cccc2ccccc12
Product: C=CCOc1ccc(C(=O)N(C(=O)[C@@H](N)[C@@H](C)CC)C(C)C)cc1
Yield: 54.1 %

Procedure:
(S)-N-Isoleucyl-4-allyloxybenzamide isopropyl ester was prepared as in Example 1 except 2.6 g (0.015 mole) of 4-allyloxybenzoic acid and 2.5 g (0.014 mole) of (S)-isopropyl isoleucinate were used in Example 2 rather than the 2.0 g of 4-allyloxybenzoic acid and 2 g (S)-1-(1-naphthyl)ethylamine in Example 1. The product was recrystallized twice from petroleum ether (30°-60°) to give 2.1 g (37%) of (S)-N-isoleucyl-4-allyloxybenzamide isopropyl ester as a white crystalline solid; mp 48°-48.5° C.; [α]D25 +48.93° (c=0.329, CHCl3); IR (KBr): 3300, 1725 and 1625 cm-1 ; NMR (δ): 0.96-1.12 (6H, m), 1.36 (6H, d, J=7.2 Hz), 1.40-1.76 (2H, m), (1H, broad, signal disappeared in D2O), 1.96-2.16 (1H, m,), 4.46 (2H, d, J=6.3 Hz), 4.74-5.20 (2H, m) 5.24-5.56 (2H, m) 5.88-6.28 (1H, m) 6.96 (2H, d, J=8.5 Hz), 7.80 (2H, d, J=8.5 Hz). Anal. for C19H27NO4 : Calcd: C, 68.47; H, 8.11; N, 4.20. Found: C, 68.50: H, 8.00; N, 4.30.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[N:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][N:15]=3)[C:8]=2[F:13])[C:3]=1[OH:27].[CH2:28]([CH:31]1[O:33][CH:32]1[CH2:34]O)[CH2:29][CH3:30]>>[CH2:21]([O:20][C:17]1[CH:18]=[N:19][C:14]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[C:3]=3[O:27][CH2:34][CH:32]3[CH:31]([CH2:28][CH2:29][CH3:30])[O:33]3)[C:8]=2[F:13])=[N:15][CH:16]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCOc1cnc(-c2ccc3c(O)c(F)c(F)cc3c2F)nc1
Reactant: CCCC1OC1CO
Product: CCCCCCOc1cnc(-c2ccc3c(OCC4OC4CCC)c(F)c(F)cc3c2F)nc1

Procedure:
From 2,3,5-trifluoro-6-(5-hexyloxypyrimidin-2-yl)naphthalen-1-ol and (3-propyloxiranyl)methanol by means of the Mitsunobu reaction.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[N:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>CN(C)C=O>[C:23]([O:17][CH2:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([NH2:1])=[N:3][C:4]=3[NH:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH:12]=[CH:13]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(NCC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC[C@@H]1C=C[C@H](n2cnc3c(NCC4CC4)nc(N)nc32)C1

Procedure:
A solution of (%)-cis-4-(2 amino-6-(cyclopropylmethylamino)-9H-purin-9-yl)-2-cyclopentene-1-methanol from Example 7 (0.30 g, 1 mmol), acetic anhydride (0.204 g, 2 mmol), N,N-dimethylaminopyridine (0.005 g, 0.04 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature under nitrogen overnight. H2O (1 mL was added and the solution allowed to stir an additional hour, then concentrated under high vacuum. The residual oil was partitioned between saturated sodium bicarbonate solution (5 mL) and chloroform (3×50 mL). The combined chloroform extracts were dried (MgSO4), solvent evaporated and residue chromatographed on silica gel. Title compound was eluted with 4% methanol-chloroform; foamed from ethanol under high vacuum (0.330 g, 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][C:8]2([CH3:18])[CH3:17])([O-:3])=[O:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:19](=[O:21])[CH3:20])[C:8]2([CH3:18])[CH3:17])([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Product: CC(=O)N1c2ccccc2-c2c([N+](=O)[O-])cnn2C1(C)C
Yield: 69 %

Procedure:
1-Nitro-5,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline is treated with acetic anhydride to give 1-nitro-5,5-dimethyl-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline with a yield of 69%. M.p.: 182°-183° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>ClCCl.CN(C=O)C>[C:23]([NH:27][C:8]([C:5]1[N:6]=[CH:7][C:2]([Br:1])=[CH:3][N:4]=1)=[O:10])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)NC(=O)c1ncc(Br)cn1
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
5-Bromopyrimidine-2-carboxylic acid (1 g, 4.93 mmol) was suspended in dichloromethane (10 ml) and DMF (20 μl). Oxalyl chloride (520 μl, 5.91 mmol, 1.2 equiv.) was added drop wise at room temperature and the mixture was stirred for 16 hours. The reaction mixture was then cooled to 0-5° C. and pyridine (480 μl, 5.91 mmol, 1.2 equiv.) and tert-butyl amine (621 μl, 5.91 mmol, 1.2 equiv.) were added drop wise at 0-5° C. The mixture was stirred for 4 hours at room temperature. The reaction mixture was extracted with saturated NaHCO3 solution and dichloromethane. The organic layers were extracted with water and brine, dried over sodium sulfate and evaporated to dryness. The desired 5-bromo-pyrimidine-2-carboxylic acid tert-butylamide (960 mg, 76% yield) was obtained as a light yellow solid, MS: m/e=258.0/259.9 (M+H+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19](=[O:33])[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@:22]1([CH2:31][OH:32])[CH2:27][CH2:28][CH2:29][OH:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19](=[O:33])[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@:22]1([CH:31]=[O:32])[CH2:27][CH2:28][CH:29]=[O:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(N[C@@H]1CCCC[C@]1(CO)CCCO)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCC[C@@]1(C=O)CCCC[C@H]1NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A solution of dimethyl sulfoxide (1.6 g, 19 mmol) in dichloromethane (50 mL) was cooled to −78° C. and treated dropwise with oxalyl chloride (1.42 g, 11.2 mmol). After the addition was complete, the solution was stirred for 30 minutes and was then treated dropwise with a solution of [(1R,2S)-2-hydroxymethyl-2-(3-hydroxypropyl)-cyclohexyl]-carbamic acid benzyl ester (0.65 g, 1.9 mmol) in dichloromethane (10 mL). After the addition was complete, the solution was stirred for 40 minutes and then treated with triethylamine (1.8 g, 18 mmol). The mixture was stirred for 30 minutes before removing the cooling bath and stirring at room temperature for 1 hour. The mixture was quenched with saturated aqueous sodium bicarbonate (100 mL) and the organic phase was separated and washed successively with water and saturated aqueous sodium chloride, and then dried over sodium sulfate. The solvent was removed under vacuum to give an oil (0.6 g). 1H NMR (300 MHz, CDCl3) δ9.74 (bs, 1H), 9.43 (bs, 1H), 7.39-7.27 (m, 5H), 5.06 (m, 2H), 4.91 (bd, J=9 Hz, 1H), 4.14 (bm, 1H), 2.60-1.30 (m, 12H). Mass spec (ES+) m/z 318.2 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][S:14]2(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][S:14]2(=[O:19])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][N:28]([C:22]2[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][N:23]=2)[CH2:29][CH2:30]1)=[O:6]
Reactant: COC(=O)c1ccc(CN2CCCS2(=O)=O)cc1Br
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3Br)CC2)c(C)c1
Yield: 84.6 %

Procedure:
Using methyl 2-bromo-4-(1,1-dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoate (312 mg) described in Preparation Example 177 and 1-(3,5-dimethylpyridin-2-yl)piperazine (171 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (384 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[Cl:7][CH2:8][C:9](Cl)=[O:10]>C1COCC1>[Cl:7][CH2:8][C:9]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:10]
Reactant: Cn1cccc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: Cn1cccc1C(=O)CCl
Yield: 106.4 %

Procedure:
A solution of 15 g (0.186 mole) N-methylpyrrole and 19.2 mL (0.186 mole) chloroacetyl chloride in 600 mL dry THF was heated under reflux overnight with a nitrogen stream bubbling through the reaction mixture. After cooling, the organics were washed with water, 1N NaOH, water, brine and dried (MgSO4). Evaporation of the solvent gave 31.2 g of a green solid: mp (decomp.) 280° C.; NMR 300 MHz (CDCl3) d 7.05 (d, 1H); 6.95 (s, 1H); 6.2 (m, 1H); 4.5 (s, 2H); 3.9 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 60.6 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (8.0 g, 56 mmol) and 4-(2-chloroethyl)-morpholine hydrochloride (15.7 g, 84 mmol) and potassium carbonate (11.5 g, 83 mmol) in toluene (50 ml) was heated at reflux. After 4 days, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water and then extracted with dilute hydrochloric acid. The acidic layer was separated, basified with 5 N sodium hydroxide and the product was extracted into ethyl acetate. The organics were removed in vacuo and the residue was purified by flash chromatography (elution gradient 3% acetone/methylene chloride) to give methyl 3-(2-morpholin-4-ylethoxy)benzoate (9.0 g) as an oil.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=3)=[N:14][N:15]=2)=[O:10])=[CH:3][CH:2]=1.C1(CCCCCCC(C2OC(C3N=C([C:54]([O:56][CH3:57])=[O:55])C=CC=3)=NN=2)=O)C=CC=CC=1>CO.C(Cl)Cl>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([C:11]2[O:12][C:13]([C:16]3[N:17]=[C:18]([C:54]([O:56][CH3:57])=[O:55])[CH:19]=[CH:20][CH:21]=3)=[N:14][N:15]=2)=[O:10])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2nnc(C(=O)CCCCCCc3ccccc3)o2)n1
Reactant: O=C(CCc1ccc(-c2ccccc2)cc1)c1nnc(-c2cccc(Br)n2)o1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2nnc(C(=O)CCc3ccc(-c4ccccc4)cc3)o2)n1
Yield: 48 %

Procedure:
The title compound was prepared from 30 (70 mg, 0.16 mmol) by using a procedure similar to that detailed for 8f. Flash chromatography (SiO2, 2.5×15 cm, 0-1% MeOH—CH2Cl2) afforded the title compound (32 mg, 48%) as a white solid: 1H NMR (CDCl3, 600 MHz) δ 8.47 (d, 1H, J=7.8 Hz), 8.34 (d, 1H, J=7.8 Hz), 8.10 (t, 1H, J=7.8 Hz), 7.57 (d, 2H, J=7.2 Hz), 7.53 (d, 2H, J=8.1 Hz), 7.43 (t, 2H, J=7.7 Hz), 7.33 (m, 3H), 4.06 (s, 3H), 3.61 (t, 2H, J=7.5 Hz), 3.19 (t, 2H, J=7.5 Hz); 13C NMR (CDCl3, 150 MHz) δ 186.1, 164.9, 164.6, 161.5, 149.3, 142.9, 141.0, 139.7, 138.9, 138.8, 129.0, 128.9, 127.9, 127.5, 127.3, 127.2, 127.1, 53.4, 41.8, 29.1; HRMS-ESI-TOF m/z 414.1451 ([M+H]+, C24H19N3O4 requires 414.1448).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Cl[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]2[CH2:17][N:16]([C:18]([C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:23][N:24]=3)=[O:19])[CH2:15]2)=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:2][N:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13][CH:14]2[CH2:17][N:16]([C:18]([C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:23][N:24]=3)=[O:19])[CH2:15]2)=[CH:11][CH:12]=1)[CH3:4]
Reactant: CNC
Reactant: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CCl)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)Cc1ccc(SC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.6 %

Procedure:
Dimethylamine hydrochloride (0.10 g, 1.24 mmol) and 60B (0.16 g, 0.41 mmol) were mixed in DCM (5 ml). Triethylamine (0.290 ml, 2.07 mmol) was added and the mixture was stirred at RT for 2.5 h. More of triethylamine (0.290 ml, 2.07 mmol) and dimethylamine hydrochloride (0.10 g, 1.24 mmol) were added. The mixture was stirred overnight at RT and then diluted with DCM (10 ml). The mixture was washed with water, filtered through a phase separator and then evaporated. The residue was purified by column chromatography eluting with NH3 in MeOH (2M)/DCM (1:99, 2:98). There was obtained 0.14 g (84%) of 60 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.20 (s, 6H), 3.38 (s, 2H), 4.16 (m, 2H), 4.61 (m, 2H), 5.07 (m, 1H), 7.50 (t, 2H), 7.56 (t, 1H), 8.12 (d, 2H), MS (APCI+) m/z 395 [M+H]+, LC purity: 97%.